Specific Bioactivity Research Articles

Sol-Gel Technologies to Obtain Advanced Bioceramics for Dental Therapeutics.

The aim of this work is to review the application of bioceramic materials in the context of current regenerative dentistry therapies, focusing on the latest advances in the synthesis of advanced materials using the sol-gel methodology. Chemical synthesis, processing and therapeutic possibilities are discussed in a structured way, according to the three main types of ceramic materials used in regenerative dentistry: bioactive glasses and glass ceramics, calcium phosphates and calcium silicates. The morphology and chemical composition of these bioceramics play a crucial role in their biological properties and effectiveness in dental therapeutics. The goal is to understand their chemical, surface, mechanical and biological properties better and develop strategies to control their pore structure, shape, size and compositions. Over the past decades, bioceramic materials have provided excellent results in a wide variety of clinical applications related to hard tissue repair and regeneration. Characteristics, such as their similarity to the chemical composition of the mineral phase of bones and teeth, as well as the possibilities offered by the advances in nanotechnology, are driving the development of new biomimetic materials that are required in regenerative dentistry. The sol-gel technique is a method for producing synthetic bioceramics with high purity and homogeneity at the molecular scale and to control the surfaces, interfaces and porosity at the nanometric scale. The intrinsic nanoporosity of materials produced by the sol-gel technique correlates with the high specific surface area, reactivity and bioactivity of advanced bioceramics.

Digestion-Related Enzyme Inhibition Potential of Selected Mexican Medicinal Plants (Ludwigia octovalvis (Jacq.) P.H.Raven, Cnidoscolus aconitifolius and Crotalaria longirostrata).

Medicinal plants offer a valuable source of natural compounds with specific and selective bioactivity. These compounds have been isolated since the mid-nineteenth century and are now commonly used in modern medications. L. octovalvis (Jacq.) P.H.Raven, C. aconitifolius, and C. longirostrata are Mexican medicinal plants consumed regularly, and research has shown that they contain bioactive compounds capable of promoting the inhibition of digestive enzymes. This is noteworthy since enzyme inhibitors are bioactive substances that interact with enzymes, diminishing their activity and thereby contributing to the management of diseases and metabolic disturbances. To investigate the activity of these plants, individual analyses were conducted, assessing their proximal composition, bioactive compounds, and inhibition of α-Amylase, α-Glucosidase, lipase, and pepsin. The results revealed that all three plants exhibited enzymatic inhibition. When comparing the plants, it was determined that C. aconitifolius had the lowest concentration required for a 50% inhibition in α-Amylase, α-Glucosidase, and lipase, as indicated by the IC50 values. For pepsin, C. longirostrata demonstrated the lowest IC50 value. By understanding the bioactive compounds present in these plants, we can establish the relationship they have with enzymatic inhibition, which can be utilized for future investigations.

Linking traditional medicine to modern phytotherapy: Chemical characterization and assessment of antioxidant and anticholinesterase effects in vitro of a natural Persian remedy for dementia

Several natural remedies are used in the Traditional Persian Medicine (TPM) to prevent dementia, but their efficacy is debated. In this work, an improved “Safoof-e-Nesyān” formulation described in the “Qarābādin-e-Azam” pharmacopoeia was developed, and its chemical composition and antioxidant and anti-cholinesterase properties were assessed. The formulation contains a mixture (FM) of Cinnamomum cassia (CC), C. verum (CV), Pistacia lentiscus (PL), Rheum palmatum (RP), Syzygium aromaticum (SA), and Zingiber officinalis (ZO) powdered plants. Its total phenolic content is 110.45 mg GAE/g, while the total flavonoid content is 6.28 mg RE/g. 66 secondary metabolites (mainly tannins, flavonoids, anthraquinones, and gingerols) were identified by UPLC-QToF-MS analysis. FM exerts antioxidant effects by scavenging radicals, and by reducing and chelating metals such as Mb, Cu and Fe. The anticholinesterase activity of one gram of the FM equals that of 3.60 mg of the reference drug galantamine, on both acetyl- and butyryl-cholinesterase. Correlations between specific compounds and bioactivities were highlighted by multivariate analysis of data: lyoniresinol 9′-glucoside strongly correlates with antiradical activities on DPPH and ABTS and reducing activity on Cu, and with anti-AChE effects. Most of the identified flavonoids and the ellagic acid derivatives positively correlate with the reducing activity on Fe and Mb, and with anti-BChE effects. Finally, a tablet formulation of the FM was developed, and its physical properties were preliminarily assessed. Overall, our results indicate that the FM may be a useful natural remedy for dementia, although further safety and efficacy assessments in vivo are required.

Characterizing On-Chip Angiogenesis Induction in a Microphysiological System as a Functional Measure of Mesenchymal Stromal Cell Bioactivity.

Mesenchymal stromal cells (MSCs) continue to be proposed for clinical investigation to treat myriad diseases given their purported potential to stimulate endogenous regenerative processes, such as angiogenesis. However, MSC functional heterogeneity has hindered clinical success and still poses a substantial manufacturing challenge from a product quality control perspective. Here, a quantitative bioassay based on an enhanced-throughput is described, microphysiological system (MPS) to measure the specific bioactivity of MSCs to stimulate angiogenesis as a potential measure of MSC potency. Using this novel bioassay, MSCs derived from multiple donors at different passages are co-cultured with human umbilical vein endothelial cells and exhibit significant heterogeneity in angiogenic potency between donors and cell passage. Depending on donor source and cellular passage number, MSCs varied in their ability to stimulate tip cell dominant or stalk cell dominant phenotypes in angiogenic sprout morphology which correlated with expression levels of hepatocyte growth factor (HGF). These findings suggest that MSC angiogenic bioactivity may be considered as a possible potency attribute in MSC quality control strategies. Development of a reliable and functionally relevant potency assay for measuring clinically relevant potency attributes of MSCs will help to improve consistency in quality and thereby, accelerate clinical development of these cell-based products.

Comparative genome features and secondary metabolite biosynthetic potential of Kutzneria chonburiensis and other species of the genus Kutzneria

Actinobacteria are well known as a rich source of diversity of bioactive secondary metabolites. Kutzneria, a rare actinobacteria belonging to the family Pseudonocardiaceae has abundance of secondary metabolite biosynthetic gene clusters (BGCs) and is one of important source of natural products and worthy of priority investigation. Currently, Kutzneria chonburiensis SMC256T has been the latest type-strain of the genus and its genome sequence has not been reported yet. Therefore, we present the first report of new complete genome sequence of SMC256T (genome size of 10.4 Mbp) with genome annotation and feature comparison between SMC256T and other publicly available Kutzneria species. The results from comparative and functional genomic analyses regarding the phylogenomic and the clusters of orthologous groups of proteins (COGs) analyses indicated that SMC256T is most closely related to Kutzneria sp. 744, Kutzneria kofuensis, Kutzneria sp. CA-103260 and Kutzneria buriramensis. Furthermore, a total of 322 BGCs were also detected and showed diversity among the Kutzneria genomes. Out of which, 38 clusters showing the best hit to the most known BGCs were predicted in the SMC256Tgenome. We observed that six clusters responsible for biosynthesis of antimicrobials/antitumor metabolites were strain-specific in Kutzneria chonburiensis. These putative metabolites include virginiamycin S1, lysolipin I, esmeraldin, rakicidin, aclacinomycin and streptoseomycin. Based on these findings, the genome of Kutzneria chonburiensis contains distinct and unidentified BGCs different from other members of the genus, and the use of integrative genomic-based approach would be a useful alternative effort to target, isolate and identify putative and undiscovered secondary metabolites suspected to have new and/or specific bioactivity in the Kutzneria.

Gambierone and Sodium Channel Specific Bioactivity Are Associated with the Extracellular Metabolite Pool of the Marine Dinoflagellate Coolia palmyrensis.

Tropical epibenthic dinoflagellate communities produce a plethora of bioactive secondary metabolites, including the toxins ciguatoxins (CTXs) and potentially gambierones, that can contaminate fishes, leading to ciguatera poisoning (CP) when consumed by humans. Many studies have assessed the cellular toxicity of causative dinoflagellate species to better understand the dynamics of CP outbreaks. However, few studies have explored extracellular toxin pools which may also enter the food web, including through alternative and unanticipated routes of exposure. Additionally, the extracellular exhibition of toxins would suggest an ecological function and may prove important to the ecology of the CP-associated dinoflagellate species. In this study, semi-purified extracts obtained from the media of a Coolia palmyrensis strain (DISL57) isolated from the U.S. Virgin Islands were assessed for bioactivity via a sodium channel specific mouse neuroblastoma cell viability assay and associated metabolites evaluated by targeted and non-targeted liquid chromatography tandem and high-resolution mass spectrometry. We found that extracts of C. palmyrensis media exhibit both veratrine enhancing bioactivity and non-specific bioactivity. LC-HR-MS analysis of the same extract fractions identified gambierone and multiple undescribed peaks with mass spectral characteristics suggestive of structural similarities to polyether compounds. These findings implicate C. palmyrensis as a potential contributor to CP and highlight extracellular toxin pools as a potentially significant source of toxins that may enter the food web through multiple exposure pathways.

Application of Polysaccharide-Based Edible Coatings on Fruits and Vegetables: Improvement of Food Quality and Bioactivities

Most foods derived from plant origin are very nutritious but highly perishable products. Nowadays, the food industry is focusing on the development of efficient preservation strategies as viable alternatives to traditional packaging and chemical treatments. Hence, polysaccharide-based edible coatings have been proposed because of their properties of controlled release of food additives and the protection of sensitive compounds in coated foods. Thus, this technology has allowed for improving the quality parameters and extends the shelf life of fruits and vegetables through positive effects on enzyme activities, physicochemical characteristics (e.g., color, pH, firmness, weight, soluble solids), microbial load, and nutritional and sensory properties of coated foods. Additionally, some bioactive compounds have been incorporated into polysaccharide-based edible coatings, showing remarkable antioxidant and antimicrobial properties. Thus, polysaccharide-based edible coatings incorporated with bioactive compounds can be used not only as an efficient preservation strategy but also may play a vital role in human health when consumed with the food. The main objective of this review is to provide a comprehensive overview of materials commonly used in the preparation of polysaccharide-based edible coatings, including the main bioactive compounds that can be incorporated into edible coatings, which have shown specific bioactivities.

The (Poly)phenolic Profile of Separate Winery By-Products Reveals Potential Antioxidant Synergies.

The by-products of grapes (Vitis vinifera L.) in the winemaking process present a diverse phytochemical profile of (poly)phenols, essentially represented by phenolic acids, flavonoids, and stilbenes, which have health benefits. In winemaking, solid (grape stems and pomace) and semisolid (wine lees) by-products are generated, negatively impacting the sustainability of the agro-food activity and the local environment. Although information on the phytochemical profile of grape stems and pomace has been reported, especially information concerning (poly)phenols, research on wine lees is necessary to take advantage of the compositional traits of this residue. So, in the present work, an updated, in-depth comparison of the (poly)phenolic profiles of these three resulting matrices in the agro-food industry has been carried out to provide new knowledge and interesting data on the action of yeast and lactic acid bacteria (LAB) metabolism in the diversification of phenolic composition; additionally, we extract complementarities for the possible joint application of the three residues. The phytochemical analysis of the extracts was carried out using HPLC-PDA-ESI-MSn. The (poly)phenolic profiles of the residues showed significant discrepancies. The results obtained showed that the greatest diversity of (poly)phenols was found in the stems of the grapes, followed closely by the lees. Through technological insights, it has been suggested that yeasts and LAB, responsible for the fermentation of must, might play a key role in the transformation of phenolic compounds. This would provide new molecules with specific bioavailability and bioactivity features, which might interact with different molecular targets and, consequently, improve the biological potential of these underexploited residues.

Ultralong hydroxyapatite nanowires-incorporated dipeptide hydrogel with enhanced mechanical strength and superior in vivo osteogenesis activity

Self-assembling peptide hydrogels have attracted considerable interest in tissue engineering for their biocompatibility, biodegradability, low immunogenicity, facile modification, and similarity to the native extracellular matrix. However, they still suffer from weak mechanical strength and lack of specific bioactivity. Ultralong hydroxyapatite nanowires (UHANWs) are synthesized to work as a reinforcement agent similar to the steel bars in the reinforced concrete to co-assemble with dipeptide nanofibers, endowing the hybrid hydrogel with enhancing and controllable mechanical properties. Furthermore, additional factors BMP-2 can be introduced into the hydrogel to improve its bioactivity. The experimental results show that the incorporation of UHANWs into the hydrogel matrix leads to an obvious increase in the storage modulus of scaffolds, exhibiting good biocompatibility and bioactivity. The hybrid hydrogels can facilitate the proliferation and osteogenetic differentiation of cells on their surface. The in vivo evaluation reveals that bone defects implanted with the as-designed hydrogel scaffolds show enhanced bone regeneration activity, implying their great potential in biomedical fields.

Fungistatic Activity Mediated by Volatile Organic Compounds Is Isolate-Dependent in Trichoderma sp. "atroviride B".

Trichoderma spp. produce multiple bioactive volatile organic compounds (VOCs). While the bioactivity of VOCs from different Trichoderma species is well documented, information on intraspecific variation is limited. The fungistatic activity of VOCs emitted by 59 Trichoderma sp. "atroviride B" isolates against the pathogen Rhizoctonia solani was investigated. Eight isolates representing the two extremes of bioactivity against R. solani were also assessed against Alternaria radicina, Fusarium oxysporum f. sp. lycopersici and Sclerotinia sclerotiorum. VOCs profiles of these eight isolates were analyzed using gas chromatography-mass spectrometry (GC-MS) to identify a correlation between specific VOCs and bioactivity, and 11 VOCs were evaluated for bioactivity against the pathogens. Bioactivity against R. solani varied among the fifty-nine isolates, with five being strongly antagonistic. All eight selected isolates inhibited the growth of all four pathogens, with bioactivity being lowest against F. oxysporum f. sp. lycopersici. In total, 32 VOCs were detected, with individual isolates producing between 19 and 28 VOCs. There was a significant direct correlation between VOC number/quantity and bioactivity against R. solani. 6-pentyl-α-pyrone was the most abundant VOC produced, but 15 other VOCs were also correlated with bioactivity. All 11 VOCs tested inhibited R. solani growth, some by >50%. Some of the VOCs also inhibited the growth of the other pathogens by >50%. This study demonstrates significant intraspecific differences in VOC profiles and fungistatic activity supporting the existence of biological diversity within Trichoderma isolates from the same species, a factor in many cases ignored during the development of biological control agents.

Formation of Oxidative Compounds during Enzymatic Hydrolysis of Byproducts of the Seafood Industry

There is a significant potential to increase the sustainability of the fishing and aquaculture industries through the maximization of the processing of byproducts. Enzymatic hydrolysis provides an opportunity to valorize downstream fish industry byproducts for the production of protein hydrolysates (FPH) as a source of bioactive peptides (BAP) with health benefits. Deteriorative oxidative reactions may occur during the enzymatic hydrolysis of byproducts, influencing the safety or bioactivities of the end product. Lipid oxidation, autolysis mediated by endogenous enzymes in viscera, protein degradation, and formation of low-molecular-weight metabolites are the main reactions that are expected to occur during hydrolysis and need to be controlled. These depend on the freshness, proper handling, and the type of byproducts used. Viscera, frames, trimmings, and heads are the byproducts most available for enzymatic hydrolysis. They differ in their composition, and, thus, require standardization of both the hydrolysis procedures and the testing methods for each source. Hydrolysis conditions (e.g., enzyme type and concentration, temperature, and time) also have a significant role in producing FPH with specific structures, stability, and bioactivity. Protein hydrolysates with good safety and quality should have many applications in foods, nutraceuticals, and pharmaceuticals. This review discusses the oxidative reactions during the enzymatic hydrolysis of byproducts from different fish industry sectors and possible ways to reduce oxidation.

Synthesis and Potential of Autoinducer‐2 and Analogs to Manipulate Inter‐Species Quorum Sensing

AbstractQuorum sensing (QS) is enabled by the production of signalling molecules called autoinducers, whose presence in the environment modulates the behavior of bacterial populations. Autoinducer‐2 (AI‐2) is unique as it is recognized by different species of bacteria and fosters signalling across different species. To further understand QS mechanisms and to discover potential novel therapeutics based on the modulation of bacterial behavior many analogs have been synthesized. This review aims to provide a critical analysis of the state‐of‐the‐art of the synthesis of AI‐2 and its analogs. It serves as a non‐exhaustive consolidation of previous studies of analogs, focusing on the synthetic approaches and the structure‐activity relationship conclusions drawn after the analysis of the chemical libraries of the research groups involved in the field. This article is intended to be a strong foundation for the rational planning of synthetic strategies of analogs with specific bioactivities.

Edible Insects an Alternative Nutritional Source of Bioactive Compounds: A Review

Edible insects have the potential to become one of the major future foods. In fact, they can be considered cheap, highly nutritious, and healthy food sources. International agencies, such as the Food and Agriculture Organization (FAO), have focused their attention on the consumption of edible insects, in particular, regarding their nutritional value and possible biological, toxicological, and allergenic risks, wishing the development of analytical methods to verify the authenticity, quality, and safety of insect-based products. Edible insects are rich in proteins, fats, fiber, vitamins, and minerals but also seem to contain large amounts of polyphenols able to have a key role in specific bioactivities. Therefore, this review is an overview of the potential of edible insects as a source of bioactive compounds, such as polyphenols, that can be a function of diet but also related to insect chemical defense. Currently, insect phenolic compounds have mostly been assayed for their antioxidant bioactivity; however, they also exert other activities, such as anti-inflammatory and anticancer activity, antityrosinase, antigenotoxic, and pancreatic lipase inhibitory activities.

Risk assessment in the 21st century: where are we heading?

Reliance on animal tests for chemical safety assessment is increasingly being challenged, not only because of ethical reasons, but also because they procrastinate regulatory decisions and because of concerns over the transferability of results to humans. New approach methodologies (NAMs) need to be fit for purpose and new thinking is required to reconsider chemical legislation, validation of NAMs and opportunities to move away from animal tests. This article summarizes the presentations from a symposium at the 2022 Annual Congress of the British Toxicology Society on the topic of the future of chemical risk assessment in the 21st century. The symposium included three case-studies where NAMs have been used in safety assessments. The first case illustrated how read-across augmented with some in vitro tests could be used reliably to perform the risk assessment of analogues lacking data. The second case showed how specific bioactivity assays could identify an NAM point of departure (PoD) and how this could be translated through physiologically based kinetic modelling in an in vivo PoD for the risk assessment. The third case showed how adverse-outcome pathway (AOP) information, including molecular-initiating event and key events with their underlying data, established for certain chemicals could be used to produce an in silico model that is able to associate chemical features of an unstudied substance with specific AOPs or AOP networks. The manuscript presents the discussions that took place regarding the limitations and benefits of these new approaches, and what are the barriers and the opportunities for their increased use in regulatory decision making.

Adhesive and Antibacterial Films Based on Marine-Derived Fucoidan and Chitosan

Marine-derived polymers are environmentally friendly and sustainable biomaterials that have structural similarities with the main components of the extracellular matrix. Moreover, some marine polymers have specific bioactivity that can be transferred to the systems made of these biomolecules. Herein, we developed antibacterial adhesive films combining two marine polysaccharides, namely, fucoidan and chitosan. Fucoidan was functionalized with catechol groups (FCat) to improve its adhesive properties. This modification enhanced also the fucoidan antibacterial properties: while fucoidan is active against Gram-positive bacteria, FCat showed bactericidal activity against Gram-positive and Gram-negative bacteria. To improve the processability and mechanical properties, FCat was blended with chitosan and solvent-casted to obtain films. These films exhibited an adhesion strength similar to the one of clinically used natural adhesives and no cytotoxicity: fibroblastic cells attached and remained viable on the films. Altogether our results demonstrated that the developed antibacterial and adhesive films are a feasible alternative of cytotoxic synthetic adhesives used for soft tissue healing applications.

Structural annotation and discovery of toxic cyclopeptides and their analogues in lethal mushroom Amanita and Lepiota species using UPLC-HRMS and molecular networking strategy

Foodborne poisoning caused by the cyclopeptide toxins-producing mushroom species seriously endangers human life health. In recent years discovery of new cyclopeptides is getting more attention not only for their toxicity but also for their specific bioactivity. In this study, a combined strategy using liquid chromatography tandem high resolution mass spectrometry and the feature-based molecular networking analysis was established to identify the known cyclopeptide toxins and discover new cyclopeptides in the cyclopeptide toxins-producing mushroom species. The specific fragmentation behaviors of the known cyclopeptide toxins were systematically annotated. Four new phallotoxin analogues were identified for the first time, the chemical structures of which were completely deduced. Moreover, the chemical profiles of the toxic cyclopeptides in lethal mushroom Amanita and Lepiota species were investigated by the self-built cyclopeptides database. The developed strategy could be utilized as a useful tool for identifying the cyclopeptide toxins-induced food poisoning, as well as aid in the discovery of more unknown cyclopeptides.

Efficacy and Safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd) is a recombinant fusion protein of diphtheria toxin and human interleukin-2. Dd was approved and marketed as ONTAK in the US from 1999-2014 for treatment of pts with relapsed/refractory CTCL. ONTAK was voluntarily taken off the market in 2014 due to manufacturing difficulties. E7777 was developed as a result of a refined manufacturing process and has an increased percentage of protein monomer species, with a concomitant decrease in levels of misfolded protein and protein aggregates. E7777 has ~1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK and is considered a new drug by the FDA. Methods: Objectives: Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial designed to assess efficacy and safety of E7777 in patients with relapsed/refractory CTCL. E7777 was given IV at 9 mcg/kg/day (established from Lead-in) over 60 min for 5 days every 21 days up to 8 cycles. Key inclusion/exclusion criteria included histopathologic diagnosis of CTCL (MF or SS); ECOG performance status 0 or 1; no prior exposure to ONTAK. The primary efficacy endpoint was objective response rate (ORR; CR+PR) per Independent Review Committee (IRC) assessment based on Global Response Score GRS (Olsen, et al., 2011). Secondary efficacy endpoints included duration of response (DOR), time-to-response (TTR), skin response (according to modified Severity Weighted Assessment Tool [mSWAT]), safety and tolerability of E7777, PK, and immunogenicity. Exploratory objectives included progression free survival (PFS), time to progression (TTP), pruritus improvement, and quality of life assessment. Results: A total of 112 patients with CTCL stage I-IV were enrolled in the study: 21 in the Lead-in and 91 in the Main Study. The primary efficacy population is comprised of 69 patients with stage I-III CTCL treated at 9 mcg/kg/day. Median number of prior anticancer therapies in Study 302 were 4.0 (range: 1 to 18). Forty-five patients (65.2%) received ≥4 prior anticancer therapies. Approximately half (34 of 69; 49.3%) of patients had prior exposure to 1 or more FDA-approved targeted therapeutics: romidepsin, brentuximab, or mogamulizumab. Demographic and baseline characteristics of patients included a median age of 64 (range 28-87); ECOG status 0 (56.5%) and 1 (43.5%); Race: 72.5% White, 18.8% Black; 9% Other. There disease stages were 43.5% IA/IB/IIA; 34.8% IIB; and 21.7% IIIA/IIIB. The median (range) number of cycles of E7777 received was 6.0 (1, 42). The primary efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR. ORR (95% CI) by Investigator was 42.3% (30.6%, 54.6%), with 8.5% achieving a CR (Table 1). DOR was at least 6 months for 13 (52.0%) responders and at least 12 months for 5 (20.0%) responders. TTR was rapid (median=1.41 months); the majority of responders (~70%) had a response after 1 to 2 cycles of treatment. Treatment with E7777 did not demonstrate any new or unexpected safety findings as compared to prior ONTAK experience. Most patients (98.6%) experienced at least 1 TEAE. Most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles, then decreased and remained low/stable over the remainder of therapy. Key adverse events of special interest (AESIs) associated with ONTAK in the past (i.e. capillary leak syndrome, hepatotoxicity, infusion reaction, and visual impairment) were primarily Grade 1/2 in our current study and will be discussed in detail in a separate abstract. Conclusions: In study 302, E7777 at a dose of 9 mcg/kg/day demonstrated clinical efficacy and clinically meaningful benefit in heavily pre-treated patients with relapsed/refractory CTCL. The ORR of 36.2% per IRC (42.3% by investigator assessment) showed that a substantial proportion of these heavily pretreated patients experienced clinical benefit after E7777 treatment similar to ONTAK. The observed tumor responses were rapid, durable, and deep. A BLA submission to the FDA is planned for the 2nd half of 2022. E7777 will provide a novel, efficacious, safe, and non-cross-resistant therapeutic option for CTCL patients who have failed other treatments and thus fulfill a serious unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Plant-associated Bacillus mobilizes its secondary metabolites upon perception of the siderophore pyochelin produced by a Pseudomonas competitor

Bacillus velezensis is considered as model species for plant-associated bacilli providing benefits to its host such as protection against phytopathogens. This is mainly due to the potential to secrete a wide range of secondary metabolites with specific and complementary bioactivities. This metabolite arsenal has been quite well defined genetically and chemically but much remains to be explored regarding how it is expressed under natural conditions and notably how it can be modulated upon interspecies interactions in the competitive rhizosphere niche. Here, we show that B. velezensis can mobilize a substantial part of its metabolome upon the perception of Pseudomonas, as a soil-dwelling competitor. This metabolite response reflects a multimodal defensive strategy as it includes polyketides and the bacteriocin amylocyclicin, with broad antibiotic activity, as well as surfactin lipopeptides, contributing to biofilm formation and enhanced motility. Furthermore, we identified the secondary Pseudomonas siderophore pyochelin as an info-chemical, which triggers this response via a mechanism independent of iron stress. We hypothesize that B. velezensis relies on such chelator sensing to accurately identify competitors, illustrating a new facet of siderophore-mediated interactions beyond the concept of competition for iron and siderophore piracy. This phenomenon may thus represent a new component of the microbial conversations driving the behavior of members of the rhizosphere community.

A microphysiological system-based potency bioassay for the functional quality assessment of mesenchymal stromal cells targeting vasculogenesis

Mesenchymal stromal cells (MSCs) continue to be proposed for use in clinical trials to treat various diseases due to their therapeutic potential to pleiotropically influence endogenous regenerative processes, such as vasculogenesis. However, the functional heterogeneity of MSCs has hampered their clinical success and poses a significant manufacturing challenge with respect to MSC quality control. Here, we evaluated and qualified a quantitative bioassay based on an enhanced-throughput, microphysiological system to measure the specific paracrine bioactivity of MSCs to stimulate vasculogenesis as a measure of MSC potency. Using this novel bioassay, MSCs derived from multiple donors at different passages were co-cultured with human umbilical vein endothelial cells (HUVECs) and exhibited significant heterogeneity in vasculogenic potency between donors and cell passage. Using our microphysiological system (MPS)-based platform, we demonstrated that variations in MSC vasculogenic bioactivity were maintained when assayed across laboratories and operators. The differences in MSC vasculogenic bioactivity were also correlated with the baseline expression of several genes involved in vasculogenesis (hepatocyte growth factor (HGF), angiopoietin-1 (ANGPT)) or the production of matricellular proteins (fibronectin (FN), insulin-like growth factor-binding protein 7 (IGFBP7)). These findings emphasize the significant functional heterogeneity of MSCs in vasculogenic bioactivity and suggest that changes in baseline gene expression of vasculogenic or matricellular protein genes during manufacturing may affect this bioactivity. The development of a reliable and functionally relevant potency assay for measuring the specific vasculogenic bioactivity of manufactured MSCs will help to reliably assure their quality when used in appropriate clinical trials.

New Alternatives to Milk From Pulses: Chickpea and Lupin Beverages With Improved Digestibility and Potential Bioactivities for Human Health.

There is a strong demand for plant-based milk substitutes, often low in protein content (<1.5% w/v). Protein-rich pulse seeds and the right processing technologies make it possible to make relevant choices. The major objective of this study was to assess the impact of processing on the nutritional characteristics of beverages with a high impact on health, in particular on digestibility and specific bioactivities. The results suggest that pulse beverages are as high in protein content (3.24% w/v for chickpea and 4.05% w/v for lupin) as cow’s milk. The anti-nutrient level characteristics of pulses have been considerably reduced by strategic processing. However, when present in small quantities, some of these anti-nutritional factors may have health benefits. Controlling processing conditions play a crucial role in this fine balance as a tool to take advantage of their health benefits. There is evidence of protein hydrolysis by in vitro digestion and limited bioaccessibility of minerals. In addition to being highly digestible, lupin and chickpea beverages have anti-inflammatory and anti-carcinogenic potential evaluated through the inhibition of metalloproteinase MMP-9.