Bioactive Molecules Research Articles

Identification and Biological Characterization of a Novel NRF2 Activator Molecule Released From the Membranes of Heat-Treated Bifidobacterium breve NCC 2950.

Postbiotics are defined as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". They represent an attractive alternative to probiotics as they could be used in a broader range of applications, where probiotic stability is limiting. To date knowledge on the mechanism of action of inanimate microorganisms is relatively scarce. In this study, we investigated the impact of heat treatment on NRF2 activation by several candidate probiotic strains from the Nestlé Culture Collection (NCC), including species encompassed in the Bifidobacterium genus and the Lactobacillaceae family. We identified an NRF2-activating bioactive molecule, 4-oxo-2-pentenoic acid (OPA), specifically released during heat treatment of Bifidobacterium breve NCC 2950. We explored cellular pathways that can be modulated by OPA, such as antiinflammatory signals and organismal defense against oxidative stress in zebrafish in vivo. We identified a new B. breve NCC 2950-derived postbiotic that, based on the mode of action, may have important applications for nutritional strategies to benefit human health.

Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids.

The value of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA) was demonstrated by the coronavirus disease 2019 (COVID-19) mRNA vaccines, but the ability to use LNPs to deliver plasmid DNA (pDNA) would provide additional advantages, such as longer-term expression and availability of promoter sequences. However, pDNA-LNPs face substantial challenges, such as toxicity and low delivery efficiency. Here we show that pDNA-LNPs induce acute inflammation in naive mice that is primarily driven by the cGAS-STING pathway. Inspired by DNA viruses that inhibit this pathway for replication, we loaded endogenous lipids that inhibit STING into pDNA-LNPs. Loading nitro-oleic acid (NOA) into pDNA-LNPs (NOA-pDNA-LNPs) ameliorated serious inflammatory responses in vivo, enabling safer, prolonged transgene expression-11.5 times greater than that of mRNA-LNPs at day 32. Additionally, we performed a small LNP formulation screen to iteratively optimize transgene expression and increase expression 50-fold in vitro. pDNA-LNPs loaded with NOA and other bioactive molecules should advance genetic medicine by enabling longer-term and promoter-controlled transgene expression.

GDF15 Analogues Acting as GFRAL Ligands.

Growth differentiation factor 15 (GDF15) is a TGF-β superfamily member involved in diverse physiological and pathological processes. It is expressed in various tissues and its circulating levels rise during exercise, aging, pregnancy, and conditions such as cancer, cardiovascular disease, and infections. The biological activities of GDF15, including anorexia and cachexia, are primarily mediated through the GFRAL receptor, localized in the brainstem and functioning via RET co-receptor recruitment. This signaling is crucial for energy homeostasis and nausea induction. Recent studies suggest a broader GFRAL distribution, potentially explaining GDF15's distinct roles. These findings sparked interest in leveraging GDF15-GFRAL pathways for therapeutic development. Two primary strategies include GDF15 analogues as GFRAL agonists for obesity treatment and GDF15-derived peptides as antagonists to counteract cancer-induced cachexia and related disorders. This review highlights advancements in understanding GDF15-GFRAL signaling and its implications, summarizing bioactive GDF15-derived molecules, their pharmacological applications, and offering insights into novel treatment avenues for GDF15-associated conditions.

Mesenchymal stem cells and their extracellular vesicle therapy for neurological disorders: traumatic brain injury and beyond

Traumatic brain injury (TBI) is a complex condition involving mechanisms that lead to brain dysfunction and nerve damage, resulting in significant morbidity and mortality globally. Affecting ~50 million people annually, TBI's impact includes a high death rate, exceeding that of heart disease and cancer. Complications arising from TBI encompass concussion, cerebral hemorrhage, tumors, encephalitis, delayed apoptosis, and necrosis. Current treatment methods, such as pharmacotherapy with dihydropyridines, high-pressure oxygen therapy, behavioral therapy, and non-invasive brain stimulation, have shown limited efficacy. A comprehensive understanding of vascular components is essential for developing new treatments to improve blood vessel-related brain damage. Recently, mesenchymal stem cells (MSCs) have shown promising results in repairing and mitigating brain damage. Studies indicate that MSCs can promote neurogenesis and angiogenesis through various mechanisms, including releasing bioactive molecules and extracellular vesicles (EVs), which help reduce neuroinflammation. In research, the distinctive characteristics of MSCs have positioned them as highly desirable cell sources. Extensive investigations have been conducted on the regulatory properties of MSCs and their manipulation, tagging, and transportation techniques for brain-related applications. This review explores the progress and prospects of MSC therapy in TBI, focusing on mechanisms of action, therapeutic benefits, and the challenges and potential limitations of using MSCs in treating neurological disorders.

Catalytic Hydrogenolysis of Lignin into Serviceable Products.

ConspectusLignin, a major component of lignocellulosic biomass, accounts for nearly 30% of organic carbon on Earth, making it the most abundant renewable source of aromatic carbon. The valorization of lignin beyond low-value heat and power has been one of the foremost challenges for a long time. On the other hand, aromatic compounds, constituting a substantial segment of the chemical industry and projected to reach a market value of $382 billion by 2030, are predominantly derived from fossil resources, contributing to increased CO2 emissions. Integrating lignin into the aromatic chemical supply chain will offer a promising strategy to reduce the carbon footprint and boost the economic viability of biorefineries. Thus, depolymerizing lignin biopolymers into aromatic chemicals suitable for downstream processing is an important starting point for its valorization. However, owing to lignin's complexity and heterogeneity, achieving efficient and selective depolymerization that yields desirable, isolable aromatic monomers remains a significant scientific challenge.The structure of lignins varies significantly in terms of subunits and linkages across plant species, leading to considerable differences in their reactivity, in the distribution of resulting monomers, and in their subsequent utilization. In this context, this Account highlights our recent studies on the catalytic hydrogenolysis of lignin into serviceable products for preparing valuable materials, fuels, and chemicals. First, we designed a series of catalytic systems for lignin hydrogenolysis specifically tailored to the structural features of lignin from wood, grass, and certain seed coats. To reduce reliance on expensive commercial catalysts like Pd/C, Ru/C, and Pt/C, we advanced heterogeneous metal catalysts by shifting from high-loaded nanostructured metals to low-loaded, atomically dispersed metals and replacing precious metals with nonprecious alternatives. This approach significantly reduces the cost of catalysts, enhances their atomic economy, and improves their catalytic activity and/or selectivity. Then, using the developed catalysts, phenolic monomers tethering a distinct side chain were selectively generated from the hydrogenolysis of lignin (from various plants), achieving yields close to the theoretical maximum. The high selectivity allowed the separation and purification of monomeric phenols from lignin reaction mixtures readily. To gain deeper insights into the cleavage of lignin C-O bonds, we designed deuterium-incorporated β-O-4 mimics (dimers and one polymer) for a mechanistic study, which excluded the pathways involving the loss of linkage protons and led to the proposal of a concerted hydrogenolysis process for β-O-4 cleavage. Finally, to enable the utilization of depolymerized lignin phenolic monomers, unconventional feedstocks in the current chemical industry, we developed a series of methods to transform them into valuable bioactive molecules, functional materials, and high-energy fuels. Overall, these contributions opened new avenues for converting lignin into serviceable products, encompassing upstream processing and downstream applications.

Purified adipose tissue-derived extracellular vesicles facilitate adipose organoid vascularization through coordinating adipogenesis and angiogenesis.

One of the major challenges in the way of better fabricating vascularized adipose organoids is the destructive effect of adipogenic differentiation on preformed vasculature, which probably stems from the discrepancy between the in vivo physiological microenvironment and the in vitro culture conditions. As an intrinsic component of adipose tissue (AT), adipose tissue-derived extracellular vesicles (AT-EVs) have demonstrated both adipogenic and angiogenic ability in recent studies. However, whether AT-EVs could be employed to coordinate the angiogenesis and adipogenesis in the vascularization of adipose organoids remains largely unexplored. Herein, we present an efficient method for isolating higher-purity AT-EV preparations from lipoaspirates, and verify the superiority of AT-EV preparations' angiogenic and adipogenic capabilities over those from unpurified lipoaspirates. Next, in the spheroid culture model, it was discovered that the addition of AT-EVs could effectively improve the aggregation through enhancing intercellular adhesion of monoculture spheroids composed of human umbilical vascular endothelial cells (HUVECs), and helped produce vascularized adipose organoids with proper lipolysis and glucose uptake ability in the coculture spheroids comprised of adipose-derived stem cells (ADSCs) and HUVECs. Subsequently, it was observed that AT-EVs could exert a retaining effect on the vasculature of prevascularized coculture spheroids cultured in an adipogenic environment, compared to the reduced vascular networks where AT-EVs were absent. Altogether, these results indicate that AT-EVs, by means of releasing bioactive molecules that emulate the in vivo microenvironment, can modify non-replicative in vitro microenvironments, coordinate in vitro adipogenesis and angiogenesis, and facilitate the fabrication of vascularized adipose organoids.&#xD.

Obesity and Adipose-Derived Extracellular Vesicles: Implications for Metabolic Regulation and Disease

Obesity, a global epidemic, is a major risk factor for chronic diseases such as type 2 diabetes, cardiovascular disorders, and metabolic syndrome. Adipose tissue, once viewed as a passive fat storage site, is now recognized as an active endocrine organ involved in metabolic regulation and inflammation. In obesity, adipose tissue dysfunction disrupts metabolic balance, leading to insulin resistance and increased production of adipose-derived extracellular vesicles (AdEVs). These vesicles play a key role in intercellular communication and contribute to metabolic dysregulation, affecting organs such as the heart, liver, and brain. AdEVs carry bioactive molecules, including microRNAs, which influence inflammation, insulin sensitivity, and tissue remodeling. In the cardiovascular system, AdEVs can promote atherosclerosis and vascular dysfunction, while those derived from brown adipose tissue offer cardioprotective effects. In type 2 diabetes, AdEVs exacerbate insulin resistance and contribute to complications such as diabetic cardiomyopathy and cognitive decline. Additionally, AdEVs are implicated in metabolic liver diseases, including fatty liver disease, by transferring inflammatory molecules and lipotoxic microRNAs to hepatocytes. These findings highlight the role of AdEVs in obesity-related metabolic disorders and their promise as therapeutic targets for related diseases.

Synthesis of Highly Functionalized Tetrahydropyridines by Ring Opening of [3.3.1]‐Heterobicyclic Compounds with Grignard Reagents

We herein report our study about the ring opening of 1,3‐diaza‐4‐oxa‐[3.3.1]‐nonene derivatives with organometallic reagents leveraging on their inherent ring strain and presence of reactive functionalities. The ring‐opening occurs with Grignard reagents at the carbon bearing the two nitrogen atoms affording unconventional functionalized trans‐2,3‐disubstituted 1,2,3,6‐tetrahydropyridines that are important structural frameworks due to their synthetic versatility and presence in bioactive molecules. The possibility to prepare enantioenriched tetrahydropyridines was also formally explored with success. A computational DFT points to the formation of a transient iminium ion intermediate in which the coordination of magnesium to the oxygen of the carbonyl and the N‐O endocyclic oxygen promotes the ring‐opening process at the gem‐diamine carbon atom.

Effects of Supramaximal Intensity Interval Training on Resistin and Cardiometabolic Health Indices in Overweight Nonpostmenopausal Women.

Adipose tissue is an endocrine organ that produces various bioactive molecules known as adipokines, including resistin, which is be highly expressed in people with obesity and cardiovascular disease (CVD). The effects of supramaximal high intensity interval training (HIIT) and moderate-intensity interval training (MIIT) on serum levels of resistin and various cardiometabolic health indices, were investigated. Supramaximal and moderate interval training induce comparable effects on serum resistin levels and cardiometabolic health indices. Cohort study. Thirty overweight adult women were assigned to 1 of 3 groups: HIIT (2 sets of 8 intervals, each with 30 seconds exercise at 100%-110% maximal aerobic speed [MAS] followed by 30 seconds rest at 50% MAS; for 6 weeks with 3 sessions per week), MIIT (2 sets of 8 intervals, each with 30 seconds exercise at 70%-80% MAS followed by 30 seconds rest at 50% MAS; for 6 weeks with 3 sessions per week), or a control group. Triglyceride levels were significantly higher in the control group compared with both the HIIT and MIIT groups (P = .02 and .01, respectively). High-density lipoprotein levels were also elevated significantly in the experimental groups compared with the control group (P = .04 and .03, respectively). Serum resistin increased significantly from pretest levels in the control group (P < .01). Between-group comparisons showed that resistin levels were significantly higher in the control group than in the experimental groups (P < .01 and .01, respectively). Six weeks of HIIT can reduce resistin levels and improve cardiometabolic health indicators in nonpostmenopausal women. Although 6 weeks of MIIT does not reduce resistin, it does decrease systolic blood pressure and obesity-related factors in nonmenopausal women. Supramaximal interval training may be recommended to control bioactive molecules produced from adipose tissue that are linked to CVD.

Isolation and Bioassay of Linear Veraguamides from a Marine Cyanobacterium (Okeania sp.)

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new (veraguamide O (1) and veraguamide P (2)) and one known (veraguamide C (3)) analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane-bound receptors. The planar structures were determined based on NMR and MS data along with a comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be an Okeania sp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 μM) against ER-positive cells (MCF-7) with 13 μM IC50 against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor, making them potential leads for the development of non-toxic sigma 2 targeting ligands.

Enantioselective Synthesis of Indole-Fused Polycycles Bearing Four Consecutive Stereocenters via Rhodium Catalysis.

Indole-fused polycycles are common in natural products and bioactive molecules, yet their concise and efficient synthesis remains challenging, especially for compounds with multiple stereocenters. Herein, we report the application of a chiral CpxRhIII catalyst in the enantioselective C-H activation/[4+2] annulation of indoles with bicyclic alkenes. This chiral catalytic system exhibits high enantioselectivity and broad functional group tolerance and operates under benign conditions. The scope of this methodology encompasses a variety of substrates, delivering novel polycyclic compounds with four consecutive stereocenters and a bridged ring in good to excellent yields and remarkable enantioselectivities (≤1:99 er). This approach facilitates the synthesis of structurally diverse molecules that retain their bicyclic integrity while introducing chirality. More importantly, chiral 3ab significantly inhibited the proliferation of CESS and Kasumin-1 cells with IC50 values of 0.76 and 0.28 μM, respectively. In addition, 3ab has been demonstrated as an effective agent for promoting apoptosis in CESS cells.

Reactivity in cell culture medium and in vitro anticancer activity of 3,5-di-tert-butylcatechol: link to metal-catechol interactions

IntroductionCatechol moieties are common in natural bioactive molecules, and their ability to bind metal ions is widely explored both naturally with siderophores and in the development of metal-based drugs. The reactivities and biology activities of a sterically hindered model catechol compound, 3,5-di-tert-butylcatechol (dtbH2) and its oxidation product 3,5-di-tert-butyl-o-quinone (dtbQ), were studied in cell culture medium to understand better the medicinal roles of this class of molecules.MethodsAnti-proliferative activities of dtbH2 and dtbQ in fresh and aged solutions of the molecules were studied in two common human cancer cell lines, T98G (glioblastoma) and A549 (lung carcinoma). Electrospray mass spectrometry and UV/Vis spectroscopy were used to study the reactivities of the molecules in buffer solutions and cell culture medium, in the presence and absence of glutathione and imidazole.Results and DiscussionThe dtbH2 and dtbQ molecules showed high anti-proliferative activity (IC50 &amp;lt; 10 μM in 72 h assays) in T98G and A549 cell lines in the absence of added metal ions. The activity was observed when dtbH2 and dtbQ were freshly added to cell culture medium, while pre-incubation with the medium for 24 h reduced their activity 5-10-fold. This deactivation was avoided when the biological reductant, glutathione (GSH), was added to the medium at a physiologically relevant intracellular concentration (5.0 mM). These results were explained by speciation studies (UV/Vis spectroscopy and mass spectrometry) of dtbH2 and dtbQ in cell culture medium, aqueous buffers, or organic solvents in the presence or absence of GSH. These studies showed that a redox equilibrium was established between dtbH2 and dtbQ, with the latter rapidly coupling the GSH in an oxidative manner. The resultant adduct is likely to be responsible for the high toxicity of dtbH2 and dtbQ in GSH-rich cancer cells via oxygen-dependent radical chain reactions. Deactivation of dtbH2 and dtbQ in cell culture medium in the absence of GSH was due to the reactions of dtbQ with nucleophiles, such as amino acids, followed by the formation of polymeric species. The reported high anti-proliferative activity of V(V)-catecholato complexes can be explained by a combination of their efficient cellular uptake and rapid decomposition in thiol-rich intracellular environment with the formation of active V(V) and dtbH2/dtbQ adducts with thiols (mainly GSH). Slower decomposition and deactivation of the complexes was observed in thiol-poor extracellular environments. These data show that speciation in cell culture medium is crucial for the biological activity not only of metal complexes but also of their ligands when the complexes dissociates.

Divergent alkynylative difunctionalization of amide bonds through C–O deoxygenation versus C–N deamination

The transformation and utilization of amides are significant in organic synthesis and drug discovery. Here we demonstrate a divergent alkynylative difunctionalization of amides in a single transformation. In this reaction, amides react with an organometallic nucleophile to form a tetrahedral intermediate. By altering the N-substitution or the acyl group, the tetrahedral intermediate species selectively undergoes C–O or C–N cleavage with a concomitant capture by an alkynyl nucleophile generated in situ. This process enables the selective introduction of two different functional groups into the amide molecular architecture, producing valuable propargyl amine and propargyl alcohol products. The selectivity between deoxygenation and deamination process has been further elucidated by DFT calculations. Overall, this reaction successfully transforms the traditional mode of nucleophilic acyl addition to amides to a divergent C–O/C–N cleavage. The particularly wide substrate scope, including late-stage modification of bioactive molecules, demonstrates its potential broad applications in organic synthesis.

Isolation and anti-Xanthomonas citri activity of unguinol produced by Aspergillus unguis CBMAI 2140.

This research investigated active biomolecules from the endophytic fungus Aspergillus unguis (CBMAI 2140), isolated from Passiflora incarnata leaves, as potential antibacterial agents against Xanthomonas citri subsp. citri, the causative agent of citrus canker. The fungal extract was obtained via liquid-liquid extraction with ethyl acetate. Antibacterial activity was assessed using the Resazurin Microtiter Assay Plate (REMA), determining inhibitory concentrations (IC90) and the Minimum Bactericidal Concentration (MBC). The extract displayed microbicidal activity at 1050 µg.mL⁻¹ and inhibited bacterial growth at 350 µg.mL⁻¹. Fractionation of the extract via normal-phase column chromatography yielded six fractions, with fraction F11 showing the highest antibacterial potential (MBC: 200 µg.mL⁻¹). Nuclear magnetic resonance (NMR) analysis identified Unguinol as the main compound in F11. Fluorescence microscopy demonstrated rapid permeabilization of the X. citri cell membrane upon exposure to the compound, with significant effects observed after 15-30 minutes. Although no notable anti-biofilm activity was detected, this study represents the first report of Unguinol's antibacterial activity against Xanthomonas species. These findings highlight its potential for agricultural applications, contributing to sustainable development goal (SDG) 2.

Osteogenic Evaluation of 3D-printed PLA scaffolds Integrated with Khellin-loaded Chitosan-Alginate Sponges for Bone Tissue Engineering.

Bone tissue engineering (BTE) offers promising strategies for bone regeneration, yet the effective delivery of bioactive molecules remains a challenge. Khellin (KH), a plant-derived furanochromone, possesses various biological properties, though its potential in promoting osteogenesis has not been thoroughly investigated. In this study, 3D-printed polylactic acid (PLA) scaffolds were integrated with KH-loaded chitosan-alginate sponges (PLA/ALG/CS-KH) to facilitate controlled and sustained delivery of KH. Using sol-gel and freeze-drying techniques, KH was incorporated at varying concentrations (60, 70, and 80 μM) to enhance its bioavailability. Comprehensive physicochemical analyses demonstrated that KH incorporation did not alter the scaffolds' porosity, swelling capacity, protein adsorption, degradation rates, or biomineralization potential. In vitro studies revealed that the PLA/ALG/CS-KH scaffolds were biocompatible with mesenchymal stem cells and effectively promoted osteogenic differentiation, particularly at a concentration of 70 μM KH. These results suggest that PLA/ALG/CS-KH scaffolds have significant potential as osteoinductive platforms for BTE applications, providing a novel approach for enhancing bone regeneration through the sustained release of KH.

Unveiling potential functional applications of grape pomace extracts based on their phenolic profiling, bioactivities, and circular bioeconomy

Abstract Grape pomace (GP), a by-residue from the wine industry, contains bioactive molecules such as phenolic compounds, and anthocyanins, among others, with potential health benefits. In the current study, these bioactive molecules were extracted from GP of different Vitis vinifera L. varieties (Tinta Negra, Complexa, Malvasia Roxa, Malvasia, Sercial, Verdelho, Boal, Terrantez) using the micro quick, easy, cheap, effective, rugged, and safe (µQuEChERS) procedure. The GP extracts were investigated using ultra-high performance liquid chromatography (UHPLC-PDA) to establish the phenolic fingerprint, and by in vitro assays to assess the antibacterial, anti-inflammatory, and antioxidant activities. Nine phenolic compounds were identified and quantified in GP extracts, with gallic acid (ranging from 10.4 to 12.9 g/100 g), catechin (2.97 to 5.08 g/100 g), quercetin (2.17 to 2.85 g/100 g), and trans-resveratrol (0.28 to 1.82 g/100 g) being the most prominent. GP from the Complexa variety exhibited the highest levels of total anthocyanin content (TAC, 6.67 mgCGE/100 g), total phenolic compounds (TPC, 4727 mgGAE/100 g), and antioxidant activity (DPPH, 9472 mgTE/100 g), while the Tinta Negra variety had the highest total catechin content (TCC, 947 mgCATE/100 g). A strong correlation (p &lt; 0.001) was observed between the TPC-TAC, TPC-DPPH, DPPH-TAC, and TAC-TCC. Moreover, o-coumaric acid and quercetin are significantly (p &lt; 0.001) correlated with TPC, TAC, TCC, and DPPH assays. The investigated GP extracts, at a concentration of 100 µg/mL, showed promising inhibition of albumin protein denaturation compared to aspirin (reference standard). The findings showed that the GP extracts were more useful at inhibiting Staphylococcus aureus compared to Escherichia coli. It is important to emphasise that the GP extracts demonstrated antioxidant, anti-inflammatory, and antibacterial properties, positioning it as an agro-waste with promising potential for use in the development of innovative functional foods, dietary supplements, and cosmetics, aligning with the circular bioeconomy model for its valorisation.

Exercise and exerkines: Mechanisms and roles in anti-aging and disease prevention.

Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

Blueberry-derived exosome like nanovesicles carry RNA cargo into HIEC-6 cells and down-regulate LPS-induced inflammatory gene expression: A proof-of-concept study.

Exosome-like nanovesicles (ELNs) of food origin have received great attention in the last decade, due to the hypothesis that they contain bioactive molecules. ELNs purified from edible species have been shown to be protective and are able to regulate intestinal homeostasis. Despite ELNs being potential rising stars in modern healthy diets and biomedical applications, further research is needed to address underlying knowledge gaps, especially related to the specific molecular mechanism through which they exert their action. Here, we investigate the cellular uptake of blueberry-derived ELNs (B-ELNs) using a human stabilized intestinal cell line (HIEC-6) and assess the ability of B-ELNs to modulate the expression of inflammatory genes in response to lipopolysaccharide (LPS). Our findings show that B-ELNs are internalized by HIEC-6cells and transport labeled RNA cargo into them. Pretreatment with B-ELNs reduces LPS-induced ROS generation and cell viability loss, while modulating the expression of 28 inflammatory genes compared to control. Pathway analysis demonstrates their ability to suppress inflammatory responses triggered by LPS. In conclusion, our data indicate that B-ELNs are up taken by HIEC-6cells and can modulate inflammatory responses after LPS stimulation, suggesting a therapeutic potential. This study demonstrates the role of B-ELNs in regulating crucial biological processes, like anti-inflammatory responses, which could support intestinal health.

Multiple sphingolipid-metabolizing enzymes modulate influenza virus replication.

The sphingolipid network is sustained principally by the balance of bioactive sphingolipid molecules and their regulation by sphingolipid-metabolizing enzymes. The components in the lipid system display key functions in numerous cellular and disease conditions including virus infections. During the COVID-19 pandemic, there was a fruitful effort to use an inhibitor that blocks the activity of sphingosine kinase (SphK) 2 to cure the devastating disease. Support for the inhibitor came from pre-clinical research on influenza where the inhibitor demonstrated effective protection of mice from influenza-induced morbidity and mortality. This highlights the importance of basic and translational research on the sphingolipid system for improving human health. Multiple sphingolipid-metabolizing enzymes have been reported to regulate influenza virus replication and propagation. In this review, the emphasis is placed on the roles of these enzymes that impact influenza virus life cycle and the conceivable mechanisms for the interplay between influenza virus and the sphingolipid pathway.

BXQ-350, a novel sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal cancer (mCRC) patients: A phase 1b/2 randomized study.

TPS320 Background: Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS &gt; 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years suggesting potential long-term benefit. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): 1) A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30 patient expansion cohort 2) Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Enrollment in the expansion cohort of 30 patients is nearly complete, with 26 patients enrolled as of September 2024. Clinical trial information: NCT05322590 .