Molecular Insights into Transcranial Direct Current Stimulation Effects: Metabolomics and Transcriptomics Analyses.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is an evolving non-invasive neurostimulation technique. Despite multiple studies, its underlying molecular mechanisms are still unclear. Several previous human studies of the effect of tDCS suggest that it generates metabolic effects. The induction of metabolic effects by tDCS could provide an explanation for how it generates its long-term beneficial clinical outcome. AIM: Given these hints of tDCS metabolic effects, we aimed to delineate the metabolic pathways involved in its mode of action. METHODS: To accomplish this, we utilized a broad analytical approach of co-analyzing metabolomics and transcriptomic data generated from anodal tDCS in rat models. Since no metabolomic dataset was available, we performed a tDCS experiment of bilateral anodal stimulation of 200 µA for 20 min and for 5 consecutive days, followed by harvesting the brain tissue below the stimulating electrode and generating a metabolomics dataset using LC-MS/MS. The analysis of the transcriptomic dataset was based on a publicly available dataset. RESULTS: Our analyses revealed that tDCS alters the metabolic profile of brain tissue, affecting bioenergetic-related pathways, such as glycolysis and mitochondrial functioning. In addition, we found changes in calcium-related signaling. CONCLUSIONS: We conclude that tDCS affects metabolism by modulating energy production-related processes. Given our findings concerning calcium-related signaling, we suggest that the immediate effects of tDCS on calcium dynamics drive modifications in distinct metabolic pathways. A thorough understanding of the underlying molecular mechanisms of tDCS has the potential to revolutionize its applicability, enabling the generation of personalized medicine in the field of neurostimulation and thus contributing to its optimization.

Novel bioactive lipids enhanced HDL-mediated cholesterol efflux from macrophages through the ABCA1 receptor pathway.

High-density lipoprotein (HDL) has traditionally been acknowledged as "good cholesterol" owing to its significant association with a decreased risk of atherosclerosis. This association is primarily attributed to HDL's direct involvement in cholesterol efflux capacity, which plays a pivotal role in reverse cholesterol transport. A novel active compound from Nannochloropsis microalgae termed lyso-DGTS, a lipid that contains EPA fatty acids, was previously isolated and found to increase paraoxonase 1 activity and enhance HDL-mediated cholesterol efflux and HDL-induced endothelial nitric oxide release. Here, the effect of different lyso-DGTS derivatives and analogs on HDL-mediated cholesterol efflux from macrophages was examined, and the mechanism was explored. Structure-activity relationships were established to characterize the essential lipid moieties responsible for HDL-mediated cholesterol efflux from macrophages. Lyso-DGTS, 1-carboxy-N-N-N-trimethyl-3-oleamidopropan-1-aminium, and lyso-platelet-activating factor increased HDL-mediated cholesterol efflux from macrophages dose-dependently, mainly via the ABCA1-mediated cholesterol efflux pathway. The effect of lyso-DGTS derivatives and analogs on the surface polarity of HDL was examined using the Laurdan generalized polarization (GP) assay. A reverse Pearson linear regression was obtained between Laurdan GP values and HDL-mediated cholesterol efflux. Because the incorporation of bioactive lipids into the surface phospholipid layer of HDL leads to a decrease in Laurdan GP, these bioactive lipids may induce lower phospholipid ordering and greater free space on the HDL particle surface, thereby enhancing apolipoprotein A1 binding to the ABCA1 receptor and improving ABCA1 cholesterol-mediated efflux. Our findings suggest a beneficial effect of lyso-DGTS and its bioactive lipid derivatives on increasing HDL-mediated cholesterol efflux activity from macrophages, which may impact atherosclerosis attenuation.

Effect of entomopathogenic fungus Beauveria bassiana on the growth characteristics and metabolism of black soldier fly larvae.

Beauveria bassiana is an entomopathogenic fungus widely used in agriculture to reduce populations of various pests. However, when agricultural waste is utilized for organic recycling, B. bassiana has the potential to impact recycling performance, by affecting the survival, and body mass of decomposing organisms (such as insect's larvae). Additionally, in natural conditions where decayed organic matter contains a high load of different entomopathogenic organisms, larval growth may be affected when consumed or in contact. In a laboratory study, we aimed to comprehend the effects of B. bassiana on the growth characteristics and larval metabolism of the black soldier fly larvae, which is a known decomposing insect. The experiments used both feeding (mixing the spores with the diet, hereafter BF) and contact treatments (by dipping the larva in the spores solution, hereafter BD), and were compared to a water-treated control group. The BF treatment significantly reduced larval body weight, adult emergence, and adult weight compared to both the control and the BD treatment. Furthermore, an analysis of hemolymph metabolites, categorized by class, indicated a higher accumulation of metabolites belonging to the purine and purine derivative classes, as well as carboxylic acids and their derivatives, including peptides and oligopeptides, indicating potential disruption of protein synthesis or degradation caused by the BF treatment. Pathway enrichment analysis showed significant alterations in purine metabolism and D-Arginine and D-ornithine metabolism compared to the control. Taurine and hypotaurine metabolism were significantly altered in the BD treatment compared to the control but not significantly enriched in the BF treatment. Our results suggest that the BF treatment impairs protein synthesis or degradation, affecting larval growth characteristics. Future studies should explore innate immunity-related gene expression and antimicrobial peptide production in BSF larvae to understand their immunity to pathogens.

PON1 has palmitoyl-protein thioesterase (PPT) activity, and can affect the presence of SR-B1 on the endothelial cell membrane.

The high-density lipoprotein (HDL)-associated enzyme paraoxonase 1 (PON1) is expressed almost exclusively in the liver and is then transported by HDL to the peripheral tissues. The lipophilic nature of PON1 enables its easy exchange between the lipoprotein and cell membranes in a process that is dependent on the HDL receptor scavenger receptor class B, type 1 (SR-B1). In endothelial cells, PON1 binding to the cell membrane leads to its internalization by endocytosis and subsequent lysosomal degradation. PON1 is a "promiscuous" enzyme with unusually broad substrate specificity in vitro, but its actual function and substrate are still unknown. The enzyme requires a lipid environment and becomes completely inactive upon delipidation. However, when PON1 binds HDL, its active site faces the lipoprotein's core and is inaccessible to external substrates. Hence, the HDL-bound PON1 is inactive toward substrates outside the particle's lipid core and is rapidly degraded and becomes inactive upon internalization. Consequently, the enzyme is only active in the cell membrane during its transit from HDL to the cytoplasm. To assign a function to PON1, we investigated whether it is a palmitoyl-protein thioesterase (PPT) that can hydrolyze the palmitoyl moieties of membrane proteins involved in HDL and cholesterol transport, such as SR-B1, ABCA1, or their neighboring caveola proteins to facilitate the release of HDL or trigger its endocytosis. This study shows that PON1 can hydrolyze palmitoyl-cysteine thioester bonds in vitro, has direct or indirect PPT activity in vivo, and can significantly decrease the presence of SR-B1 in the endothelial membrane.

Multiomics tools for improved atherosclerotic cardiovascular disease management.

Multiomics studies offer accurate preventive and therapeutic strategies for atherosclerotic cardiovascular disease (ASCVD) beyond traditional risk factors. By using artificial intelligence (AI) and machine learning (ML) approaches, it is possible to integrate multiple 'omics and clinical data sets into tools that can be utilized for the development of personalized diagnostic and therapeutic approaches. However, currently multiple challenges in data quality, integration, and privacy still need to be addressed. In this opinion, we emphasize that joined efforts, exemplified by the AtheroNET COST Action, have a pivotal role in overcoming the challenges to advance multiomics approaches in ASCVD research, with the aim to foster more precise and effective patient care.

Compounds originating from the edible mushroom Auricularia auricula-judae inhibit tropomyosin receptor kinase B activity.

Tropomyosin receptor kinase B (TrkB) serves as a pivotal factor in various cancers. To identify novel natural compounds with TrkB-inhibiting properties, a screening approach was applied using extracts from a collection of wild and cultivated mushroom fruiting bodies, and Ba/F3 cells that ectopically express TrkB (TPR-TrkB). We selected mushroom extracts that selectively inhibited proliferation of the TPR-TrkB cells. We then evaluated the ability of exogenous interleukin 3 to rescue growth inhibition by the selected TrkB-positive extracts. An ethyl acetate extract of Auricularia auricula-judae actively inhibited auto-phosphorylation of TrkB. LC-MS/MS analysis of this extract revealed substances that might be responsible for the observed activity. This screening approach demonstrates, for the first time, that extracts originating from the mushroom A. auricula-judae exhibit TrkB-inhibition properties that might hold therapeutic potential for TrkB-positive cancers.

Gestational diabetes is driven by microbiota-induced inflammation months before diagnosis.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities. DESIGN: We comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts. RESULTS: We found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy. CONCLUSION: GDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.

Lyso-DGTS Lipid Derivatives Enhance PON1 Activities and Prevent Oxidation of LDL: A Structure-Activity Relationship Study.

Paraoxonase 1 (PON1) plays a role in regulating reverse cholesterol transport and has antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities. Scientists are currently focused on the modulation of PON1 expression using different pharmacological, nutritional, and lifestyle approaches. We previously isolated a novel active compound from Nannochloropsis microalgae-lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS)-which increased PON1 activity, HDL-cholesterol efflux, and endothelial nitric oxide release. Here, to explore this important lipid moiety's effect on PON1 activities, we examined the effect of synthesized lipid derivatives and endogenous analogs of lyso-DGTS on PON1 lactonase and arylesterase activities and LDL oxidation using structure-activity relationship (SAR) methods. Six lipids significantly elevated recombinant PON1 (rePON1) lactonase activity in a dose-dependent manner, and four lipids significantly increased rePON1 arylesterase activity. Using tryptophan fluorescence-quenching assay and a molecular docking method, lipid-PON1 interactions were characterized. An inverse correlation was obtained between the lactonase activity of PON1 and the docking energy of the lipid-PON1 complex. Furthermore, five of the lipids increased the LDL oxidation lag time and inhibited its propagation. Our findings suggest a beneficial effect of lyso-DGTS or lyso-DGTS derivatives through increased PON1 activity and prevention of LDL oxidation.

Striatal Isolated from Cyathus striatus Extracts Induces Apoptosis in Human Pancreatic Cancer Cells.

The aim of the present study was to identify the structure of active compounds in Cyathus stratus that previously demonstrated anti-pancreatic cancer activity. The active compounds were purified from a crude extract by a series of RP-18 preparative chromatography using homemade octadecyl silica gel column. HPLC injection of the crude extract revealed a chromatogram with three main peaks with retention times (RT) 15.6, 18.2, and 22.5 min. Each fraction that exhibited promising activity in vitro was further separated using various available chromatographic techniques. The purified compound with the ultimate anti-cancer activity appeared at RT of 15.8 in the HPLC chromatogram with more than 90% purity. The main peak at the mass spectra appeared at m/z = 446.2304 with the calculated molecular formula of C25H34O7. One- and two-dimensional NMR analyses indicated that the structure of the active molecule (peak 15.8 min in HPLC) was identified as striatal C. Exposure of human pancreatic cancer cells to purified striatal C resulted in induction of apoptosis. Further studies are needed in order to develop a method for the synthesis of striatal in order to use it in clinical studies for treatment of cancer.

Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review.

The recently described phenomenon of cholesterol-loaded low-density lipoproteins (LDL) entering the arterial wall from the lumen by transcytosis has been accepted as an alternative for the long-held concept that atherogenesis involves only passive LDL movement across an injured or dysfunctional endothelial barrier. This active transport of LDL can now adequately explain why plaques (atheromas) appear under an intact, uninjured endothelium. However, the LDL transcytosis hypothesis is still questionable, mainly because the process serves no clear physiological purpose. Moreover, central components of the putative LDL transcytosis apparatus are shared by the counter process of cholesterol efflux and reverse cholesterol transport (RCT) and therefore can essentially create an energy-wasting futile cycle and paradoxically be pro- and antiatherogenic simultaneously. Hence, by critically reviewing the literature, we wish to put forward an alternative interpretation that, in our opinion, better fits the experimental evidence. We assert that most of the accumulating cholesterol (mainly as LDL) reaches the intima not from the lumen by transcytosis, but from the artery's inner layers: the adventitia and media. We have named this directional cholesterol transport transmural cholesterol flux (TCF). We suggest that excess cholesterol, diffusing from the avascular (i.e., devoid of blood and lymph vessels) media's smooth muscle cells, is cleared by the endothelium through its apical membrane. A plaque is formed when this cholesterol clearance rate lags behind its rate of arrival by TCF.

S-Nitrosylation of Paraxonase 1 (PON1) Elevates Its Hydrolytic and Antioxidant Activities.

Covalent binding between nitric oxide (NO) and a protein's free thiol group (SH) is termed protein S-nitrosylation. Protein S-nitrosylation is involved in cellular regulation mechanisms that underlie a wide range of critical functions, such as apoptosis, alteration of enzyme activities, and transcription-factor stability. Impaired protein S-nitrosylation is associated with a growing list of pathophysiological conditions, such as cardiovascular disease, multiple sclerosis, pulmonary hypertension, and sickle cell disease. The enzyme paraoxonase 1 (PON1) binds to high-density lipoprotein to provide many of its antiatherogenic properties. The enzyme has a strong antioxidant capacity, which protects fats, lipids, and lipoproteins from oxidation, in addition to breaking down oxidized fats. We investigated the effect of S-S transnitrosylation on PON1 activities. Incubation of recombinant PON1 (rePON1) with nitrosylated human serum albumin (HSA-NO) resulted in S-nitrosylation of about 70% of the rePON1, as measured by Q-TOF LC/MS. S-nitrosylation significantly increased rePON1 hydrolytic activities. It also increased rePON1's ability to inhibit low-density lipoprotein oxidation induced by Cu2+. Finally, it increased the enzyme's penetration into macrophage cells by 31%. Our findings suggest that S-nitrosylation of rePON1 improves its biological functions which may positively affect atherosclerosis disease progression.

Fishing for lipid lactones using selective reaction and characteristic fragmentation pattern.

Extensive research has been invested in developing sensitive methods to identify lipid mediators (LMs) from multiple biological matrices. Previous studies point to the existence of a potential family of lactone-containing metabolites generated from eicosanoid families, isoprostanes, and prostanoid-like compounds that may function as LMs. However, targeted lipidomic studies do not routinely include lactone-containing lipids due to their low ionizability and instability under some common sample preparation conditions. Thus, the discovery of lactone-containing LM is limited. Herein we describe a method for selective identification of lipid lactones from within biological matrices. This method is based on a selective reaction of lactones with 1-(3-aminopropyl)imidazole, followed by cation exchange solid phase extraction and the identification of characteristic fragmentation patterns unique to reaction products of lactones in LC/MS/MS. NMR and LC/MS results indicated that saturated and unsaturated aliphatic ɣ and δ lactone model compounds mixed with human serum were successfully detected. MS/MS analyses of the reaction products revealed a unique pattern for the lactones, resulting from common neutral losses and fragmentation. When applied to esters and free fatty acids, some reaction products were observed. However, these reaction products' MS/MS fragmentation did not match the specific fragmentation of the lactones' reaction products. Confirming that lactones can be detected in a highly selective manner from within complex biological matrices when using the presented method. Thus, the presented method can selectively analyze lactones and may further complement existing lipidomic approaches to discover new LMs.

Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics.

Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor's resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.

Does Routine Sedation Influence Anxiety and CRP levels in Patients Undergoing Elective Coronary Catheterization?

BACKGROUND: Cardiac catheterization is associated with patient anxiety. Benzodiazepines are often used to relieve anxiety in this setting. The association between anxiety level and C-reactive protein (CRP) remains equivocal. We sought to determine whether anxiety and CRP levels in patients undergoing elective left heart catheterization differ when routine sedation with midazolam is administered. METHODS: Patients undergoing elective left heart catheterization were randomly assigned to receive 2 mg of midazolam intravenously or placebo before access insertion in a double-blinded manner. Levels of anxiety were assessed using the State-Trait Anxiety Inventory for Adults (short form) and high-sensitivity CRP at the time of admission and discharge. Surrogate markers for anxiety, such as blood pressure and pulse, were recorded before and after the procedure. Patient-perceived discomfort was measured with a visual analog scale (VAS) on a 0-10 scale. RESULTS: One hundred patients (52 receiving treatment, 48 receiving placebo) participated in the study. Baseline demographic characteristics and previous medical conditions were well balanced between groups. Anxiety level, systolic blood pressure, and diastolic blood pressure were all higher at procedure start than post procedure, but did not differ between the groups. CRP levels were similar at both time points for patients in both groups (0.77 ± 2.53 mg/L pre procedure and 0.70 ± 2.08 mg/L post procedure in the midazolam group vs 0.79 ± 1.39 mg/L pre procedure and 0.83 ± 1.45 mg/L post procedure in the placebo group). Discomfort level assessment was also alike (2.6 ± 2.4 in the treatment group vs 3.4 ± 2.5 in the placebo group; P=.12). CONCLUSIONS: Intravenous midazolam administration does not seem to relieve patient discomfort and anxiety nor does it influence CRP level. Therefore, an approach tailored to the patient is advisable.

Trichoderma asperellum Secreted 6-Pentyl-α-Pyrone to Control Magnaporthiopsis maydis, the Maize Late Wilt Disease Agent.

Late wilt disease (LWD) is a destructive vascular disease of maize (Zea mays L.) caused by the fungus Magnaporthiopsis maydis. Restricting the disease, which is a significant threat to commercial production in Israel, Egypt, Spain, India, and other countries, is an urgent need. In the past three years, we scanned nine Trichoderma spp. isolates as biological control candidates against M. maydis. Three of these isolates showed promising results. In vitro assays, seedlings pathogenicity trials, and field experiments all support the bio-control potential of these isolates (or their secretions). Here, a dedicated effort led to the isolation and identification of an active ingredient in the growth medium of Trichoderma asperellum (P1) with antifungal activity against M. maydis. This Trichoderma species is an endophyte isolated from LWD-susceptible maize seeds. From the chloroform extract of this fungal medium, we isolated a powerful (approx. 400 mg/L) active ingredient capable of fully inhibiting M. maydis growth. Additional purification using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) separation steps enabled identifying the active ingredient as 6-Pentyl-α-pyrone. This compound is a potential fungicide with high efficiency against the LWD causal agent.

Reappraisal of ischemia-reperfusion injury in a short duration laparoscopic surgery, a pilot study.

BACKGROUND: Serum biochemical changes during laparoscopic surgery and positive pressure pneumoperitoneum (PP) may reflect mild oxidative stress due to the ischemia-reperfusion (I/R) mechanism. However, there is still a controversy regarding the exact mechanism of PP in creating oxidative stress and whether the induction of PP causes I/R effects at all. To elucidate this debated issue, we studied, for the first time, the changes of I/R parameters in the serum, in a pilot study, during laparoscopic cholecystectomy using a reliable, independent exogenous oxidative biomarker, together with common intrinsic biomarkers of oxidative stress. PATIENTS AND METHODS: Our study included 20 patients scheduled for elective laparoscopic cholecystectomy. We evaluated the levels of the extrinsic and endogenous markers for oxidative stress during awareness, under anesthesia, the end of surgery (abdominal CO2 evacuation), and 2 h afterward. RESULTS: After an initial increase in oxidative stress following anesthesia, we did not notice any further significant rise in the levels of the synthetic exogenous and the endogenous biomarkers at the end of the surgery and 2 h later on. However, a positive correlation was noted between the levels of both the intrinsic and extrinsic markers. CONCLUSIONS: In our study, the capability of the extrinsic biomarker to detect mild oxidative stress was not validated. Our study stresses the heterogeneous nature of the oxidative reactions and the diversity of the endogenous and exogenous biomarkers while detecting various biochemical patterns under mild oxidative stress, during the short period of laparoscopic surgery.

Galantamine Quantity and Alkaloid Profile in the Bulbs of Narcissus tazetta and daffodil cultivars (Amaryllidaceae) Grown in Israel.

Alkaloids produced by the bulbs of the Amaryllidaceae are a source of pharmaceutical compounds. The main alkaloid, galantamine, is a reversible acetylcholinesterase inhibitor and allosteric nicotinic receptor modulator, which slows cognitive and functional decline in mild to moderate dementia due to Alzheimer's disease. Having a complex stereochemistry, the organic synthesis of galantamine for pharmaceutical uses is highly challenging and not always economically viable, and it is therefore isolated from Amaryllidaceae bulbs. In the present study, galantamine was extracted and quantified in Narcissus bulbs from five cultivars (cvs.), Fortune, Carlton, Ice Follies, Galilee and Ziva, which were grown in Israel under various conditions. Results show that the cvs. Fortune, Carlton and Ice Follies bulbs contained 285 ± 47, 452 ± 73 and 69 ± 17 µg g-1 galantamine, respectively, while the Galilee and Ziva bulbs contained relatively low concentrations of galantamine (1-20 µg g-1). Irrigation levels and pruning conditions did not affect the galantamine contents. Additionally, the alkaloids profile of the five cvs. was analyzed and characterized using LC-MS/MS showing that galantamine-type alkaloids were mainly detected in the Fortune and Carlton bulbs, lycorine-type alkaloids were mainly detected at the Galilee and Ziva bulbs and vittatine-type alkaloids were mainly detected in the Ice Follies bulbs. The present research is the first to characterize the alkaloids profile in the Narcissus bulbs of Galilee and Ziva, indigenous cvs. grown in Israel. The antiviral and anticancer alkaloids lycorine and lycorinine were the main alkaloids detected in the bulbs of those cultivars.

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer.

Flavonoids, a class of polyphenols, consumed daily in our diet, are associated with a reduced risk for oxidative stress (OS)-related chronic diseases, such as cardiovascular disease, neurodegenerative diseases, cancer, and inflammation. The involvement of flavonoids with OS-related chronic diseases have been traditionally attributed to their antioxidant activity. However, evidence from recent studies indicate that flavonoids' beneficial impact may be assigned to their interaction with cellular macromolecules, rather than exerting a direct antioxidant effect. This review provides an overview of the recent evolving research on interactions between the flavonoids and lipoproteins, proteins, chromatin, DNA, and cell-signaling molecules that are involved in the OS-related chronic diseases; it focuses on the mechanisms by which flavonoids attenuate the development of the aforementioned chronic diseases via direct and indirect effects on gene expression and cellular functions. The current review summarizes data from the literature and from our recent research and then compares specific flavonoids' interactions with their targets, focusing on flavonoid structure-activity relationships. In addition, the various methods of evaluating flavonoid-protein and flavonoid-DNA interactions are presented. Our aim is to shed light on flavonoids action in the body, beyond their well-established, direct antioxidant activity, and to provide insights into the mechanisms by which these small molecules, consumed daily, influence cellular functions.

Photosynthetically Controlled Spirulina, but Not Solar Spirulina, Inhibits TNF-α Secretion: Potential Implications for COVID-19-Related Cytokine Storm Therapy.

An array of infections, including the novel coronavirus (SARS-CoV-2), trigger macrophage activation syndrome (MAS) and subsequently hypercytokinemia, commonly referred to as a cytokine storm (CS). It is postulated that CS is mainly responsible for critical COVID-19 cases, including acute respiratory distress syndrome (ARDS). Recognizing the therapeutic potential of Spirulina blue-green algae (Arthrospira platensis), in this in vitro stimulation study, LPS-activated macrophages and monocytes were treated with aqueous extracts of Spirulina, cultivated in either natural or controlled light conditions. We report that an extract of photosynthetically controlled Spirulina (LED Spirulina), at a concentration of 0.1 µg/mL, decreases macrophage and monocyte-induced TNF-α secretion levels by over 70% and 40%, respectively. We propose prompt in vivo studies in animal models and human subjects to determine the putative effectiveness of a natural, algae-based treatment for viral CS and ARDS, and explore the potential of a novel anti-TNF-α therapy.

Is the probable spillage of the lung surfactant dipalmitoylphosphatidylcholine the ultimate source of diabetes type 1?

The lung surfactant dipalmitoylphosphatidylcholine (DPPC) most probably leaks into the blood, settling on the luminal aspect of blood vessels to create active hydrophobic spots (AHS). Nanobubbles are formed at these spots from dissolved gas. We hypothesized that when a large molecule in the blood comes into contact with a nanobubble at the AHS, its tertiary structure is disrupted. An epitope not previously having undergone thymus education may then prompt an autoimmune response. There are thus two independent processes which may share the blame for autoimmune disease: spillage of large molecules into the blood, and the creation of AHS. DPPC was measured in 10 diabetes type 1 patients and 10 control subjects. DPPC in the diabetic group was 4.63 ± 0.68 µg/mL, non-significantly higher than in the control group (4.23 ± 0.94 µg/mL). However, in the diabetic group, DPPC was high when the samples were taken within 1.5 years of disease onset. This is closer to the time of AHS production, which takes place ahead of the disease. Further investigation, with sampling for DPPC as soon as possible after onset of the disease, may provide additional support for our hypothesis. If proved true, this may open up considerable therapeutic potential.