Modulation of Hb-O2 affinity to improve hypoxemia in COVID-19 patients.

This opinion paper aims at discussing the potential impact of modulating the Hb-O2 affinity by the nutritional supplement 5-HMF on patients affected by COVID-19. The paper describes the critical role of the oxygen affinity in hypoxemic COVID-19 patients and the potential positive effect of 5-HMF, a compound shown to increase the Hb-O2 affinity.

5-(Hydroxymethyl)furfural restores low-oxygen rheology of sickle trait blood in vitro.

Sickle cell trait (SCT) is the benign heterozygous carrier state for the sickle variant of the HBB gene. Most of the ~300 million people with SCT worldwide will not experience any significant complications. However, accumulating evidence finds SCT associated with increased risk for the common conditions of chronic kidney disease and venous thromboembolism, and severe but rare renal medullary carcinoma and exercise-induced rhabdomyolysis. The mechanism is uncertain, but probably involves pathological rheology of SCT blood in regions of low oxygen tension, resulting from sickle haemoglobin polymerization in SCT red cells and leading to reduced blood flow and further tissue hypoxia and damage. Here, we used an in vitro microfluidic flow system to study the oxygen-dependent rheology of SCT blood and show that 5-(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose-containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near-normal flow velocities at very low oxygen. While opinions regarding the clinical significance of the risks associated with SCT are still evolving, these results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT.

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease.

Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives. The choice of 5-HMF as a pharmacophore was influenced by a combination of its demonstrated attractive hemoglobin modifying and antisickling properties, well-known safety profiles, and its reported nontoxic major metabolites. The derivatives were investigated for their time- and/or dose-dependent effects on important antisickling parameters, such as modification of hemoglobin, corresponding changes in oxygen affinity, and inhibition of red blood cell sickling. The novel test compounds bound and modified Hb and concomitantly increased the protein affinity for oxygen. Five of the derivatives exhibited 1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding mode of the compounds with Hb was confirmed by X-ray crystallography and, in part, helps explain their observed biochemical properties. Our findings, in addition to the potential therapeutic application, provide valuable insights and potential guidance for further modifications of these (and similar) compounds to enhance their pharmacologic properties.

An altered REDOX environment, assisted by over-expression of fetal hemoglobins, protects from inflammatory colitis and reduces inflammatory cytokine expression.

C5BL/6 female mice receiving dextran sodium sulfate in their drinking water develop an acute inflammatory colitis within 7d, with weight loss, histopathologic signs of inflammation, and colonic expression of inflammatory cytokines. In previous studies we have reported that increased inflammatory cytokine expression in aged mice can be attenuated by oral gavage of a crude fetal extract containing glutathione (GSH), MPLA and fetal hemoglobin, or more specifically by injection of a combination of these purified reagents. We speculated that this combination led to an altered tissue redox environment in which the immune response developed, thus regulating inflammation. Accordingly, we used wild-type (WT) C57BL/6 mice, or mice lacking either murine beta Hemoglobin major (HgbßmaKO) or minor (HgbßmiKO) as recipients of DSS in their drinking water, and followed development of colitis both clinically and by inflammatory cytokine production, before/after oral treatment of mice with a crude fetal liver extract. Mice lacking an intact fetal hemoglobin chain (HgbßmiKO) developed severe colitis, with enhanced colonic expression of inflammatory cytokines, which could not be rescued by extract, unlike WT and HgbßmaKO animals. Moreover, disease in both WT and HgbßmaKO animals could also be attenuated by exposure to 5-hydroxymethyl furfural (5HMF), hydroxyurea or rapamycin. The former has been used as an alternative means of stabilizing the conformation of adult hemoglobin in a manner which mimicks the oxygen-affinity of fetal hemoglobin, while we show that both hydroxyurea and rapamycin augment expression of murine fetal hemoglobin chains. Our data suggests there may be a clinical value in exploring agents which alter local REDOX environments as an adjunctive treatment for colitis and attenuating inflammatory cytokine production.

5-HMF Attenuates Liver Fibrosis in CCl4-Plus-Alcohol-Induced Mice by Suppression of Oxidative Stress.

The aim of this study was to investigate the effects of 5-hydroxymethyl-2-furfural (5-HMF) on liver fibrosis induced by carbon tetrachloride (CCl4) and alcohol. Male ICR mice were treated with CCl4 dissolved in olive oil (10% v/v, 2.5 µg/L) intraperitoneally (i.p.), and given at a dose of 2.5×10-5 mg/kg B.W. twice a week for 7 wk. Concurrently, mice received drinking water with or without alcohol. The mice in treatment groups and positive control group were gavaged with 5-HMF (7.5, 15, and 30 mg/kg B.W.) or Huganpian (350 mg/kg B.W.) daily starting in the fourth week and lasting for 4 wk. The blood samples were analyzed for biochemical markers of hepatic injury and tissue samples were subjected for estimation of liver antioxidants and histopathological studies. The concentrations of HA (hyaluronic acid), LN (laminin), CIV (collagen type IV), and MDA (malondialdehyde), as well as the serum levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) were markedly reduced by 5-HMF. On the other hand, enzymatic antioxidants SOD (superoxide dismutase), CAT (catalase) and GSH-Px (glutathione peroxidase) were markedly elevated in liver tissue treated with 5-HMF. Histopathological examination revealed that 5-HMF treatment noticeably prevented hepatocyte apoptosis, fatty degeneration and inflammatory cell infiltration on liver fibrosis induced by CCl4 and alcohol. Hoechst 33258 staining also revealed hepatocyte apoptosis. 5-HMF could exert protective effects against liver injury and reduce liver fibrosis induced by CCl4 and alcohol in mice.

Ameliorative effects of 5-hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on alcoholic liver oxidative injury in mice.

The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

5-Hydroxymethylfurfural, an antioxidant agent from Alpinia oxyphylla Miq. improves cognitive impairment in Aß 1-42 mouse model of Alzheimer's disease.

5-Hydroxymethylfurfural (5-HMF) is a main effective compound of Alpinia oxyphylla Miq. ethanol extract, which showed memory improvement activity against Alzheimer's disease in previous study. In order to identify a potential therapeutic agent, the neuroprotective effects of 5-HMF on impairment of cognition and memory function induced by intracerebroventricular (ICV) injection of Aß 1-42 were investigated in vivo. The mice were treated with 5-HMF at dose of 15 µg/kg and 150 µg/kg (ICV) for five consecutive days after ICV-Aß 1-42. The results showed that 5-HMF significantly ameliorated learning and memory impairment evaluated by the locomotor activity, Y-maze test, and Morris water maze test. Furthermore, 5-HMF significantly inhibited the ß-secretase activity, decreased the content of Aß 1-42 and malondialdehyde (MDA), and increased the antioxidative enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GPx). Results of hippocampus slices showed that neuronal were integrated and regularly arranged in the groups which were administered along with 5-HMF, indicating that 5-HMF could mitigate the degree of neuronal damage. The present study indicated that 5-HMF may serve as a potential therapeutic agent for the treatment of Alzheimer's disease.

Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin.

The pathophysiology of sickle cell disease involves the polymerization of sickle hemoglobin in its T state, which develops under low oxygen saturation. One therapeutic strategy is to develop pharmacologic agents to stabilize the R state of hemoglobin, which has higher oxygen affinity and is expected to have slower kinetics of polymerization, potentially delaying the sickling of red cells during circulation. This strategy has stimulated the investigation of aromatic aldehydes, aspirin derivatives, thiols, and isothiocyanates that can stabilize the R state of hemoglobin in vitro. One representative aromatic aldehyde agent, 5-hydoxymethyl-2-furfural, protects sickle cell mice from the effects of hypoxia.

Isolation of bioactive phytoconstituent from Alpinia galanga L. with anti-hyperlipidemic activity.

The present study was undertaken to explore the antihyperlipidemic effect of ethanolic extract of rhizomes of Alpinia galanga L. and its chloroform fraction in Triton-induced hyperlipidemic rats. Bioactivity guided fractionation was followed by chromatographic studies. Flash chromatography was done for the most active fraction resulting in the isolation of 5-(hydroxymethyl) furfural. Animals were administered with i.p. injection of Triton WR 1339 at dose of 400 mg/kg body weight. After 24 hr of Triton administration, the ethanolic extract and its fraction were administered orally at doses of 200 and 400 mg/kg body weight in rats. The treatment was continued for 5 days with a view to see the effect on lipid profile. Serum samples were subjected to biochemical analysis. The study dose dependently inhibited the total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) level, and significantly increased high-density lipoprotein (HDL) level. Phytochemical screening revealed the presence of tannins, coumarins, flavanoids, sterols, and glycosides. Phytochemical investigation of the chloroform fraction of A. galanga L. resulted in the isolation of 5-(hydroxymethyl) furfural. UV λmax was found to be 276 nm for the isolated component. Acute treatment caused a stimulatory effect on the HDL level and inhibition in TC and TG elevation induced by triton.

The protective role of 5-hydroxymethyl-2-furfural (5-HMF) against acute hypobaric hypoxia.

Our previous study showed that pretreatment with 5-hydroxymethyl-2-furfural (5-HMF) led to protection against hypoxic injury via a p-ERK-mediated pathway in vitro. Whether the protection of 5-HMF against hypoxia is effective in vivo is unknown. The present study is aimed to verify the role of 5-HMF in acute hypobaric hypoxia using Kunming mice as an in vivo model and further investigate the underlying mechanisms. Mice pretreated with or without 5-HMF for 1 h were exposed to acute hypobaric hypoxic condition for 6 h and then the survival time, the survival rate, the permeability of blood-brain barrier (BBB), the histological analysis in hippocampus and cortex, and the phosphorylation level of mitogen-activated protein kinases (ERK, JNK, and p38) were investigated. The results showed that 5-HMF significantly increased the survival time and the survival rate of mice. Accordingly, pretreatment with 5-HMF markedly attenuated acute hypobaric hypoxia-induced permeability of BBB (P < 0.01). In addition, the cellular damage extent of the hippocampus and the cortex induced by hypoxia for 6 h was also attenuated by pretreatment with 5-HMF, especially in the hippocampus CA1 region. Furthermore, the activation of ERK rather than JNK and p38 was involved in the protection of 5-HMF against acute hypobaric hypoxia. In summary, 5-HMF enhanced the survival capability of mice and decreased acute hypoxic damage to the brain, which may be associated with the effects on BBB and p-ERK.

5-Hydroxymethyl-2-furfural, a clinical trials agent for sickle cell anemia, and its mono/di-glucosides from classically processed steamed Rehmanniae Radix.

Rehmanniae Radix (Di Huang) is one of the most important traditional Chinese medicines (TCM), and is used for multiple therapeutic purposes. In our investigation of the chemical constituents of Rehmanniae Radix, steamed roots were prepared by the classical processing method. Reversed-phase HPLC of the 50% MeOH extract of steamed Rehmanniae Radix yielded three 5-hydroxymethylfurfural derivatives. The new furfural disaccharide 5-(alpha-D-glucopyranosyl-(1-->6)-alpha-D-glucopyranosyloxymethyl)-2-furancarboxaldehyde (1) was isolated and characterized, together with its known aglycone 5-hydroxymethyl-2-furfural (3), which is currently in sickle cell anemia Phase I clinical trials, and its corresponding monosaccharide 5-(alpha-D-glucopyranosyloxymethyl)-2-furancarboxaldehyde (2), which was isolated as a natural product for the first time. The presence of these three compounds, particularly 3, which were not found in the unprocessed extract of Rehmanniae Radix, could substantiate the traditional medicinal use of steamed Rehmanniae Radix.

Alternativa antibiótica en derivados del furfural II: cepas salvajes Gramnegativas / Antibiotic alternative in furaldehyde II derivated: wild strains gram negative

La búsqueda de nuevas drogas contra agentes patógenos tiene hoy en la síntesis unavariante que permite la obtención de numerosos derivados del furfural entre los que sepredice (según estructura química) la posibilidad de bioactividadEl poder antibacteriano de A-51 se estudia mediante experimentación enfrentándolo acepas salvajes de bacterias Gram negativas con el objetivo de calcular la MínimaConcentración Inhibitoria adoptando la metodología NCCLS/92 vigentes para pruebasde susceptibilidad por microdilución en caldo. Los valores se comparan con los deotros principios activos conocidos y es posible arribar a conclusiones sobre el poderantibacteriano del compuesto ensayado, de manera que pueda seguir la ruta críticade estudio teniendo en cuenta las buenas prácticas de laboratorio (AU)

Futura alternativa antibiótica en derivados del furfural: estudio frente a Cepas control / Antibiotic alternative future in derivated of furaldehyde

Numerosas investigaciones han propuesto nuevas sustancias con actividad biológicapara ampliar el espectro terapéutico contra bacterias y hongos levaduriformes que enel mundo actual cobran cada vez mayor poder patógeno tanto para el hombre como enlos animales. Y en Cuba, donde la caña de azúcar y sus derivados (principalmente elfurfural) siguen siendo objeto de estudio nuestro proyecto de investigación hapermitido la opción de que algunos furfuroderivados obtenidos por síntesis funcionalsean sometidos a evaluación de su bioactividad.El objetivo principal del trabajo es calcular MCI a un grupo de sustancias a las que lespredijo actividad antimicrobiana mediante el programa OREX cepas control ATCCsegún la metodología recomendada por NCCLS/92, obteniéndose resultadosfavorables que permiten avalarla para pruebas de toxicidad con vistas al diseño denuevas drogas (AU)

5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells.

In an attempt to find new types of anti-sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5-hydroxymethyl-2-furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high-affinity Schiff-base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Further studies with transgenic (Tg) sickle mice showed that orally administered 5HMF was rapidly absorbed into the bloodstream from the gastrointestinal tract without being destroyed, traversed the red blood cell membrane and specifically bound with, and modified, HbS molecules at levels as high as 90%. Pretreatment of Tg sickle mice with 5HMF inhibited the formation of sickle cells and significantly prolonged survival time under severe hypoxia, compared with untreated mice, which died within 15 min because of sickling-dependent pulmonary sequestration. These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease.

In vitro anti-tyrosinase activity of 5-(hydroxymethyl)-2-furfural isolated from Dictyophora indusiata.

The inhibition of mushroom tyrosinase by methanolic extract of Dictyophora indusiata was evaluated and the bioactive component was characterized and identified as 5-(hydroxymethyl)-2-furfural (HMF) by chromatographic and spectroscopic means. Kinetic studies revealed it to be a noncompetitive inhibitor for the oxidation of L-DOPA. On the basis of these findings some related analogues were also tested for their anti-tyrosinase activity, in order to gain more insight into structure and activity relationship among these heterocyclic compounds.

Specificity of the in vitro interaction of methylfurfural with DNA.

Methylfurfural (MF) or 5-methyl 2-furaldehyde is a dietary mutagen and is present in various food products and beverages. Alkaline unwinding of calf thymus DNA and the protection of cleavage sites in lambda phage DNA from the action of various restriction enzymes was used to study the interaction of MF with DNA. Alkaline unwinding experiments showed the formation of an increasing number of strand breaks in duplex DNA, both with increasing MF concentration and time of reaction. Treatment of lambda phage DNA with MF protected cleavage with restriction endonucleases EcoRI and EcoRI* but not with SmaI and HaeIII. These results indicate that under the conditions used MF reacts exclusively with AT base pairs. A minimum of three to four consecutive AT base pairs is required for this reaction. This was determined by the use of restriction enzymes whose hexanucleotide recognition sequences contain subsets of AT base pairs. Indirect evidence further indicates that modification (possibly alkylation) of DNA bases and phosphates may also occur.