Generation of autoantibodies against glycated fibrinogen: Role in diabetic nephropathy and retinopathy.

The process of glycation, characterized by the non-enzymatic reaction between sugars and free amino groups on biomolecules, is a key contributor to the development and progression of both microvascular and macrovascular complications associated with diabetes, particularly due to persistent hyperglycemia. This glycation process gives rise to advanced glycation end products (AGEs), which play a central role in the pathophysiology of diabetes complications, including nephropathy. The d-ribose-mediated glycation of fibrinogen plays a central role in the pathogenesis of diabetes nephropathy (DN) and retinopathy (DR) by the generation and accumulation of advanced glycation end products (AGEs). Glycated fibrinogen with d-ribose (Rb-gly-Fb) induces structural changes that trigger an autoimmune response by generating and exposing neoepitopes on fibrinogen molecules. The present research is designed to investigate the prevalence of autoantibodies against Rb-gly-Fb in individuals with type 2 diabetes mellitus (T2DM), DN & DR. Direct binding ELISA was used to test the binding affinity of autoantibodies from patients' sera against Rb-gly-Fb and competitive ELISA was used to confirm the direct binding findings by checking the bindings of isolated IgG against Rb-gly-Fb and its native conformer. In comparison to healthy subjects, 32% of T2DM, 67% of DN and 57.85% of DR patients' samples demonstrated a strong binding affinity towards Rb-gly-Fb. Both native and Rb-gly-Fb binding by healthy subjects (HS) sera were non-significant (p > 0.05). Furthermore, the early, intermediate, and end products of glycation have been assessed through biochemical and physicochemical analysis. The biochemical markers in the patient groups were also significant (p < 0.05) in comparison to the HS group. This study not only establishes the prevalence of autoantibodies against d-ribose glycated fibrinogen in DN but also highlights the potential of glycated fibrinogen as a biomarker for the detection of DN and/or DR. These insights may open new avenues for research into novel therapeutic strategies and the prevention of diabetes-related nephropathy and retinopathy.

D-ribose metabolic disorder and diabetes mellitus.

D-ribose, an ubiquitous pentose compound found in all living cells, serves as a vital constituent of numerous essential biomolecules, including RNA, nucleotides, and riboflavin. It plays a crucial role in various fundamental life processes. Within the cellular milieu, exogenously supplied D-ribose can undergo phosphorylation to yield ribose-5-phosphate (R-5-P). This R-5-P compound serves a dual purpose: it not only contributes to adenosine triphosphate (ATP) production through the nonoxidative phase of the pentose phosphate pathway (PPP) but also participates in nucleotide synthesis. Consequently, D-ribose is employed both as a therapeutic agent for enhancing cardiac function in heart failure patients and as a remedy for post-exercise fatigue. Nevertheless, recent clinical studies have suggested a potential link between D-ribose metabolic disturbances and type 2 diabetes mellitus (T2DM) along with its associated complications. Additionally, certain in vitro experiments have indicated that exogenous D-ribose exposure could trigger apoptosis in specific cell lines. This article comprehensively reviews the current advancements in D-ribose's digestion, absorption, transmembrane transport, intracellular metabolic pathways, impact on cellular behaviour, and elevated levels in diabetes mellitus. It also identifies areas requiring further investigation.

Oxolane Ammonium Salts (Muscarine-Like)-Synthesis and Microbiological Activity.

Commercially available 2-deoxy-D-ribose was used to synthesize the appropriate oxolane derivative-(2R,3S)-2-(hydroxymethyl)oxolan-3-ol-by reduction and dehydration/cyclization in an acidic aqueous solution. Its monotosyl derivative, as a result of the quaternization reaction, allowed us to obtain eight new muscarine-type derivatives containing a quaternary nitrogen atom and a hydroxyl group linked to the oxolane ring. Their structure was fully confirmed by the results of NMR, MS and IR analyses. The crystal structure of the pyridinium derivative showed a high similarity of the conformation of the oxolane ring to previously published crystal structures of muscarine. Two reference strains of Gram-negative bacteria (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853), two reference strains of Gram-positive staphylococci (Staphylococcus aureus ATCC 25923 and Staphylococcus aureus ATCC 29213) and four reference strains of pathogenic yeasts of the genus Candida spp. (Candida albicans SC5314, Candida glabrata DSM 11226, Candida krusei DSM 6128 and Candida parapsilosis DSM 5784) were selected for the evaluation of the antimicrobial potential of the synthesized compounds. The derivative containing the longest (decyl) chain attached to the quaternary nitrogen atom turned out to be the most active.

Phase I Single Ascending Dose and Food Effect Study in Healthy Adults and Phase I/IIa Multiple Ascending Dose Study in Patients with Pulmonary Tuberculosis to Assess Pharmacokinetics, Bactericidal Activity, Tolerability, and Safety of OPC-167832.

OPC-167832, an inhibitor of decaprenylphosphoryl-ß-d-ribose 2'-oxidase, demonstrated potent antituberculosis activity and a favorable safety profile in preclinical studies. This report describes the first two clinical studies of OPC-167832: (i) a phase I single ascending dose (SAD) and food effects study in healthy participants; and (ii) a 14-day phase I/IIa multiple ascending dose (MAD; 3/10/30/90 mg QD) and early bactericidal activity (EBA) trial in participants with drug-susceptible pulmonary tuberculosis (TB). OPC-167832 was well tolerated at single ascending doses (10 to 480 mg) in healthy participants and multiple ascending doses (3 to 90 mg) in participants with TB. In both populations, nearly all treatment-related adverse events were mild and self-limiting, with headache and pruritus being the most common events. Abnormal electrocardiograms results were rare and clinically insignificant. In the MAD study, OPC-167832 plasma exposure increased in a less than dose-proportional manner, with mean accumulation ratios ranging from 1.26 to 1.56 for Cmax and 1.55 to 2.01 for area under the concentration-time curve from 0 to 24 h (AUC0-24h). Mean terminal half-lives ranged from 15.1 to 23.6 h. Pharmacokinetics (PK) characteristics were comparable to healthy participants. In the food effects study, PK exposure increased by less than ~2-fold under fed conditions compared to the fasted state; minimal differences were observed between standard and high-fat meals. Once-daily OPC-167832 showed 14-day bactericidal activity from 3 mg (log10 CFU mean ± standard deviation change from baseline; -1.69 ± 1.15) to 90 mg (-2.08 ± 0.75), while the EBA of Rifafour e-275 was -2.79 ± 0.96. OPC-167832 demonstrated favorable pharmacokinetic and safety profiles, as well as potent EBA in participants with drug-susceptible pulmonary TB.

Effects of d-ribose on human erythrocytes: Non-enzymatic glycation of hemoglobin, eryptosis, oxidative stress and energy metabolism.

d-Ribose is not only an important component of some biomacromolecules, but also an active pentose with strong reducibility and non-enzymatic glycation ability. Previous studies reported the diverse role of d-ribose in different cells. In this study, the effects of d-ribose on non-enzymatic glycation of hemoglobin (Hb), as well as eryptosis, oxidative stress and energy metabolism of erythrocytes were observed by molecular fluorescence spectrophotometry, multi-wavelength spectrophotometry, high-pressure liquid chromatography (HPLC), mass spectrometry (MS) and flow cytometer. The results showed that d-ribose had the strongest non-enzymatic glycation ability to Hb in vitro when compared with other monosaccharides, and could enter the erythrocytes in a concentration-dependent manner, which was not inhibited by the specific glucose transporter 1 (GLUT1) inhibitor WZB117. In addition, d-ribose incubation increased the HbA1c, hemolysis, eryptosis, and ROS level of erythrocytes significantly more than that of d-glucose, however, no changes were observed in the levels of ATP, NADPH, and other intermediate energy metabolites in d-ribose treatment. Therefore, the strong non-enzymatic glycation ability of d-ribose may play an important role in erythrocyte damage.

Metabolomic profile of seminal plasma from Guzerá bulls (Bos indicus) with contrasting sperm freezability phenotypes.

The present study evaluated the seminal plasma metabolome of Bos indicus Guzerá bulls with good (n = 4) and poor (n = 5) sperm freezability. Animals were raised in natural pasture of a 'Caatinga' ecosystem, in the semi-arid region of Brazil. Seminal plasma samples were subjected to gas chromatography coupled to mass spectrometry and data, analysed using bioinformatics tools (Cytoscape with the MetScape plug-in). Sixty-two metabolites were identified in the bovine seminal plasma. Fatty acids and conjugates and organic compounds were the predominant seminal fluid metabolites, followed by carboxylic acids and derivatives, amino acids, benzenes and steroids and derivatives, carbohydrates and carbohydrate conjugates and prenol lipids. Multivariate analysis indicated a distinct separation of seminal plasma metabolomes from bulls with contrasting sperm freezability. Abundances of propanoic acid, d-ribose and glycine were greater in the seminal plasma of bulls with good sperm freezability. Heptadecanoic acid and undecanoic acid were the predominant in bulls of poor sperm freezability. Propanoic acid is an energy source for spermatozoa and may act as an antimicrobial component in semen. Glycine acts against oxidizing and denaturing reactions. d-ribose is also an energy source and reduces apoptosis and oxidative stress. Undecanoic acid may protect sperm against fungal damage. This study provides fundamental information approximately the seminal plasma metabolome of tropically adapted bulls and its association with sperm freezability. However, further studies with larger groups of animals are needed to validate those metabolites as markers of sperm freezability. This strategy could support the selection of sires with superior sperm cryoresistance.

Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1-Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

Rapid Assembly of Pyrrole-Ligated 1,3,4-Oxadiazoles and Excellent Antibacterial Activity of Iodophenol Substituents.

Pyrrole-ligated 1,3,4-oxadiazole is a very important pharmacophore which exhibits broad therapeutic effects such as anti-tuberculosis, anti-epileptic, anti-HIV, anti-cancer, anti-inflammatory, antioxidant, and antibacterial activities. A one-pot Maillard reaction between D-Ribose and an L-amino methyl ester in DMSO with oxalic acid at 2.5 atm and 80 °C expeditiously produced pyrrole-2-carbaldehyde platform chemicals in reasonable yields, which were utilized for the synthesis of pyrrole-ligated 1,3,4-oxadiazoles. Benzohydrazide reacted with the formyl group of the pyrrole platforms to provide the corresponding imine intermediates, which underwent I2-mediated oxidative cyclization to the pyrrole-ligated 1,3,4-oxadiazole skeleton. The structure and activity relationship (SAR) of the target compounds with varying alkyl or aryl substituents of the amino acids and electron-withdrawing or electron-donating substituents on the phenyl ring of benzohydrazide were evaluated for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii as representative Gram(-) and Gram(+) bacteria. Branched alkyl groups from the amino acid showed better antibacterial activities. Absolutely superior activities were observed for 5f-1 with an iodophenol substituent against A. baumannii (MIC < 2 µg/mL), a bacterial pathogen that displays a high resistance to commonly used antibiotics.

Functional investigation of the antitubercular drug target Decaprenylphosphoryl-ß-D-ribofuranose-2-epimerase DprE1/DprE2 complex.

Tuberculosis (TB) is one of the leading causes of death worldwide, due to a single pathogen, Mycobacterium tuberculosis. To eradicate TB, management of drug-resistant strains is fundamental, therefore, the identification and characterization of drug targets is pivotal. In this work we aim at describing the relationships with the well-known drug target DprE1 and DprE2, working in association for the biosynthesis of the arabinogalactan precursor, essential component of mycobacterial cell wall. We demonstrated that the enzymes behave as a stable heterodimeric complex, once co-expressed into the same system. This complex showed improved catalytic properties, compared to the singularly expressed enzymes, demonstrating that co-expression is fundamental to achieve the proper folding of the active sites. Our results represent an important step forward in deciphering the functional properties of these enzymes, and lay the foundations for structural studies, useful for development of more specific inhibitors helpful to contrast the spreading of drug-resistant strains.

Synthetic Supramolecular Host for D-(-)-Ribose: Ratiometric Fluorescence Response via Multivalent Lectin-Carbohydrate Interactions.

Easily synthesizable, carbazole-based organic nanoaggregates have been designed for selective detection of D-(-)-ribose at physiological pH. The addition of D-ribose results in a ratiometric change in fluorescence color from green to cyan (LOD: ∼12 µM). The mechanistic studies indicate the presence of multipoint noncovalent interactions, such as hydrogen bonding and CH⋅⋅⋅π interactions between D-ribose and acyl hydrazone and terminal pyridyl units of the probe molecule. However, such multipoint interactions dissociate the preformed self-assembled nanoclusters and induce change in optical response. The probe molecule was further exploited in analyzing D-ribose content in biological fluids (diluted human urine and blood serum) and oral supplements. The small standard deviation values (2-3.8 %) with nearly quantitative recovery (93.5-105.5 %) indicate the high accuracy of the presented method. Further, low-cost portable device based coated paper strips were designed for 'on-location' rapid, detection of D-ribose even at remote locations.

Synthetic Activity of Recombinant Whole Cell Biocatalysts Containing 2-Deoxy-D-ribose-5-phosphate Aldolase from Pectobacterium atrosepticum.

In nature 2-deoxy-D-ribose-5-phosphate aldolase (DERA) catalyses the reversible formation of 2-deoxyribose 5-phosphate from D-glyceraldehyde 3-phosphate and acetaldehyde. In addition, this enzyme can use acetaldehyde as the sole substrate, resulting in a tandem aldol reaction, yielding 2,4,6-trideoxy-D-erythro-hexapyranose, which spontaneously cyclizes. This reaction is very useful for the synthesis of the side chain of statin-type drugs used to decrease cholesterol levels in blood. One of the main challenges in the use of DERA in industrial processes, where high substrate loads are needed to achieve the desired productivity, is its inactivation by high acetaldehyde concentration. In this work, the utility of different variants of Pectobacterium atrosepticum DERA (PaDERA) as whole cell biocatalysts to synthesize 2-deoxyribose 5-phosphate and 2,4,6-trideoxy-D-erythro-hexapyranose was analysed. Under optimized conditions, E. coli BL21 (PaDERA C-His AA C49M) whole cells yields 99 % of both products. Furthermore, this enzyme is able to tolerate 500 mM acetaldehyde in a whole-cell experiment which makes it suitable for industrial applications.

Nonenzymatic glycosylation of isolated human immunoglobulin-G by D-ribose.

Glycation is vital in terms of its damaging effect on macromolecules resulting in the formation of end products, which are highly reactive and cross-linked irreversible structures, known as advanced glycation end products (AGEs). The continuous accumulation of AGEs is associated with severe diabetes and its associated ailments. Saccharides with their reducing ends can glycate amino acid side chains of proteins, among them glucose is well-known for its potent glycating capability. However, other reducing sugars can be more reactive glycating agents than glucose. The D-ribose is a pentose sugar-containing an active aldehyde group in its open form and is responsible for affecting the biological processes of the cellular system. D-ribose, a key component of many biological molecules, is more reactive than most reducing sugars. Protein glycation by reducing monosaccharides such as D-ribose promotes the accelerated formation of AGEs that could lead to cellular impairments and dysfunctions. Also, under a physiological cellular state, the bioavailability rate of D-ribose is much higher than that of glucose in diabetes, which makes this species much more active in protein glycation as compared with D-glucose. Due to the abnormal level of D-ribose in the biological system, the glycation of proteins with D-ribose needs to be analyzed and addressed carefully. In the present study, human immunoglobulin G (IgG) was isolated and purified via affinity column chromatography. D-ribose at 10 and 100 mM concentrations was used as glycating agent, for 1-12 days of incubation at 37°C. The postglycation changes in IgG molecule were characterized by UV-visible and fluorescence spectroscopy, nitroblue tetrazolium assay, and various other physicochemical analyses for the confirmation of D-ribose mediated IgG glycation.

Antiglycation potential of plant based TiO2 nanoparticle in D-ribose glycated BSA in vitro.

Biosynthetic procedure is one of the best alternatives, inexpensive and ecologically sound for the synthesis of titanium dioxide (TiO2 ) nanoparticles using a methanolic extract of medicinal plant. The main prospect of this study was to investigate the antiglycation activity of the TiO2 nanoparticles (TNP) prepared by ethanolic leaf extract of the Coleus scutellarioides. In this study, biosynthesized TNP characterized with UV-Visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscope. These TNP were further investigated with respect to their antiglycation property and it was checked in the mixture of d-ribose glycated bovine serum albumin (BSA) by measuring ketoamine, carbonyl content, Advanced glycation end products (AGEs) and aggregation of protein instigated by glycation process. The inhibitory effect of TNP to restore the structure of BSA in presence of d-ribose were also characterize by biophysical techniques mentioned above. Therefore, the findings of this study suggest repurposing of TNP for its antiglycation property that could be helpful in prevention of glycation instigated AGEs formation and structural loss of proteins.

Urine D-ribose levels correlate with cognitive function in community-dwelling older adults.

BACKGROUND: D-ribose is involved in the pathogenesis of Alzheimer's Disease. The study aimed to determine the association between D-ribose and cognitive function in a sample of community-dwelling older adults. METHODS: A cross-sectional study was conducted in Chaoyang District, Beijing in 2019-2020. Eligible participants were community-based older adults aged 60 years and above. D-ribose was analyzed from the morning urine. Cognitive function, subjective cognitive decline, and depressive symptoms were measured by a battery of neuropsychological tests. Linear regressions were performed to determine the relationship between the urine D-ribose levels and cognitive performance. RESULTS: A sample of 1725 participants (67.1% female) aged 60 to 85 years (69.40 ± 5.87 years, mean ± SD) was enrolled in the analysis. The urine D-ribose concentrations ranged from 1.53 to 208.89 µmol/L (median 38.10 µmol/L; interquartile range 22.52-64.96 µmol/L). Higher levels of D-ribose were associated with worse performance on Mini-Mental State Examination and verbal fluency when age, gender, education, depressive symptoms, and cardiovascular risk factors were included as covariates. CONCLUSIONS: The urine D-ribose was negatively correlated with cognitive function in community-dwelling older adults. The findings suggest that the dysmetabolism of D-ribose may play a role at the early stage of cognitive impairment.

D-ribose-L-cysteine modulates lead acetate-induced hematobiochemical alterations, hormonal imbalance, and ovarian toxicity in adult female Wistar rats.

Lead is a common environmental toxicant associated greatly with hematological and hormonal imbalance, biochemical alterations, and reproductive abnormalities. This study was conducted to evaluate the effects of D-ribose-L-cysteine (DRLC) on hematobiochemical and reproductive toxicity associated with lead acetate exposure in adult female Wistar rats. Thirty-two adult female Wistar rats (165 ± 20 g) were divided into four groups (n = 8). Group A received normal saline as placebo; Group B received 100 mg/kg BW of lead acetate only; Group C received 100 mg/kg BW of lead acetate and 10 mg/kg BW DRLC (low dose); Group D received 100 mg/kg BW of lead acetate and 30 mg/kg BW of DRLC (high dose). All administration was done via oral gavage for 42 days, thereafter animals were sacrificed; serum was obtained from the blood collected for analysis, ovaries, and uterus was harvested for analysis. The lead acetate only group showed a significant difference in hematological indices relative to control. Additionally, there was a significant decrease in body weight, sodium dismutase, catalase, reduced glutathione, progesterone with a corresponding increase in ovarian weight, MDA, FSH, and LH among the lead acetate only group relative to the control. Histological observation showed atretic antral follicles, with detached granulosa cells, pyknotic nuclei in the granulosa wall in the ovaries of the lead-exposed only group compared to the control. Co-administration of DRLC and lead attenuate the toxicity of lead exposure by restoring the hematological values, biochemical parameters, hormone profile, and morphology of the ovary. Exposure to lead acetate causes deleterious toxicity to hematological and reproductive functions which were ameliorated DRLC supplementation through its antioxidant mechanisms.

D-Ribose-Induced Glycation and Its Attenuation by the Aqueous Extract of Nigella sativa Seeds.

Background and Objectives: Glycation and oxidative stress are the major contributing factors responsible for diabetes and its secondary complications. Aminoguanidine, a hydrazine derivative, is the only approved drug that reduces glycation with its known side effects. As a result, research into medicinal plants with antioxidant and antiglycation properties is beneficial in treating diabetes and its consequences. This investigation aimed to examine the efficacy of the aqueous extract of Nigella sativa seeds against the D-ribose-induced glycation system. Materials and Methods: The suppression of α-amylase and α-glucosidase enzymes were used to assess the antidiabetic capacity. UV-Visible, fluorescence, and FTIR spectroscopy were used to characterize the Nigella sativa seed extract and its efficacy in preventing glycation. The inhibition of albumin glycation, fluorescent advanced glycation end products (AGEs) formation, thiol oxidation, and amyloid formation were used to evaluate the extracts' antiglycation activity. In addition, the extent of glycoxidative DNA damage was analyzed using agarose gel electrophoresis. Results: The IC50 for the extract in the α-amylase and α-glucosidase enzyme inhibition assays were approximately 1.39 ± 0.016 and 1.01 ± 0.022 mg/mL, respectively. Throughout the investigation, it was found that the aqueous extract of Nigella sativa seeds (NSAE) inhibited the level of ketoamine, exerted a considerable drop in fluorescence intensity, and reduced carbonyl production and thiol modification when added to the D-ribose-induced glycation system. In addition, a reduction in the BSA-cross amyloid formation was seen in the Congo red, thioflavin T assay, and electrophoretic techniques. NSAE also exhibited a strong capability for DNA damage protection. Conclusion: It can be concluded that Nigella sativa could be used as a natural antidiabetic, antiglycation treatment and a cost-effective and environmentally friendly source of powerful bioactive chemicals.

Rational design to enhance the catalytic activity of 2-deoxy-D-ribose-5-phosphate aldolase from Pseudomonas syringae pv. syringae B728a.

The 2-Deoxy-d-ribose-5-phosphate aldolase (DERA) enzyme in psychrophilic bacteria has gradually attracted the attention of researchers. A novel gene, deoC (681 bp), encoding DERAPsy, was identified in Pseudomonas syringae pv. syringae B728a, recombinantly expressed in E. coli BL21 and purified via affinity chromatography, which yielded a homodimeric enzyme of 23 kDa. The specific activity of DERAPsy toward 2-deoxy-d-ribose-5-phosphate (DR5P) was 7.37 ± 0.03 U/mg, and 61.32% of its initial activity remained after incubation in 300 mM acetaldehyde at 25 °C for 2 h. Based on the calculation results (dock binding free energy) with the ligand chloroacetaldehyde (CAH), five target substitutions (T16L, F69R, V66K, S188V, and G189R) were identified, in which the DERAPsy mutant (G189R) exhibited higher catalytic activity toward DR5P than DERAPsy. Only the DERAPsy mutant (V66K) exhibited 12% higher activity toward chloroacetaldehyde and acetaldehyde condensation reactions than DERAPsy. Fortunately, the aldehyde tolerance of these mutants exhibited no significant decline compared with the wild type. These results indicate an effective strategy for enhancing DERA activity.

Developing Wound Dressings Using 2-deoxy-D-Ribose to Induce Angiogenesis as a Backdoor Route for Stimulating the Production of Vascular Endothelial Growth Factor.

2-deoxy-D-Ribose (2dDR) was first identified in 1930 in the structure of DNA and discovered as a degradation product of it later when the enzyme thymidine phosphorylase breaks down thymidine into thymine. In 2017, our research group explored the development of wound dressings based on the delivery of this sugar to induce angiogenesis in chronic wounds. In this review, we will survey the small volume of conflicting literature on this and related sugars, some of which are reported to be anti-angiogenic. We review the evidence of 2dDR having the ability to stimulate a range of pro-angiogenic activities in vitro and in a chick pro-angiogenic bioassay and to stimulate new blood vessel formation and wound healing in normal and diabetic rat models. The biological actions of 2dDR were found to be 80 to 100% as effective as VEGF in addition to upregulating the production of VEGF. We then demonstrated the uptake and delivery of the sugar from a range of experimental and commercial dressings. In conclusion, its pro-angiogenic properties combined with its improved stability on storage compared to VEGF, its low cost, and ease of incorporation into a range of established wound dressings make 2dDR an attractive alternative to VEGF for wound dressing development.

Identification of the Protein Glycation Sites in Human Myoglobin as Rapidly Induced by d-Ribose.

Protein glycation is an important protein post-translational modification and is one of the main pathogenesis of diabetic angiopathy. Other than glycated hemoglobin, the protein glycation of other globins such as myoglobin (Mb) is less studied. The protein glycation of human Mb with ribose has not been reported, and the glycation sites in the Mb remain unknown. This article reports that d-ribose undergoes rapid protein glycation of human myoglobin (HMb) at lysine residues (K34, K87, K56, and K147) on the protein surface, as identified by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). Moreover, glycation by d-ribose at these sites slightly decreased the rate of the met heme (FeIII) in reaction with H2O2 to form a ferryl heme (FeIV=O). This study provides valuable insight into the protein glycation by d-ribose and provides a foundation for studying the structure and function of glycated heme proteins.

d-Ribose Catabolism in Archaea: Discovery of a Novel Oxidative Pathway in Haloarcula Species.

The Haloarcula species H. marismortui and H. hispanica were found to grow on d-ribose, d-xylose, and l-arabinose. Here, we report the discovery of a novel promiscuous oxidative pathway of pentose degradation based on genome analysis, identification and characterization of enzymes, transcriptional analysis, and growth experiments with knockout mutants. Together, the data indicate that in Haloarcula spp., d-ribose, d-xylose, and l-arabinose were degraded to α-ketoglutarate involving the following enzymes: (i) a promiscuous pentose dehydrogenase that catalyzed the oxidation of d-ribose, d-xylose, and l-arabinose; (ii) a promiscuous pentonolactonase that was involved in the hydrolysis of ribonolactone, xylonolactone, and arabinolactone; (iii) a highly specific dehydratase, ribonate dehydratase, which catalyzed the dehydration of ribonate, and a second enzyme, a promiscuous xylonate/gluconate dehydratase, which was involved in the conversion of xylonate, arabinonate, and gluconate. Phylogenetic analysis indicated that the highly specific ribonate dehydratase constitutes a novel sugar acid dehydratase family within the enolase superfamily; and (iv) finally, 2-keto-3-deoxypentanonate dehydratase and α-ketoglutarate semialdehyde dehydrogenase catalyzed the conversion of 2-keto-3-deoxypentanonate to α-ketoglutarate via α-ketoglutarate semialdehyde. We conclude that the expanded substrate specificities of the pentose dehydrogenase and pentonolactonase toward d-ribose and ribonolactone, respectively, and the presence of a highly specific ribonate dehydratase are prerequisites of the oxidative degradation of d-ribose in Haloarcula spp. This is the first characterization of an oxidative degradation pathway of d-ribose to α-ketoglutarate in archaea.IMPORTANCE The utilization and degradation of d-ribose in archaea, the third domain of life, have not been analyzed so far. We show that Haloarcula species utilize d-ribose, which is degraded to α-ketoglutarate via a novel oxidative pathway. Evidence is presented that the oxidative degradation of d-ribose involves novel promiscuous enzymes, pentose dehydrogenase and pentonolactonase, and a novel sugar acid dehydratase highly specific for ribonate. This is the first report of an oxidative degradation pathway of d-ribose in archaea, which differs from the canonical nonoxidative pathway of d-ribose degradation reported for most bacteria. The data contribute to our understanding of the unusual sugar degradation pathways and enzymes in archaea.