Acinetobacter baumannii is a Gram‐negative bacterium commonly found in soil and water that can cause human infections of the blood, lungs, and urinary tract. Of particular concern is its prevalence ...in health‐care settings where it can survive on surfaces and shared equipment for extended periods of time. The capsular polysaccharide surrounding the organism is known to be the major contributor to virulence. The structure of the K57 capsular polysaccharide produced by A. baumannii isolate BAL_212 from Vietnam was recently shown to contain the rare sugar 4‐acetamido‐4,6‐dideoxy‐d‐glucose. Three enzymes are required for its biosynthesis, one of which is encoded by the gene H6W49_RS17300 and referred to as VioB, a putative N‐acetyltransferase. Here, we describe a combined structural and functional analysis of VioB. Kinetic analyses show that the enzyme does, indeed, function on dTDP‐4‐amino‐4,6‐dideoxy‐d‐glucose with a catalytic efficiency of 3.9 x 104 M−1 s−1 (±6000), albeit at a reduced value compared to similar enzymes. Three high‐resolution X‐ray structures of various enzyme/ligand complexes were determined to resolutions of 1.65 Å or better. One of these models represents an intermediate analogue of the tetrahedral transition state. Differences between the VioB structure and those determined for the N‐acetyltransferases from Campylobacter jejuni (PglD), Caulobacter crescentus (PerB), and Psychrobacter cryohalolentis (Pcryo_0637) are highlighted. Taken together, this investigation sheds new insight into the Type I sugar N‐acetyltransferases.
Recent technological advancements have increased the efficacy of radiotherapy, leading to effective management of cancer patients with enhanced patient survival and improved quality of life. Several ...important developments like multileaf collimator, integration of imaging techniques like positron emission tomography (PET) and computed tomography (CT), involvement of advanced dose calculation algorithms, and delivery techniques have increased tumor dose distribution and decreased normal tissue toxicity. Three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), stereotactic radiotherapy, image-guided radiotherapy (IGT), and particle therapy have facilitated the planning procedures, accurate tumor delineation, and dose estimation for effective personalized treatment. In this review, we present the technological advancements in various types of EBRT methods and discuss their clinical utility and associated limitations. We also reveal novel approaches of using biocompatible yttrium oxide scintillator-photosensitizer complex (YSM) that can generate X-ray induced cytotoxic reactive oxygen species, facilitating X-ray activated photodynamic therapy (XPDT (external beam) and/or iXPDT (internal X-ray source)) and azido-derivatives of 2-deoxy-D-glucose (2-DG) as agents for site-specific radiation-induced DNA damage.
Kaposi's sarcoma‐associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS‐associated malignancy. Effective treatments against KS remain to be developed. The sugar ...analog 2‐deoxy‐
d‐glucose (2‐DG) is an anticancer agent that is well‐tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2‐DG inhibits glycolysis and N‐glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2‐DG with 2‐fluoro‐deoxy‐
d‐glucose, a glycolysis inhibitor, and 2‐deoxy‐fluoro‐
d‐mannose (2‐DFM), a specific N‐glycosylation inhibitor. At doses similar to those clinically achievable with 2‐DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2‐DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2‐DFM, we found that
d‐mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N‐glycosylation is the main antiviral target using
d‐mannose competition experiments. Suppression of N‐glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV‐induced inhibition of the protein kinase R‐like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV‐induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N‐glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2‐DG and the newly identified 2‐DFM as antiviral drugs.
The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. ...Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.
D‐Glucose and 3‐O‐Methyl‐D‐glucose (3OMG) have been shown to provide contrast in magnetic resonance imaging‐chemical exchange saturation transfer (MRI‐CEST) images. However, a systematic comparison ...between these two molecules has yet to be performed. The current study deals with the assessment of the effect of pH, saturation power level (B1) and magnetic field strength (B0) on the MRI‐CEST contrast with the aim of comparing the in vivo CEST contrast detectability of these two agents in the glucoCEST procedure. Phosphate‐buffered solutions of D‐Glucose or 3OMG (20 mM) were prepared at different pH values and Z‐spectra were acquired at several B1 levels at 37°C. In vivo glucoCEST images were obtained at 3 and 7 T over a period of 30 min after injection of D‐Glucose or 3OMG (at doses of 1.5 or 3 g/kg) in a murine melanoma tumor model (n = 3–5 mice for each molecule, dose and B0 field). A markedly different pH dependence of CEST response was observed in vitro for D‐Glucose and 3OMG. The glucoCEST contrast enhancement in the tumor region following intravenous administration (at the 3 g/kg dose) was comparable for both molecules: 1%–2% at 3 T and 2%–3% at 7 T. The percentage change in saturation transfer that resulted was almost constant for 3OMG over the 30‐min period, whereas a significant increase was detected for D‐Glucose. Our results show similar CEST contrast efficiency but different temporal kinetics for the metabolizable and the nonmetabolizable glucose derivatives in a tumor murine model when administered at the same doses.
This study investigated the CEST properties of D‐Glucose and 3‐O‐Methyl‐D‐glucose (30MG) in vitro and after intravenous injection in a murine melanoma model. A marked and opposite pH dependence of the CEST contrast was observed in vitro for D‐Glucose and 3OMG, whereas both molecules showed a similar CEST enhancement following the in vivo administration at 7 T, but a reduced detectability at 3 T.
Although imaging glucose metabolism with positron emission tomography combined with X-ray CT (FDG-PET/CT) has become a standard diagnostic modality for the discovery and surveillance of malignant ...tumors and inflammatory processes, its origins extend back to more than a century of notable discoveries in the fields of inorganic and organic chemistry, nuclear physics, mathematics, biochemistry, solute transport physiology, metabolism, and imaging, accomplished by pioneering and driven investigators, of whom at least ten were recipients of the Nobel Prize. These tangled and diverse roots eventually coalesced into the FDG-PET/CT method, that through its many favorable characteristics inherent in the isotope used (
18
F), the accurate imaging derived from coincidence detection of positron annihilation radiation combined with computed tomography, and the metabolic trapping of 2-deoxy-2-
18
Ffluoro-
d
-glucose (FDG) in tissues, provides safety, sensitivity, and specificity for tumor and inflammation detection. The authors hope that this article will increase the appreciation among its readers of the insight, creativity, persistence, and drive of the many investigators who made this technique possible. This article is followed by a review of the many applications of FDG-PET/CT to the gastrointestinal tract and hepatobiliary system (Mandelkern in Dig Dis Sci 2022).
N‐acetylated sugars are often found, for example, on the lipopolysaccharides of Gram‐negative bacteria, on the S‐layers of Gram‐positive bacteria, and on the capsular polysaccharides. Key enzymes ...involved in their biosynthesis are the sugar N‐acetyltransferases. Here, we describe a structural and functional analysis of one such enzyme from Helicobacter pullorum, an emerging pathogen that may be associated with gastroenteritis and gallbladder and liver diseases. For this analysis, the gene BA919‐RS02330 putatively encoding an N‐acetyltransferase was cloned, and the corresponding protein was expressed and purified. A kinetic analysis demonstrated that the enzyme utilizes dTDP‐3‐amino‐3,6‐dideoxy‐d‐glucose as a substrate as well as dTDP‐3‐amino‐3,6‐dideoxy‐d‐galactose, albeit at a reduced rate. In addition to this kinetic analysis, a similar enzyme from Helicobacter bilis was cloned and expressed, and its kinetic parameters were determined. Seven X‐ray crystallographic structures of various complexes of the H. pullorum wild‐type enzyme (or the C80T variant) were determined to resolutions of 1.7 Å or higher. The overall molecular architecture of the H. pullorum N‐acetyltransferase places it into the Class II left‐handed‐β‐helix superfamily (LβH). Taken together, the data presented herein suggest that 3‐acetamido‐3,6‐dideoxy‐d‐glucose (or the galactose derivative) is found on either the H. pullorum O‐antigen or in another of its complex glycoconjugates. A BLAST search suggests that more than 50 non‐pylori Helicobacter spp. have genes encoding N‐acetyltransferases. Given that there is little information concerning the complex glycans in non‐pylori Helicobacter spp. and considering their zoonotic potential, our results provide new biochemical insight into these pathogens
PDB Code(s): 7s3u, 7s3w, 7s41, 7s42, 7s43, 7s44 and 7s45;
Effects of α-
d- and β-
d-glucose as electron donors on photocatalytic hydrogen generation over Pt/TiO
2 have been investigated. α-
d-Glucose exhibits better photocatalytic activity for hydrogen ...evolution than β-
d-glucose. The effects of initial pH of the anomer solutions on photocatalytic hydrogen generation have also been studied. Weak basic condition is favorable for the photocatalytic hydrogen generation. There is a large activity difference between α-
d- and β-
d-glucose under neutral condition, while the difference is very small under basic and acidic conditions. The possible mechanism was discussed.
α-
d-Glucose as an electron donor exhibits better photocatalytic activity for hydrogen evolution than β-
d-glucose.
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► We investigate effect of epimerization of
d-glucose on photocatalytic H
2 evolution. ► α-
d-glucose exhibits better activity for the H
2 evolution than β-
d-glucose. ► α-
d-glucose exhibits higher reactivity with hydroxyl radical than β-
d-glucose.
Starvation therapy aims to “starve” tumor cells by cutting off their nutritional supply. However, due to the complex and varied energy metabolism of tumors, targeting a single nutrient supply often ...fails to yield significant therapeutic benefits. This study proposes a tumor energy cocktail therapy that combines metformin, an oxidative phosphorylation inhibitor, with 2-deoxy-d-glucose (2-DG), a glycolysis inhibitor, to target tumor cells. To minimize the dosage of both drugs, we have developed a drug delivery strategy that prepared metformin as a nanoderivative, denoted as MA-dots. These MA-dots not only preserve the antitumor properties of metformin but also serve as a targeted delivery platform for 2-DG, ensuring its direct reach to the tumor site. Upon reaching the acidic tumor environment, the composite disintegrates, releasing 2-DG to inhibit glycolysis by targeting hexokinase 2 (HK2), the key enzyme in glycolysis, while MA-dots inhibit mitochondrial OXPHOS. This dual action significantly reduces ATP production in tumor cells, leading to apoptosis. In human lung tumor cells, the half-maximal inhibitory concentration (IC50) of 2-DG@MA-dots was significantly lower than that of either metformin or 2-DG alone, showing a nearly 100-fold and 30-fold reduction in IC50 values to 11.78 µg mL−1, from 1159 µg mL−1 and 351.20 µg mL−1, respectively. In studies with A549 tumor-bearing mice, the combination of low-dose 2-DG and metformin did not impede tumor growth, whereas 2-DG@MA-dots markedly decreased tumor volume, with the mean final tumor volume in the combination treatment group being approximately 89 times greater than that in the 2-DG@MA-dot group.
Metformin is a promising antitumor agent capable of modulating mitochondrial oxidative phosphorylation to inhibit cancer growth. However, its antitumor efficacy is limited when used alone due to compensatory energy mechanisms. Hence, we introduced glycolysis inhibitor 2-deoxy-d-glucose (2-DG) to inhibit an alternative tumor energy pathway. In our study, we developed a drug delivery strategy using metformin-derived nanomedicine (MA-dots) to load 2-DG. This approach enables the co-delivery of both drugs and their synergistic effect at the tumor site, disrupting both energy pathways and introducing an innovative “energy cocktail therapy”.
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Background
We evaluated the ability of different (18F)fluoro‐deoxy‐d‐glucose (FDG)‐positron emission tomography (PET)‐based and magnetic resonance (MR)‐based parameters to identify prevertebral space ...(PVS) infiltration by hypopharyngeal carcinoma.
Methods
Retrospective study on 59 patients with advanced hypopharyngeal squamous cell carcinoma undergoing cross‐sectional imaging and triple endoscopy for staging.
Results
Obliteration of retropharyngeal fat plane on T1‐weighted MR images was found more often (P < .001) in tumors fixated to the PVS. Complete fat plane obliteration best predicted tumor fixation to PVS (accuracy 99%; CI: 97%‐100%; P < .001). With similar accuracy, PET‐based models predicted PVS fixation (combination of standardized uptake value SUVmax of the primary tumor and presence of focal FDG‐uptake in prevertebral muscles accuracy 98%; CI 94%‐100%; P < .001; metabolic tumor volume MTV accuracy 98%; CI 95%‐100%; P < .001).
Conclusion
Both the MR‐based parameter of complete fat plane obliteration and PET‐based models (increased SUVmax in combination with presence of focal FDG‐uptake of prevertebral muscles; increased MTV) predict PVS involvement independently with high accuracy.