Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

Production of L-sorbose from D-sorbitol by Gluconobacter oxydans is the first step to produce L-ascorbic acid on industrial scale. The sldhAB gene, which encodes the sorbitol dehydrogenase (SLDH), was overexpressed in an industrial strain G. oxydans WSH-003 with a strong promoter, P tufB . To enhance the mRNA abundance, a series of artificial poly(A/T) tails were added to the 3'-terminal of sldhAB gene. Besides, their role in sldhAB overexpression and their subsequent effects on L-sorbose production were investigated.

Abstract: Photothermal therapy (PTT) using a near-infrared (NIR) heptamethine cyanine fluorophore has emerged as an alternative strategy for targeted cancer therapy. NIR fluorophores showing a high molar extinction coefficient and low fluorescence quantum yield have considerable potential applications in photothermal cancer therapy. In this study, a bifunctional sorbitol-ZW800 conjugate was used as an advanced concept of photothermal therapeutic agents for in vivo cancer imaging and therapy owing to the high tumor targetability of the sorbitol moiety and excellent photothermal property of NIR heptamethine cyanine fluorophore. The sorbitol-ZW800 showed an excellent photothermal effect increased by 58.7 °C after NIR laser irradiation (1.1 W/cm2) for 5 min. The HT-29 tumors targeted by sorbitol-ZW800 showed a significant decrease in tumor volumes for 7 days after photothermal treatment. Therefore, combining the bifunctional sorbitol-ZW800 conjugate and NIR laser irradiation is an alternative way for targeted cancer therapy, and this approach holds great promise as a safe and highly efficient NIR photothermal agent for future clinical applications.

We report here interesting synergistic effects of proline and sorbitol, two well-known chemical chaperones, in the inhibition of fibrillation of two proteins, insulin and lysozyme. A combination of many biophysical techniques has been used to understand the structural morphology and modes of interaction of the chaperones with the proteins during fibrillation. Both the chaperones establish stronger polar interactions in the elongation and saturation stages of fibrillation compared to that in the native stage. However, when presented as a mixture, we also see contribution of hydrophobic interactions. Thus, a co-operative adjustment of polar and hydrophobic interactions between the chaperones and the protein surface seems to drive the synergistic effects in the fibrillation process. In insulin, this synergy is quantitatively similar in all the stages of the fibrillation process. These observations would have significant implications for understanding protein folding concepts, in general, and for designing combination therapies against protein fibrillation, in particular.

In insects, perception of chemical stimuli is involved in the acceptance or rejection of food. Gustatory receptors (Grs) that regulate external signals in chemosensory organs have been found in many insects. Tribolium castaneum, a major pest of stored products, possesses over 200 Gr genes. An expanded repertoire of Gr genes appears to be required for diet recognition in species that are generalist feeders; however, it remains unclear whether T. castaneum recognizes a suite of chemicals common to many products or whether its feeding is activated by specific chemicals, and whether its Grs are involved in feeding behavior. It is difficult to determine the food preferences of T. castaneum based on dietary intake due to a lack of appropriate methodology. This study established a novel dietary intake estimation method using gypsum, designated the TribUTE (Tribolium Urges To Eat) assay. For this assay, T. castaneum adults were fed a gypsum block without added organic compounds. Sweet preference was determined by adding sweeteners and measuring the amount of gypsum in the excreta. Mannitol was the strongest activator of T. castaneum dietary intake. In a Xenopus oocyte expression, TcGr20 was found to be responsible for mannitol and sorbitol responses, but not for responses to other tested non-volatile compounds. The EC50 values of TcGr20 for mannitol and sorbitol were 72.6 mM and 90.6 mM, respectively, suggesting that TcGr20 is a feasible receptor for the recognition of mannitol at lower concentrations. We used RNAi and the TribUTE assay to examine whether TcGr20 expression was involved in mannitol recognition. The amounts of excreta in TcGr20 dsRNA-injected adults decreased significantly, despite the presence of mannitol, compared to control adults. Taken together, our results indicate that T. castaneum adults recognized mannitol/sorbitol using the TcGr20 receptor, thereby facilitating the dietary intake of these compounds.

Flame retardancy is often required in various textile applications. Halogenated flame retardants (FR) are commonly used since they have good FR performance. Several of these components are listed under REACH. Halogen-free FR compounds have been developed as alternatives. So far, not many biobased FR have made it to the market and are being applied in the textile sector, leaving great opportunities since biobased products are experiencing a renaissance. In this study, renewable FR based on sorbitol and isosorbide were synthesised. The reaction was performed in the melt. The resulting biobased FR were characterised via FT-IR, thermogravimetric analysis (TGA) and X-ray fluorescence (XRF). Cotton fabrics functionalized with the developed biobased FR passed ISO 15025 FR test. After washing, the FR properties of the fabrics decreased (longer afterflame and afterglow time) but still complied with ISO 15025, indicating the biobased FR were semi-permanent. The amount of residue of modified sorbitol and isosorbide measured at 600 °C in air was 31% and 27%, respectively. Cotton treated with biobased modified FR showed no ignition during cone calorimetry experiments, indicating a flame retardancy. Furthermore, a charring of the FR containing samples was observed by means of cone calorimetry and TGA measurements.

Chewing gum containing xylitol may help prevent caries by reducing levels of mutans streptococci (MS) and lactobacilli in saliva and plaque. Very little is known about other species which are possibly beneficial to oral health. In this study, we employed high-throughput sequencing of the 16S rRNA gene to profile microbial communities of saliva and plaque following short-term consumption of xylitol and sorbitol containing chewing gum. Participants (n = 30) underwent a washout period and were randomly assigned to one of two groups. Each group chewed either xylitol or sorbitol gum for three weeks, before undergoing a second four-week washout period after which they switched to the alternate gum for three weeks. Analysis of samples collected before and after each intervention identified distinct plaque and saliva microbial communities that altered dependent on the order in which gum treatments were given. Neither the xylitol nor sorbitol treatments significantly affected the bacterial composition of plaque. Lactobacilli were undetected and the number of Streptococcus mutans sequence reads was very low and unaffected by either xylitol or sorbitol. However, sorbitol affected several other streptococcal species in saliva including increasing the abundance of S. cristatus, an oral commensal shown to inhibit bacteria associated with chronic periodontitis.

No abstract available

Promotion of erythropoietin (EPO) production is important for erythropoiesis as well as cell viability. The most effective inducing factor for EPO production is hypoxia. Hypoxia inducible factor (HIF), a regulator of EPO production, is increased under hypoxic conditions and is also affected by various regulators such as sirtuin1 (SIRT1). SIRT1 is regulated by the cytoplasmic redox state, which is thought to affect EPO production. Therefore, we investigated the effects of sorbitol and lactic acid, which serve as substrates for cellular respiration and bring cells into a reduced state, on EPO production in HepG2 cells. The addition of low-concentration sorbitol to HepG2 cells produced a mildly reduced state similar to that of hypoxia and increased NAD+, SIRT1, and HIF-α, and EPO mRNA expression. On the other hand, lactate suppressed EPO mRNA expression at all concentrations. Inhibition of lactate production from pyruvate abolished the effect of low sorbitol concentrations on EPO mRNA expression. When low-concentration sorbitol and a reducing agent were administered simultaneously, the effect of increasing EPO mRNA expression disappeared. It was suggested that SIRT1 and EPO production increased under conditions where lactate production was not suppressed, even under mildly reduced conditions similar to hypoxia.

Sorbitol dehydrogenase (SDH, EC 1.1.1.14) is the key enzyme involved in sorbitol metabolism in higher plants. SDH genes in some Rosaceae species could be divided into two groups. L-idonate-5-dehydrogenase (LIDH, EC 1.1.1.264) is involved in tartaric acid (TA) synthesis in Vitis vinifera and is highly homologous to plant SDHs. Despite efforts to understand the biological functions of plant SDH, the evolutionary history of plant SDH genes and their phylogenetic relationship with the V. vinifera LIDH gene have not been characterized.

1-Deoxy-D-sorbitol, the 1-deoxy analogue of D-sorbitol, has been detected in human urine as well as in natural herbs and spices. Although there are sporadic reports about 1-deoxy-D-sorbitol dehydrogenase, the complete catabolic pathway of 1-deoxy-D-sorbitol remains unsolved. Informed by the promiscuous activities of fructose-6-phosphate aldolase (FSA) which is involved in the sorbitol (glucitol) utilization (gut) operon and guided by the large scale bioinformatics analysis, we predicted and then experimentally verified the gut operon encoded by Bacillus licheniformis ATCC14580 is responsible for the catabolism of both D-sorbitol and 1-deoxy-D-sorbitol by in vitro activity assays of pathway enzymes, in vivo growth phenotypes, and transcriptomic studies. Moreover, the phylogenetic distribution analysis suggests that the D-sorbitol and 1-deoxy-D-sorbitol catabolic gene cluster is mostly conserved in members of Firmicutes phylum.

The research included corn starch (CS) films using sorbitol (S), glycerol (G), and their combination (SG) as plasticizers at 30, 45, and 60 wt %, with a traditional solution casting technique. The introduction of plasticizer to CS film-forming solutions led to solving the fragility and brittleness of CS films. The increased concentration of plasticizers contributed to an improvement in film thickness, weight, and humidity. Conversely, plasticized films reduced their density and water absorption, with increasing plasticizer concentrations. The increase in the amount of the plasticizer from 30 to 60% showed a lower impact on the moisture content and water absorption of S-plasticized films. The S30-plasticized films also showed outstanding mechanical properties with 13.62 MPa and 495.97 MPa, for tensile stress and tensile modulus, respectively. Glycerol and-sorbitol/glycerol plasticizer (G and SG) films showed higher moisture content and water absorption relative to S-plasticized films. This study has shown that the amount and type of plasticizers significantly affect the appearances, physical, morphological, and mechanical properties of the corn starch biopolymer plastic.

Gelatin-based films modified with sorbitol were produced from gelatin solution or gelatin/starch blends using a simple and low-cost solvent casting method, and subsequently, their physicochemical, mechanical, and biocompatibility properties were characterized. This work focused on developing and optimizing a biopolymeric blend to improve the pure biopolymers' properties for potential biomedical applications such as wound dressing. The films were characterized in terms of morphology and transparency, mechanical, moisture and swelling properties, thermal stability, and degradation potential. Moreover, hemocompatibility, as well as cytocompatibility of prepared films, were examined. The addition of sorbitol contributed to improving mechanical properties, swelling reduction, and increasing biostability over time. The cytocompatibility of obtained films was confirmed in vitro with two different human cell lines, fibroblastic and osteoblastic, and a more favorable cellular response was received for fibroblasts. Further, in hemocompatibility studies, it was found that all films may be classified as non-hemolytic as they did not have a negative effect on the human erythrocytes. The obtained results indicate the great potential of the gelatin/starch blends modified with sorbitol as regenerative biomaterials intended for wound healing applications.

Sorbitol has been reported to have anticancer effects in several tumor models, however its effects on colorectal cancer remain elusive. In the present study, the effects of sorbitol on growth inhibition and apoptosis in the colorectal cancer HCT116 cell line were evaluated and its mechanism of action was examined. An MTT assay was utilized to determine the effect of sorbitol on HCT116 cell proliferation at different time points and variable doses. Western blot analysis was used to examine the effect of sorbitol on apoptosis-related protein expression and the p38 MAPK signaling pathway. The results revealed that sorbitol may inhibit the growth of HCT116 cells in a time- and dose-dependent manner. Following treatment with sorbitol for 3 h, western blotting demonstrated cleavage of the caspase-3 zymogen protein and a cleavage product of poly (ADP-ribose) polymerase (PARP), a known substrate of caspase-3, was also evident. During sorbitol-induced apoptosis, the mitochondrial pathway was activated by a dose-dependent increase in Bax expression and cytochrome c release, while the expression of anti-apoptotic protein Bcl-2 was significantly decreased in a dose-dependent manner. The investigation for the downstream signal pathway revealed that sorbitol-induced apoptosis was mediated by an increase in phosphorylated p38 MAPK expression. Overall, the observations from the present study imply that sorbitol causes increased levels of Bax in response to p38 MAPK signaling, which results in the initiation of the mitochondrial death cascade. Therefore, sorbitol is a promising candidate as a potential chemotherapeutic agent for the treatment of colorectal cancer HCT116 cells.

Gluconobacter oxydans sorbitol dehydrogenase (GoSLDH) exhibits a higher catalytic efficiency than other L-sorbose producing enzymes. During the reaction catalysed by GoSLDH, NADP+ is reduced to NADPH and D-sorbitol is oxidized to L-sorbose. However, GoSLDH activity is inhibited by the NADPH (Ki = 100 μM) formed during the enzymatic reaction. Therefore, Escherichia coligosldh-lrenox producing both GoSLDH for D-sorbitol oxidation and LreNOX (NAD(P)H oxidase from Lactobacillus reuteri) for NADP+ regeneration was generated and used for L-sorbose production. Whole cell biocatalysts with the LreNOX cofactor recycling system showed a high conversion rate (92%) of D-sorbitol to L-sorbose in the presence of low concentration of NADP+ (0.5 mM). By alleviating NADPH accumulation during the catalytic reactions, E. coligosldh-lrenox exhibited 23-fold higher conversion rate of D-sorbitol than E. coligosldh. L-Sorbose production by E. coligosldh-lrenox reached 4.1 g/L after 40 min, which was 20.5-fold higher than that of E. coligosldh. We also constructed G. oxydansgosldh and G. oxydansgosldh-lrenox strains, and they exhibited 1.2- and 2.9-fold higher conversion rates than the wild-type G. oxydans KCTC 1091. The results indicate that overcoming NADPH product inhibition using LreNOX improves chemical production in NADP+-dependent enzymatic reactions.

Short chain dehydrogenases/reductases (SDR) are NAD(P)(H)-dependent oxidoreductases with a highly conserved 3D structure and of an early origin, which has allowed them to diverge into several families and enzymatic activities. The SDR196C family (http://www.sdr-enzymes.org) groups bacterial sorbitol dehydrogenases (SDH), which are of great industrial interest. In this study, we examine the phylogenetic relationship between the members of this family, and based on the findings and some sequence conserved blocks, a new and a more accurate classification is proposed.

Despite novel advances in screening, targeting and immunotherapies, early diagnosis and satisfactory treatments against hepatocellular carcinoma (HCC) remain formidable challenges. Given the unique advantages, carbon quantum dots (CQDs) become a smart theranostic nanomaterial for cancer diagnosis and therapy.

In July 2014, an outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 in England involved 31 patients, 13 (42%) of whom had hemolytic uremic syndrome. Isolates were sequenced, and the sequences were compared with publicly available sequences of E. coli O55:H7 and O157:H7. A core-genome phylogeny of the evolutionary history of the STEC O55:H7 outbreak strain revealed that the most parsimonious model was a progenitor enteropathogenic O55:H7 sorbitol-fermenting strain, lysogenized by a Shiga toxin (Stx) 2a-encoding phage, followed by loss of the ability to ferment sorbitol because of a non-sense mutation in srlA. The parallel, convergent evolutionary histories of STEC O157:H7 and STEC O55:H7 may indicate a common driver in the evolutionary process. Because emergence of STEC O157:H7 as a clinically significant pathogen was associated with acquisition of the Stx2a-encoding phage, the emergence of STEC O55:H7 harboring the stx2a gene is of public health concern.

Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.

The majority of patients with hepatocellular carcinoma (HCC) undergoing curative resection experience tumor recurrence. To examine the association between preoperative serum sorbitol dehydrogenase (SORD), a liver-derived enzyme that reflects liver damage, and recurrence of HCC after curative resection, 92 patients were randomly selected who underwent curative resection for HCC between 2011 and 2012 from a prospective registry. Recurrence-free survival (RFS) was compared based on serum SORD levels. Cox proportional hazard models were used to investigate prognostic factors for RFS. During a median follow-up duration of 57.1 months, 43 patients experienced HCC recurrence. Patients with serum SORD ≥15 ng/mL (HR, 3.46; 95% CI, 1.76-6.81; p < 0.001) had worse RFS compared with patients with serum SORD <15 ng/mL. Serum AFP and SORD levels were two independent prognostic factors for RFS. When patients were stratified by baseline serum SORD and AFP levels, patients with serum AFP levels ≥400 ng/mL and serum SORD levels ≥15 ng/mL had a distinctly poor prognosis with the lowest RFS rates (HR, 22.08; 95% CI, 6.91-70.50; p < 0.001). Baseline serum SORD is an effective prognostic factor for HCC after resection. It may help guide patient selection for surgery, especially when combined with serum AFP levels.