Sorbitol Levels Research Articles

Optimization of Xanthan Gum and Sorbitol Levels in the Mycophenolate Mofetil Powder for Oral Suspension

Background Mycophenolate mofetil as an immunosuppressive agent is widely administered in patients with kidney disorders and following organ transplantation. The amounts of xanthan gum and sorbitol, as two excipients of mycophenolate mofetil, are influential on the final quality and stability of the suspension. Objective In this experimental study, we aim to optimize the levels of xanthan gum and sorbitol in the Mycophenolate mofetil powder. Methods A Central composite design was used to prepare the formulations. The amounts of xanthan gum and sorbitol were considered as independent variables while the sedimentation volume (F value) and concentration of active pharmaceutical ingredient (API) after preparation and after 3 months of storage at 45 ͦC were considered as dependent variables. The samples were prepared through wet granulation process. Chromatography analysis and determination of F value and API were then performed. Results Analysis of variance showed that the increase in the amounts of xanthan up to 75 mg provided higher F value and better protection of API after 3 months by 98%, while the increase of sorbitol from 10 to 25 g had no significant effect on these variables. Optimized sample composed of 16.69 g sorbitol and 68.81 mg xanthan gum. Predicted error was desirably less than 5%. Conclusion The proposed formulation of mycophenolate mofetil powder for oral suspension with optimum amounts of xanthan gum and sorbitol has good stability. High level of xanthan gum and moderate level of sorbitol are recommended for preparing an optimal product.

IMPROVING DROUGHT STRESS TOLERANCE IN POTATO (Solanum tuberosum L.) USING MAGNETITE AND ZINC OXIDE NANOPARTICLES

Potato is a very sensitive to drought stresses, necessitates specific amounts and quality of water. Making substantial changes to increasing tolerances are not easily due to their narrow genetic base. Researchers developed many techniques to reduce the effects of abiotic stress. In current work we studied the effect Nano Particles of Zinc dioxide (ZnO-NPs) and Magnetite (Fe3O4-NPs) at (0.0, 2.5, 5.0 ppm) in elevating the negative effect of drought stress (Sorbitol) at (0.0, 1, 2, 3, 4 Mm) on micropropagation, microtuberization and some biochemical characters, using two potato cultivars (Almond, and Picasso). Maximum mean values were achieved by Almond cultivar and by ZnO-NP in most vegetative, harvesting parameters in vitro. In experiment 1: increases sorbitol levels caused reduction in all parameters inversely, and growth was stopped completely by (0.40) M which considered as a lethal dose to potato explants for both cultivars. In experiment 2: results illustrated that, significant improved due to add nanoparticles of ZnO or Fe3O4 at two concentrations (2.50 and 5.00) ppm on all morphological, harvesting parameters at 0.40 M and 0.3 M of sorbitol. About secondary metabolites: the maximum record of flavonoids (querecetin and kaempferol) and antioxidant capacity was achieved by Almond with sorbitol 0.3M. Almond also recorded the maximum mean of quercetin, kaempferol and, DPPH scavenging activity was decreased in sorbitol 0.3M for both NPs treatments. At 0.4M, secondary enhanced accumulation metabolites and scavenging activity especially at ZnO NPs (5 ppm) and Fe3O4 NPs (2.5 ppm), in quercetin and kaempferol with Fe3O4-NPs (5.0 ppm).

Calcium Biofortification of Rocha Pear Fruits: Implications on Mineral Elements, Sugars and Fatty Acids Accumulation in Tissues

Following an agronomic approach for the Ca enrichment of Rocha pears, this study aimed to assess the interactions between mineral nutrients in fruit tissues at harvest and after storage for 5 months and to characterize the implications on the profile of sugars and fatty acids (FA). A total of seven foliar sprays (with concentrations of 0.1–0.6 kg·ha−1 Ca(NO3)2 and 0.8–8 kg·ha−1 CaCl2) were applied to pear trees. After harvest, the fruits were stored for 5 months, in environmentally controlled chambers, and the mineral contents in five regions (on the equatorial section) of the fruits were assessed, while the sugar and FA content were quantified. For both dates, all foliar sprayed treatments, at different extends, increased Ca content in the center and near the epidermis of Rocha pear fruits and the levels of K, Mn, Fe, Zn and Cu also varied. At harvest, the Ca treatments did not affect the levels of sucrose, glucose, fructose and sorbitol and, after storage, their concentrations remained higher in Ca-treated fruits. Additionally, the tendency of the relative proportions of FA was C18:2 > C18:1 > C16:0 > C18:3 > C18:0 > chains inferior to 16 C (<16:0), but after storage it was C18:2 > C16:0 > C18:3 > C18:0 > C18:1 > chains inferior to 16 C (<16:0). It is concluded that the heterogeneous distribution of Ca in the tissues of Rocha pear fruits results from its absorption in the peel after Ca(NO3)2 and CaCl2 sprays and from the xylemic flux in the core prior to maturity. Additionally, the hydrolysis of complex polysaccharides affects the contents of simpler sugars during maturation, ripening and senescence, while storage decreases the amount of total fatty acids (TFA), but the double bond index (DBI) indicate that cell membrane fluidity remains unaffected.

Sorbitol and biochar have key roles in microbial and enzymatic activity of saline-sodic and calcareous soil in millet cropping.

Strengthening the microbial and enzymatic activities of the soil can be a way to increase the resistance of the plant to saline and sodic conditions. This research aimed to study the effect of sorbitol and biochar on improving the biological and chemical properties of saline and sodic soil in a millet cropping system. The field experiment was performed in a randomized block design with a factorial arrangement in three replications in field conditions. Experimental factors include three levels of sorbitol (S0: 0 t ha−1, S1.5: 1.5 t ha−1, and S3: 3 t ha−1) and two levels of sunflower stem biochar (B0: 0 t ha−1 biochar, B: 15 t ha−1 biochar). The results showed that sorbitol (S1.5, S3) and biochar increased microbial activity (BR and MBC) and soil enzymatic activity (DHA, ALP, UA, and CAT). Sorbitol had no significant effect on soil pH but reduced soil ECe (26%, 33%) compared to without sorbitol treatment. Sorbitol and biochar increased soil available nitrogen, available phosphorus, and dissolved organic carbon. 3 t ha−1 sorbitol increased millet yield by 50% more than 1.5 t ha−1 sorbitol and 72% more than biochar treatment. According to the results, using sorbitol and biochar in saline and sodic soil increased millet yield by improving the soil's biological and chemical properties.

The consumption of sea buckthorn (Hippophae rhamnoides L.) effectively alleviates type 2 diabetes symptoms in spontaneous diabetic rats

Sea buckthorn (Hippophae rhamnoides L.) is described by various beneficial effects as it contains several bioactive substances characterized by antioxidant effects. These effects are closely related to the reduction of oxidative stress that is involved in the development of the disease. One such diseases is Diabetes mellitus, the prevalence of which is growing and is associated primarily with diet, lack of exercise and/or genetics. This study intends to examine the effects of sea buckthorn and metformin on body weight, water and feed intake, glycaemia, insulinemia, sorbitol accumulation and cataract development in Zucker diabetic fatty rats, which represent an animal model of type 2 Diabetes mellitus, as well as to characterize the individual content of bioactive substances and the antioxidant activity of sea buckthorn. Particular concentrations were applied (500 and 1000 mg.kg−1 body weight of sea buckthorn, and combinations with 150 mg.kg−1 body weight of metformin) by gastric gavage. The total antioxidant capacity and bioactive compounds were determined by spectrophotometric analysis. The best results of the study showed suppression of hyperglycaemia, water intake, decreased sorbitol levels in the lens of the eyes after sea buckthorn treatment. Determination of bioactive compounds showed significantly higher values in dry berries when compared to fresh berries of sea buckthorn and high total antioxidant capacity. Our results represent an interest in sea buckthorn and its potential use in the treatment of Diabetes mellitus as well as other experimental studies.

Novel topical esmolol hydrochloride improves wound healing in diabetes by inhibiting aldose reductase, generation of advanced glycation end products, and facilitating the migration of fibroblasts.

Aims/ObjectivesWound healing in people with diabetes is delayed secondary to impaired nitric oxide generation, advanced glycation end products (AGE), and poor migration of epithelial cells. We developed a novel topical esmolol hydrochloride (Galnobax) and assessed its efficacy for wound healing in streptozocin-induced diabetic hairless rat.MethodsAll experiments were performed at an animal laboratory and tertiary-care research facility. Ex vivo aldose reductase inhibition was assessed from enzymes obtained from a bacterial culture (spectrophotometer), sorbitol content in homogenized red blood cells, and AGE in glucose and bovine serum by fluorometry following the addition of esmolol in varying concentrations. A scratch assay of human fibroblasts, endothelial cells, and keratinocytes was assessed under a high-glucose environment and after esmolol by phase-contrast microscopy. The efficacy evaluation of the topical application of Galnobax (14 and 20%) or vehicle was conducted in streptozotocin-induced diabetic hairless rats, and endogenous nitrite and hydroxyproline from homogenized wound tissue were measured along with pharmacokinetic and dermal toxicity in Hanford miniature swine.ResultsEsmolol inhibited the formation of sorbitol by 59% in erythrocytes in comparison to glucose-induced sorbitol levels. AGE generation in bovine serum albumin was reduced at 1 mM esmolol concentrations (2.6 ± 1.7) compared with control (p < 0.05) and similar to that of diclofenac (2.5 ± 1.3). Esmolol at 1 and 10 µM enhanced the migration of fibroblasts, epithelial cells, and keratinocytes compared with control. The nitric oxide levels (day 7) were 44 and 112% higher with Galnobax (14%) than those of the diabetic group (p < 0.05) and the vehicle control group (p < 0.05), respectively. The days 7 and 14 hydroxyproline in the wound was higher by 22 and 44% following Galnobax (14%) compared with the diabetic and vehicle control groups. The wound area exhibited better reduction with Galnobax at 14% up to day 10 follow-up compared with the controls. The pharmacokinetic and dermal toxicity in miniature swine suggested no significant adverse event with Galnobax.ConclusionsTopical esmolol hydrochloride is a novel, safe, and effective treatment modality that acts through pleotropic mechanisms to hasten wound healing in diabetes.

207-LB: Aldose Reductase Inhibition by AT-001 Limits Diastolic Dysfunction and Adverse Remodelling in Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DbCM) increases mortality and morbidity in type 2 diabetes (T2D) subjects. Increased cardiac aldose reductase (AR) activity has been correlated with impaired cardiac function and less effective energy metabolism in DbCM subjects. The aim of the present study was to evaluate the effect AT-001, a potent and selective AR inhibitor, on cardiac function, structure, and energy metabolism in diabetic cardiomyopathic mice that overexpress the human AR (hAR-Tg) . The effects of AT-001 were compared to those of dapagliflozin, a sodium-glucose cotransporter inhibitor that decreases the risk of cardiovascular death. DbCM was induced in human AR overexpressing transgenic (hAR-Tg) mice by subjecting them to a high-fat diet (60% kcal from lard) for 10-wk with a single intraperitoneal streptozotocin injection (75 mg/kg) at 4-wk. Male mice were randomized to receive either vehicle, AT-001 (40 mg/kg/day) ,or dapagliflozin (1 mg/kg/day) for the final 3-wk. AT-001 treatment improved diastolic function in vivo (a decrease in the E/e’ ratio and an increase in the E’/A’) and reduced left ventricular mass (LV) mass in DbCM mice compared to vehicle-treated DbCM mice. Cardioprotection by AT-001 was associated with reduced cardiac AR activity, decreased circulating blood sorbitol levels, and a reduction in cardiac fatty acid oxidation rates in the DbCM mice. Treatment with dapagliflozin did not significantly affect either diastolic function or LV mass in DbCM mice. In addition, dapagliflozin did not have a significant effect on cardiac fatty acid oxidation rates. In summary, the present study demonstrates that AT-001 attenuates diastolic dysfunction and cardiac hypertrophy in DbCM. AT-001-induced cardioprotection is accompanied by reduced cardiac fatty oxidation rates in DbCM. Disclosure Q. G. Karwi: None. R. Ramasamy: Consultant; Applied Therapeutics. J. R. Ussher: None. G. Lopaschuk: None. K. Gopal: None. S. Tabatabaei dakhili: None. C. S. Wagg: None. L. Zhang: None. Q. Sun: None. C. T. Saed: None. S. Panidarapu: None. R. Perfetti: Employee; Applied Therapeutics.

Blood sorbitol measurement in diabetic rats treated with an aldose reductase inhibitor using an improved fiber-optic sorbitol biosensor

Sorbitol is known as a biomarker for the evaluation of the progress of diabetic complications. We have developed a sorbitol biosensor using an optical fiber for rapid diagnosis and pathological evaluation of diabetic complications. In this paper, we measured blood sorbitol in diabetic rats using an improved biosensor, and discussed the effectiveness of the developed biosensor and the significance of sorbitol measurement. In order to investigate the effectiveness of the developed biosensor, the blood sorbitol level of type II diabetic rats prepared by streptozotocin administration was measured with the developed sensor. The values of sorbitol were highly correlated with the values measured by the F-kit of food analysis and that we confirmed the sorbitol concentration could be quantified using the developed biosensor. Furthermore, the aldose reductase inhibitor “eparlrestat”, which is a therapeutic drug that suppresses the accumulation of sorbitol, was administered to diabetic rats, and the blood sorbitol level was measured with the developed biosensor. As a result, the blood glucose level was high in both the treated group and the non-treated group, but the blood sorbitol level in the treated group decreased. The results suggest that the measurement of the sorbitol level with the developed biosensor in addition to the blood glucose level enables evaluation of complications like diabetic neuropathy. In the future, we expected that the developed sorbitol biosensor will be miniaturized, the pretreatment method for blood samples will be simplified, and it will be applied to the development of therapeutic agents for diabetic complications and personalized medicine.

Biallelic mutations in sord are a common cause of potentially treatable genetic neuropathy

IntroductionAs opposed to CMT1, for which over 90% of cases have mutations in known genes, only 20–30% of CMT2/dHMN patients receive a genetic diagnosis. Since up to 70% of CMT2 and dHMN cases are sporadic, identifying candidate pathogenic genes from single cases remains challenging also for next-generation sequencing techniques.MethodsWe took advantage of the largest collection of over 1,100 CMT patients in whom WES and/or WGS has been performed in the GENESIS analysis platform. We specifically looked for genes for which significant DNA variants are present in multiple families as well as for individual alleles overrepresented in CMT cases.ResultsWe identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG;p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein and increased intracellular sorbitol. Also, as a biomarker, serum fasting sorbitol level was over 100 times higher in patients compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibi- tors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes.ConclusionsWe demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. These findings establish a potentially treatable cause in a sig- nificant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.andrea.cortese@ucl.ac.uk

Metabolomics of oxidative stress: Nrf2 independent depletion of NAD or increases of sugar alcohols

Nrf2 encodes a transcription factor best known for regulating the expression of antioxidant and detoxification genes. Recent evidence suggested that Nrf2 mediates metabolic reprogramming in cancer cells. However, the role of Nrf2 in the biochemical metabolism of cardiac cells has not been studied. Using LC-MS/MS-based metabolomics, we addressed whether knocking out the Nrf2 gene in AC16 human cardiomyocytes affects metabolic reprogramming by oxidative stress. Profiling the basal level metabolites showed an elevated pentose phosphate pathway and increased levels of sugar alcohols, sorbitol, L-arabitol, xylitol and xylonic acid, in Nrf2 KO cells. With sublethal levels of oxidative stress, depletion of NAD, an increase of GDP and elevation of sugar alcohols, sorbitol and dulcitol, were detected in parent wild type (WT) cells. Knocking out Nrf2 did not affect these changes. Biochemical assays confirmed depletion of NAD in WT and Nrf2 KO cells due to H2O2 treatment. These data support that although Nrf2 deficiency caused baseline activation of the pentose phosphate pathway and sugar alcohol synthesis, a brief exposure to none-lethal doses of H2O2 caused NAD depletion in an Nrf2 independent manner. Loss of NAD may contribute to oxidative stress associated cell degeneration as observed with aging, diabetes and heart failure.

A sorbitol transporter gene plays specific role in the occurrence of watercore by modulating the level of intercellular sorbitol in pear

Watercore is a physiological disorder which often occurs on the fruits of pear and closely related to the influence of environment factors, such as high temperature. The excessive accumulation of sorbitol in fruit intercellular space is considered to be an important cause of watercore. Sorbitol transporter (SOT) is the key translocation protein of sorbitol and our previous study found the PpSOT3 expression was significantly decreased in high temperature induced-watercore pear fruit by transcriptome method. How PpSOT3 regulates the occurrence of watercore in pear remains unclear. The present study found that PpSOT3 had different expression pattern in watercore-susceptible (Akibae and Hosui) and watercore-resistant (Aikansui) pear cultivars of young fruit and mature fruit. Moreover, the accumulation of intercellular sorbitol in watercore fruit was significantly higher than that in healthy fruit, and the expression of PpSOT3 was significantly inhibited. After the treatment of sugar transport inhibitor (para-chloromercuribenzenesulphonic acid, PCMBS), the fruit pulp occurred water-soaking and the expression of PpSOT3 and the intercellular sorbitol content was significantly decreased and increased, respectively. Subcellular localization showed that PpSOT3 was located in plasma membrane. Both transient overexpression and RNAi assays suggested PpSOT3 had the function of sorbitol uptake. Taken together, these results demonstrate that PpSOT3 was a PCMBS-sensitive sorbitol transporter and played an important role in the occurrence of watercore by modulating the level of intercellular sorbitol content.

Sorbitol accumulation decreases oocyte quality in aged mice by altering the intracellular redox balance.

Sorbitol is a product of glucose metabolism through the polyol pathway. Many studies have demonstrated that excessive sorbitol can disrupt the intracellular redox balance. However, we still know very little about the impact of excessive intracellular sorbitol on oocyte quality, oocyte maturation, and embryo developmental potential. This study explored whether intracellular sorbitol accumulates in the oocytes of aged mice during in vitro maturation (IVM) and what roles sorbitol plays in oocyte development and maturation. Our results showed that sorbitol levels were significantly higher in in vitro-matured oocytes from aged mice than in oocytes from young mice (14.08 ± 3.78 vs. 0.23 ± 0.04 ng/oocyte). The expression of aldose reductase (AR) mRNA was significantly higher in the in vitro-cultured oocytes from 9-month-old mice than prior to culture. To decrease the excessive intracellular sorbitol in oocytes from aged mice, sorbinil, a specific inhibitor of aldose reductase, was supplemented in IVM medium, and the sorbitol level was significantly decreased (14.08 ± 3.78 vs. 0.48 ± 0.19 ng/oocyte). Our results indicated that the percentage of oocytes with first polar body extrusion (PBE) was significantly higher in the sorbinil group than in the aged group (82.4% ± 7.2% vs. 66.1% ± 6.9%), and the content of sorbitol was drastically increased in the aged group. The ROS fluorescence intensity in the sorbinil group was drastically lower than that in the aged group, while the GSH fluorescence intensity was significantly higher. Interestingly, SOD1 was upregulated in the sorbinil group. The present study suggests that excessive sorbitol accumulation is induced during IVM in aged mouse oocytes, which negatively influences oocyte quality by altering the intracellular redox balance. Inhibition of sorbitol accumulation may be a potential method to improve the nuclear maturation of aged oocytes.

Propofol suppresses cell proliferation in gastric cancer cells through NRF2‐mediated polyol pathway

Propofol, a widely used short‐acting intravenous sedative agent, has gradually gained attention due to the tumour‐suppressing role and non‐anaesthetic effect. Dysfunction of metabolic reprogramming has been recognised as a well‐documented factor for tumour progression. The aim of this study is to explore the effect of propofol on the polyol pathway in gastric cancer cells. In this study, we found that propofol treatment led to a significant downregulation of cell proliferation in BGC823 and GES‐1 cells, which was attributed to the decreased AR‐mediated polyol pathway. Both aldo‐keto reductase family 1, member B1 (AKR1B1) and AKR1B10 were significantly reduced in BGC823 and GES‐1 cells in response to propofol stimulation, leading to decreased AR activity and sorbitol level. Addition of sorbitol could reverse the inhibitory effect of propofol on cell proliferation. Mechanically, propofol treatment drastically inhibited phosphorylation and nuclear translocation of nuclear factor (erythroid‐derived 2)‐like 2 (NRF2), subsequently decreased the binding of NRF2 to AR promoter. Overexpression of NRF2 resulted in the recovery of AR expression in gastric cancer cell with propofol treatment. Taken together, these finding showed that propofol suppressed cell proliferation in BGC823 and GES‐1 cell through NRF2‐mediated polyol pathway, which would aid the selection of sedation for patients with gastric cancer.

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a.

Shikonin contributes to intestinal epithelial cell differentiation through PKM2/NRF2-mediated Polyol pathway

BackgroundAlteration of polyol pathway is a critical event in serials of disease, including inflammatory bowel disease (IBD). Shikonin, an inhibitor of PKM2, has been reported to exert a wide range of biological and pharmacological properties. However, the function of shikonin-mediated polyol pathway in IBD remained to be addressed. MethodsWe conducted WB and qPCR to analyze the effect of shikonin on intestinal epithelial cell differentiation. IF, IP, luciferase assay and ChIP were employed to demonstrate the mechanism that shikonin regulated cell differentiation through polyol pathway. Elisa was used to measure the serum sorbitol in subjects enrolled in this study, and the clinical sample was collected to detect PKM2, AR and NRF2 expression. ResultsHerein, we showed that shikonin treatment in HT-29 and CaCO2 cells not only contributed to CDX2 and its targets expression, including MUC2 and villin, leading to cell differentiation, but also induced NRF2-mediated AKR1B1 and AKR1B10 expression, resulting in increasing AR activity. A synergistic effect on CDX2-mediated cell differentiation was observed in CaCO2 cells in response to cotreatment with shikonin and AR agonist bortezomib for 24 hours, while aldose reductase inhibitor fidarestat treatment in CaCO2 cells reversed the enhanced CDX2 expression caused by shikonin. Mechanistically, PKM2 interacted with NRF2, and this interaction was enhanced in response to shikonin stimulation, resulting in NRF2 phosphorylation and nuclear translocation, which further increased AKR1B1 and AKR1B10 transactivation. Moreover, both AKR1B1 and AKR1B10 expression were decreased, while PKM2 was increased in intestinal epithelial cells labeled with E-cadherin in patients with IBD, and a negative clinical relationship was observed between PKM2 and AKR1B1/AKR1B10, respectively. What's more, the serum sorbitol level was decreased in patients with IBD. ConclusionThese results suggested that shikonin could promote intestinal cell differentiation through NRF2-mediated polyol pathway, implying that shikonin may be a promising therapeutic drug for the treatment of IBD.

Role of the Polyol Pathway in Locomotor Recovery and Wallerian Degeneration after Spinal Cord Contusion Injury.

Spinal cord contusion injury leads to Wallerian degeneration of axonal tracts, resulting in irreversible paralysis. Contusion injury causes perfusion loss by thrombosis and vasospasm, resulting in spinal cord ischemia. In several tissues, including heart and brain, ischemia activates polyol pathway enzymes—aldose reductase (AR) and sorbitol dehydrogenase (SDH)—that convert glucose to sorbitol and fructose in reactions, causing oxidative stress and tissue loss. We sought to determine whether activation of this pathway, which has been termed glucotoxicity, contributes to tissue loss after spinal cord contusion injury. We tested individual treatments with AR inhibitors (sorbinil or ARI-809), SDH inhibitor (CP-470711), superoxide dismutase mimetic (tempol), or combined sorbinil and tempol. Each treatment significantly increased locomotor recovery and reduced loss of spinal cord tissue in a standard model of spinal cord contusion in rats. Tissue levels of sorbitol and axonal AR (AKR1B10) expression were increased after contusion injury, consistent with activation of the polyol pathway. Sorbinil treatment inhibited the above changes and also decreased axonal swelling and loss, characteristic of Wallerian degeneration. Treatment with tempol induced recovery of locomotor function that was similar in magnitude, but non-additive to sorbinil, suggesting a shared mechanism of action by reactive oxygen species (ROS). Exogenous induction of hyperglycemia further increased injury-induced axonal swelling, consistent with glucotoxicity. Unexpectedly, contusion increased spinal cord levels of glucose, the primary polyol pathway substrate. These results support roles for spinal glucose elevation and tissue glucotoxicity by the polyol pathway after spinal cord contusion injury that results in ROS-mediated axonal degeneration.

Effect of caffeine on the possible amelioration of diabetic neuropathy: A spectroscopic study

ImportanceOne of the consequential and alarming complications of diabetes mellitus is diabetic neuropathy (DN). DN is assured to be caused chiefly by excess sorbitol levels in the body. The harmful consequences of DN alike peripheral nerve damage with extremity ulcers may be dodged with timely detection and treatment. The therapeutic methods for DN are scarce and expensive. Therefore economic and user friendly methodologies to prevent acquiring the disease need proper attention. ObjectiveThe present research has been conducted (1) to analyse the levels of sorbitol in diabetic blood samples and compare them with non-diabetic ones and (2) to study the reduction in sorbitol levels upon addition of an important biochemical compounds caffeine in both sample groups. Research design, setting, participants and methodSorbitol-caffeine interaction analysis of blood samples of 16 patients with type 2 diabetes from KPC Medical College, Kolkata, India was made. The spectroscopic analysis and their interpretations were compared with 16 healthy subjects. Main outcomes and measuresPresent work describes that caffeine can be helpful in reducing the sorbitol level in diabetics, so the chances of development and progression of diabetic neuropathy can be controlled with the introduction of caffeine. ResultsA total number of 32 blood samples of patients (aged 35–70 years); mean age ranges were 52.06 ± 2.68 and 53.50 ± 2.66 years for non-diabetic and diabetic ones respectively, glucose and sorbitol screening examination were done by enzymatic methodologies where concentrations were assessed by means of either absorption or fluorescence spectroscopy. The calibration range was 18.2–1119.3 mg/dL (Linear regression analysis r2 = 0.996). The sensitivity of this screening program in detecting DN with the healthy adults has been inquired and found efficient. Results of fasting insulin analyses have also been analysed for HOMA-IR (homeostasis model assessment – insulin resistance) and HOMA-B (homeostasis model assessment – pancreatic β cell function) values. Statistical significance of the results in non-diabetic and diabetic groups were performed and found to be statistically significant. ConclusionsWe have defined the relationship between blood glucose level, insulin level, sorbitol and caffeine in human body and utilized them in the plausible remediation of DN.

ALTERATIONS OF ALDOSE REDUCTASE ACTIVITY BY INDOLE-3-CARBOXALDEHYDE DERIVATIVES

In diabetic conditions, aldose reductase (AR, EC 1.1.1.21) activity is significantly increased in lens, kidney and nerve tissues. Mainly in ocular and neural tissues increased levels of sorbitol is associated with diabetic complications such as retinopathy, nephropathy, neuropahty, cataract formation and also tissue damage via increased reactive oxygen speices. Recently, there are many studies that show the relationship between this enzyme family and cancer. Aldose reductase is important for the pathway and in turn has been a potential target for drug design. Great number of aldose reductase inhibitors (ARIs) are used for prevention or delay of these diabetic complications and cancer. However, effective ARIs which has benefits in diabetic complications are still under investigation. In this study aldose reductase was partially purified from bovine lens and the inhibitory effects of 16 different indol-3-carboxyaldehydederivatives on aldose reductase enzyme activities were examined by kinetic assays. These results suggested that N'-[(5-bromo-1H-indol-3-yl)methylidene]pyridine-4-carbohydrazide showed that the highest inhibitory activity on AR.

Manufacture of 2D-Printed Precision Drug-Loaded Orodispersible Film Prepared from Tamarind Seed Gum Substrate

Two-dimensional (2D) printing is a simple technology that shows the possibility for the preparation of personalized pharmaceutical dosage forms. This technology can accurately print medicine in different sizes, which can be applied to develop a personalized, drug-loaded orodispersible film for patients with dysphagia. Seed gum from Tamarindus indica Linn was selected as the film former of the printing substrate, and sorbitol was applied as a film plasticizer. Theophylline was used as a printed model drug due to its narrow therapeutic index. From the results, the mechanical properties of the film indicated that increasing the level of sorbitol improved the flexibility and strength of the film, which rendered the gum film suitable as a printing substrate. Conversely, raising portions of the gum (more than 3.5%) led to the use of rigid and stress-resistant films that can crack during the printing process. The Fourier transform infrared result revealed that there was no interaction between theophylline and the gum after the printing process. The printed theophylline was mainly in an amorphous form based on the X-ray diffraction results. Furthermore, theophylline was deposited at the surface of the gum substrate after the drug-printing process, as depicted in the scanning electron microscope images. The printed drug on the orodispersible film can be accurately determined by varying the printing size/repeat. Lastly, the drug was completely released from the orodispersible film within 5 min. The research results showed the possibility of utilizing tamarind seed gum as a potential printing substrate for the 2D drug-printing technique. Moreover, this can be applied as an electronic prescribing system for telemedicine in the future.

Encapsulated Mixture of Methyl Salicylate and Tributyrin Modulates Intestinal Microbiota and Improves Growth Performance of Weaned Piglets.

Tributyrin and essential oils have been used as alternatives to antimicrobials to improve gut health and growth performance in piglets. This study was to evaluate the effects of a dietary supplement with two encapsulated products containing different combinations of tributyrin with oregano or with methyl salicylate on growth performance, serum biochemical parameters related to the physiological status, intestinal microbiota and metabolites of piglets. A total of 108 weaned crossbred piglets (Yorkshire × Landrace, 21 ± 1 d, 8.21 ± 0.04 kg) were randomly divided into three groups. Piglets were fed with one of the following diets for 5 weeks: a basal diet as the control (CON); the control diet supplemented with an encapsulated mixture containing 30% of methyl salicylate and tributyrin at a dosage of 3 kg/t (CMT); and the control diet supplemented with an encapsulated mixture containing 30% of oregano oil and tributyrin at a dosage of 3 kg/t (COT). At the end of the feeding trial, six piglets from each group were slaughtered to collect blood and gut samples for physiological status and gut microbiological analysis. The study found that the CMT group was larger in feed intake (FI) (p < 0.05), average daily gain (ADG) (p = 0.09), total protein (TP), albumin (ALB), glutathione peroxidase (GSH-PX) (p < 0.05), blood total antioxidant capacity (T-AOC) (p < 0.05), and crypt depth in the ileum (p < 0.05) compared with the CON group. The genus abundance of Tissierella and Campylobacter in the CMT group was significantly decreased compared with the CON group. The CMT group also resulted in significantly higher activity in amino acid metabolism and arginine biosynthesis compared with the CON group. The COT group was larger in T-AOC, and the genus abundance of Streptophyta and Chlamydia was significantly increased in the ileum compared with the CON group. Data analysis found a significantly high correlation between the genus abundance of Chlamydia and that of Campylobacter in the ileum. The genus abundance of Campylobacter was also positively correlated with the sorbitol level. In general, the results indicated that the supplementation of both encapsulated mixtures in diet of weaned piglets could improve the animal blood antioxidant capacity. Additionally, the encapsulated mixture of methyl salicylate plus tributyrin improved the growth performance and resulted in certain corresponding changes in nutrient metabolism and in the genus abundance of ileum microbial community.