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OBJECTIVE: To investigate the effect of 1-deoxynojirimycin (DNJ) for improving diabetic liver fibrosis and explore the underlying mechanism. METHODS: Mouse models of type 2 diabetes were established in 10 Kunming mice by high-fat diet feeding for 8 weeks and intraperitoneal injection of STZ, with 5 mice receiving intraperitoneal injection of citrate buffer solution with normal feeding as the control group. The mouse models were randomized into two groups (n=5) for further highfat feeding (model group) and additional treatment with 10% DNJ in drinking water (200 mg · kg(-1) per day; DNJ group) for 8 weeks. The mice were monitored for changes in body weight (BW), blood glucose, serum total cholesterol (TC), triglyceride (TG) and superoxide dismutase (SOD) levels. The pathological changes in the liver tissue were observed using HE and Sirius Red staining, and the solubility of collagens in the liver tissues was determined. The expression levels of MCP-1, TNF-α, IL-1β and TGF-β1 mRNA were detected with real-time PCR, and the protein expressions of α-SMA and collagen2 (ColA2) were determined with Western blotting. In the in vitro experiment, mouse fibroblasts L929 cells were pretreated with DNJ (10 μg/ mL) or PBS for 30 min followed by culture in high-glucose medium for 24 h, and the level of ROS production was measured using dihydroethidium (DHE) staining. RESULTS: In the mouse model of type 2 diabetes, DNJ treatment significantly lowered serum level of glucose, TC, and TG (P < 0.05) and increased serum SOD activity (P < 0.05). DNJ obviously attenuated liver fibrosis in the diabetic mice, as shown by alleviated cross-linking of collagens and reduced contents of pepsin-solubilized collagen (PSC) and total collagen (P < 0.05). DNJ treatment also significantly reduced the overexpression of the proinflammatory cytokines and fibrosis-related cytokines induced by diabetes (P < 0.05). In L929 cells exposed to high glucose, pretreatment with DNJ significantly lowered the intensity of red fluorescence in DHE staining. CONCLUSION: DNJ can attenuate type 2 diabetes-induced liver fibrosis in mice through its hypoglycemic, anti-inflammatory and anti-oxidative effects.

Sepsis is a life‐threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non‐targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad‐spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen‐stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen‐induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis‐related inflammatory disorders associated with excess cytokine secretion., Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. We report a distinct activity of iminosugars whereby modulation of the unfolded protein response occurs as a result of inhibition of ER‐resident glycoprotein processing enzymes. This results in decreased inflammation arising from diverse pathogens including replicating virus, bacterial endotoxin and fungal antigen.

Background/objectives Despite considerable literature supporting the potential health benefits of reducing postprandial glucose (PPG), and insulin (PPI) exposures, the size of a clinically relevant reduction is currently unknown. We performed a systematic review and meta-analysis to quantify effects of alpha-glucosidase-inhibiting (AGI) drugs on acute PPG and PPI responses. Methods We searched EMBASE and MEDLINE until March 13, 2018 for controlled studies using AGI drugs together with a standardized carbohydrate load or mixed meal. The mean incremental PPG and PPI levels were calculated as outcomes. Meta-analyses, stratified by diabetes state, were performed by using random effects models. Results The 66 included publications comprised 127 drug-control comparisons for PPG, and 106 for PPI, mostly testing acarbose or miglitol. The absolute effects on PPG were larger among individuals with diabetes (−1.5 mmol/l mean PPG [95% CI −1.9, −1.1] by acarbose, and −1.6 [−1.9, −1.4] by miglitol) as compared to individuals without diabetes (−0.4 [95% CI −0.5, −0.3] by acarbose, and −0.6 [−0.8, −0.4] by miglitol). Relative reductions in PPG by both drugs were similar for diabetic and non-diabetic individuals (43−54%). Acarbose and miglitol also significantly reduced mean PPI, with absolute and relative reductions being largest among individuals without diabetes. Conclusions The present meta-analyses provide quantitative estimates of reductions of PPG and PPI responses by AGI drugs in diabetes and non-diabetic individuals. These data can serve as benchmarks for clinically relevant reductions in PPG and PPI via drug or diet and lifestyle interventions.

Introduction: Alpha-glucosidase inhibitors (AGIs) – oral antihyperglycemic drugs, inhibit upper gastrointestinal enzymes that break down complex carbohydrates into glucose. As a result, the absorpt...

Background Consumption of mulberry leaves has been associated with better metabolic health in humans due to the presence of a biologically active plant metabolite, 1-deoxynojirimycin (DNJ). Although levels of DNJ is low in mulberry leaves, easy availability of DNJ through microbial production has greatly facilitated research examining its mechanism of actions. Scope and approach The present review sheds light on the recent trends in various routes of DNJ biosynthesis, its extraction methods, and its vital role in the management of non-communicable metabolic diseases. In the light of the previous research on DNJ and its health benefits, it is apposite to bring together the updated information and re-evaluate the important aspects of this important health molecule. Key findings and conclusions This review summarizes and critically analyzes merits of various methods for DNJ extraction and purification as well as different routes of DNJ biosynthesis. Also, this review looks into its role in the management of different non-communicable metabolic diseases. Finally, the possible role of DNJ as a potential candidate for functional foods is explored.

6-(N-hydroxyethyl) amino-6-deoxy- l -sorbofuranose (6NSL) is the direct precursor of miglitol for diabetes therapy. The regio- and stereo-selective dehydrogenation offered by the membrane-bound d -sorbitol dehydrogenase (mSLDH) from Gluconobacter oxydans provides an elegant enzymatic method for 6NSL production. In this study, two subunits sldA and sldB of mSLDH were introduced into G. oxydans ZJB-605, and the specific enzyme activity of mSLDH towards NHEG was enhanced by 2.15-fold. However, the endogenous PQQ level was dramatically reduced in the recombinant strain and became a bottleneck to support the holo-enzyme activity. A combined supplementation of four amino acids (Glu, Ile, Ser, Arg) involved in biosynthesis of PQQ in conventional media effectively increased extracellular accumulation of PQQ by 1.49-fold, which further enhanced mSLDH activity by 1.33-fold. The synergic improvement of mSLDH activity provided in this study supports the superior high dehydrogenate activity towards substrate N-2-hydroxyethyl-glucamine, 184.28 g·L−1 of 6NSL was produced after a repeated bioconversion process catalyzed by the resting cells of G. oxydans/pBB-sldAB, all of which presenting a great potential of their industrial application in 6NSL biosynthesis.

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been recent developments in testing that make diagnosis easier and new therapies that aim to stabilise the disease process. A new biochemical test to measure serum cholesterol metabolites supersedes the skin biopsy and is practical and robust. It is treatable with miglustat, a drug that inhibits glycosphingolipid synthesis. We describe a patient, aged 22 years, with juvenile-onset Niemann-Pick type C who presented with seizures and a label of 'cerebral palsy'. We describe the approach to this syndrome in general, and highlight the classical features and red flags that should alert a neurologist to this treatable condition.

1-Deoxynojirimycin (DNJ) has been known as a potent α-glucosidase inhibitor from mulberry leaves and considered beneficial in prevention of type 2 diabetes. Due to limited amount of DNJ in mulberry leaves, recent studies have focused in finding alternative source that can produce higher amount of DNJ. Previously, we produced a high DNJ-containing culture medium from Bacillus amyloliquefaciens AS385 and constructed a concentration method of bacterial culture medium using cation exchange column. However, less complicated concentration procedure is necessary to save time and cost during the large-scale production. Therefore, we developed a simpler concentration method using anion exchange resin to yield B. amyloliquefaciens AS385 culture broth powder (CBP; 1% DNJ) and evaluated the physiological effects of 5-wk dietary CBP intake in C57BL/6J mice. CBP intake tended to suppress the elevation of blood glucose level during oral glucose tolerance test. Moreover, CBP intake significantly lowered the fasting plasma glucose level and white adipose tissue mass. Next, we evaluated the absorption and distribution of DNJ in mice organs after daily CBP intake. We found detectable amount of DNJ in organs with intestine and kidney as the major targeted organs. We concluded that the DNJ content in CBP is absorbed from digestive tract, distributed and accumulated in organs, which most likely to contribute to the alteration of blood glucose regulation and adiposity in C57BL/6J mice. Our study was the first to report the physiological effects of CBP produced from B. amyloliquefaciens AS385 and the organ distribution of DNJ from CBP.

BackgroundPatients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD.MethodsSince current tests to determine amenability are limited to heterologous mutation expression in HEK293T cells with endogenous AGAL activity, we generated CRISPR/Cas9-mediated AGAL-deficient HEK293T cells as a basis for mutant overexpression. Furthermore, primary urinary cells from patients were isolated and immortalised as a patient-specific cell model system to evaluate the amenability to chaperone therapy.ResultsUnder treatment (>13 months), carriers of p.N215S (n=6) showed a significant reduction of plasma lyso-Gb3 (pA cells.ConclusionWe conclude that repeated AGAL activity measurements in patients’ white blood cells are mandatory to assess the in vivo amenability to migalastat. Plasma lyso-Gb3 might be an appropriate tool to measure the biochemical response to migalastat. Patients with low AGAL activities and increasing lyso-Gb3 levels despite in vitro amenability might not benefit sufficiently from chaperone treatment.

Mulberry leaves have been known to be rich in 1-Deoxynojirimycin (DNJ) which inhibits postprandial hyperglycemia by inhibiting α-glucosidase in the small intestine and thereby reducing the breakdown of starch and other complex sugar into glucose. Mulberry leaf extract also contains many other bioactive compounds and phytochemicals. They are very effective in supporting blood sugar levels and balancing cholesterol and triglycerides. The DNJ content in mulberry leaves depends on the leaf’s variety and age. In this study, the phytochemical profile and DNJ content of young leaves and mature mulberry leaves in Indonesia were determined to further promote mulberry use using High Performance Liquid Chromatography (HPLC) and Pyrolisis Gass Chromatography-Mass Spectrometry (GC-MS). The phytochemicals test result for the four leaf samples showed that all four samples contain alkaloids, phenolics, flavonoids, tannins and terpenes. The mature leaves of M. cathayana contain the highest DNJ concentration (2.90 mg DNJ/g leaves) out of eight samples. DNJ has the potential to be used as a functional food for diabetic patients. Analysis using HPLC and Py-GC-MS confirmed that mulberry species contain many beneficial phytochemicals. This study presented that Indonesian mulberry leaves extracts to have high phytochemical compositions which very potential utilized in the medicinal field.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.

A novel supramolecular multivalent glycosidase inhibitor was constructed based on the amphiphilic deoxynojirimycin derivative FA-DNJ. FA-DNJ self-assembled into spherical assemblies with the diameters between 103 nm and 137 nm under different pH values (pH 2-7) and showed a potent glycosidase effect against α-mannosidase with a Ki value of 0.11 μM, an effect that increased approximately 330-fold compared with that of miglitol. In addition, FA-DNJ exhibited a hypoglycaemic effect in mice.

Niemann Pick type C is an inborn error of metabolism (IEM), classified as a lysosomal storage disease (LSD) caused by a dysfunction in NPC transport protein, that leads to intracellular accumulation of non-esterified cholesterol and other lipids. Clinical manifestations are ample, with visceral and neurological symptoms. Miglustat, a molecule that reversibly inhibits glucosylceramide synthase is used as treatment for this disorder. Studies demonstrated the influence of oxidative stress and inflammation in IEM, as well in animal model of NP-C disease. Nonetheless, literature lacks data on patients, so our work aimed to investigate if there is influence of chronic inflammation in the pathophysiology of NP-C disease, and the effect of miglustat, N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). We evaluated the plasmatic cytokines in NPC patients at diagnosis and during the treatment with miglustat. Additionally, we performed an in vitro study with antioxidants NAC (1 mM and 2.5 mM) and CoQ10 (5 μM and 10 μM), where we could verify its effect on inflammatory parameters, as well as in cholesterol accumulation. Our results showed that NP-C patients have higher plasmatic levels of pro and anti-inflammatory cytokines (IL-6, IL-8, and IL-10) at diagnosis and the treatment with miglustat was able to restore it. In vitro study showed that treatment with antioxidants in higher concentrations significantly decrease cholesterol accumulation, and NAC at 2.5 mM normalized the level of pro-inflammatory cytokines. Although the mechanism is not completely clear, it can be related to restoration in lipid traffic and decrease in oxidative stress caused by antioxidants.

A simple synthesis, which utilizes a thin film microfluidic reactor for a problematic step, of a potent inhibitor of α-N-acetylhexosaminidases, DGJNAc, has been developed.

Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.

Background Potential use of many native, easily available vegetal materials for human consumption and value addition is not well recognized. Mulberry, being a traditional industrial crop rich in nutrients and nutraceuticals can be of great importance for the food industry. However, mulberry leaves are mainly being utilized in sericulture and are not exploited for their functional components. Thus, the selection of promising mulberry cultivars, rich in bioactive compounds, like resveratrol and 1-deoxynojirimycin, increase their potential use in functional foods. Results Chlorogenic acid, myricetin and kaempferol were the major polyphenols present in the nine selected cultivars, in the range 0.001-0.086, 0.003-0.079 and 0.003-0.163 g kg-1 fresh weight (FW), respectively. Protocatechuic acid, epicatechin and rutin were predominantly present in cultivars V-1, G-2 and ML (0.103, 0.080 and 0.121 g kg-1 FW, respectively). Similarly, resveratrol and 1-deoxynojirimycin were highest in cultivars ML and K-2 (0.078 and 0.079 g kg-1 FW, respectively). Leaf extracts of cultivars G-2 and ML were able to effectively inhibit the violacein production with 64.08% and 70.04%, respectively at the concentration of 6 mg mL-1 presumably due to a higher content of polyphenols. Chemometric evaluation of chromatographic data showed the intraspecific variability and secondary metabolite co-existence in different cultivars. Conclusions Considering phytoconstituents, cultivars G-2, ML, K-2 and V-1 could contribute efficiently to the rational utilization of mulberry in agro-food industries. Furthermore, cultivars G-2 and ML leaves can be a new source of quorum sensing inhibitory agents. This article is protected by copyright. All rights reserved.

This article reports results of one of our projects related to the investigation of interactions of miglitol (MIG) with normal human serum albumin (HSA) and glycated HSA (GHSA) with the help of recording spectroscopic and electrochemical data. The experimental data were analyzed by conventional and chemometric methods to extract useful information for comprehensive justifications of the interactions of the MIG with HSA and GHSA. Hard- and soft-modeling chemometric methods were used to extract quantitative and qualitative information. Then, molecular docking techniques were used to further investigation of the binding of the MIG with HSA and GHSA and the extracted results were compatible with those obtained by experimental methods. Finally, according to the binding of the BV with HSA and GHSA, second-order differential pulse voltammetric data were recorded and calibrated with three-way calibration methods for exploiting second-order advantage for determination of the GHSA in the presence of the HSA to develop a novel chemometrics assisted-electroanalytical method for diagnostic and monitoring of diabetic.

Iminosugar compounds are monosaccharide mimetics with broad but generally weak antiviral activities related to inhibition of enzymes involved in glycobiology. Miglustat (N-butyl-1-deoxynojirimycin), which is approved for the treatment of lipid storage diseases in humans, and UV-4 [N-(9-methoxynonyl)-1-deoxynojirimycin] inhibit the replication of hepatitis A virus (HAV) in cell culture (50% inhibitory concentrations [IC(50)s] of 32.13 μM and 8.05 μM, respectively) by blocking the synthesis of gangliosides essential for HAV cell entry. We used a murine model of hepatitis A and targeted mass spectrometry to assess the capacity of these compounds to deplete hepatic gangliosides and modify the course of HAV infection in vivo. Miglustat, given by gavage to Ifnar1(−/−) mice (4,800 mg/kg of body weight/day) depleted hepatic gangliosides by 69 to 75% but caused substantial gastrointestinal toxicity and failed to prevent viral infection. UV-4, similarly administered in high doses (400 mg/kg/day), was well tolerated but depleted hepatic gangliosides by only 20% after 14 days. UV-4 depletion of gangliosides varied by class. Several GM2 species were paradoxically increased, likely due to inhibition of β-glucosidases that degrade gangliosides. Both compounds enhanced, rather than reduced, virus replication. Nonetheless, both iminosugars had surprising anti-inflammatory effects, blocking the accumulation of inflammatory cells within the liver. UV-4 treatment also resulted in a decrease in serum alanine aminotransferase (ALT) elevations associated with acute hepatitis A. These anti-inflammatory effects may result from iminosugar inhibition of cellular α-glucosidases, leading to impaired maturation of glycan moieties of chemokine and cytokine receptors, and point to the potential importance of paracrine signaling in the pathogenesis of acute hepatitis A. IMPORTANCE Hepatitis A virus (HAV) is a common cause of viral hepatitis. Iminosugar compounds block its replication in cultured cells by inhibiting the synthesis of gangliosides required for HAV cell entry but have not been tested for their ability to prevent or treat hepatitis A in vivo. We show that high doses of the iminosugars miglustat and UV-4 fail to deplete gangliosides sufficiently to block HAV infection in mice lacking a key interferon receptor. These compounds nonetheless have striking anti-inflammatory effects on the HAV-infected liver, reducing the severity of hepatitis despite enhancing chemokine and cytokine expression resulting from hepatocyte-intrinsic antiviral responses. We propose that iminosugar inhibition of cellular α-glucosidases impairs the maturation of glycan moieties of chemokine and cytokine receptors required for effective signaling. These data highlight the potential importance of paracrine signaling pathways in the inflammatory response to HAV and add to our understanding of HAV pathogenesis in mice.

We aimed to establish a 1-Deoxynojirimycin (DNJ) sustained-release delivery system to improve the hypoglycemic effect of DNJ. We used a transdermal diffusion meter in an in vitro orthogonal experiment to determine the optimal composition of the DNJ sustained-release transdermal system. Based on the in vitro analysis results, a sustained-release patch was prepared, and its pharmacokinetics and other properties were determined in vivo. The results showed that 30% hydroxypropyl methylcellulose (K100M ), 14% carboxymethyl cellulose sodium and 26% oleic acid-azone compound as the matrix material, drug excipient, and penetration enhancer, respectively, produced an optimal DNJ sustained-release delivery system. In vitro release tests showed that the system slowly released DNJ within 12 hr, conforming to the Higuchi equation. In vivo experiments showed that the prepared patch had good hypoglycemic activity and continuously released DNJ within 10 hr. In vivo pharmacokinetic study results showed that compared to conventional patches, the prepared patch exhibited significantly different maximum concentration (Cmax ), time to achieve Cmax (Tmax ), and area under the curve from 0 to time t (AUC[0-t] ) as well as improved pharmacokinetics. In conclusion, the prepared DNJ patch has high stability, a sustained-release effect, and relatively good pharmacokinetics and is a safe dosage form that does not cause skin irritation.

Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.

Background Niemann-Pick Disease Type C (NPC) is an ultra-rare progressive neurodegenerative disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes that lead to premature death, with most individuals dying between 10 and 25 years of age. NPC can present at any age and many individuals with NPC may be misdiagnosed or undiagnosed. A key challenge with recognizing NPC is the heterogeneous and nonspecific clinical presentation. Currently, there are no approved treatments for NPC in the United States; miglustat, an FDA-approved treatment for Gaucher disease, is used off-label for NPC and GM1 gangliosidosis. Objectives To estimate the number of people in the United States that 1) have an NPC diagnosis 2) have an NPC diagnosis and/or are treated off-label with miglustat for NPC and 3) are likely to have NPC. Methods For the first two objectives, patients were identified using the Symphony Integrated DataVerse database (Oct 2015-Jan 2020). To identify the number of people with NPC for Objective 1, cases of NPC were defined as any patients with an ICD-10 code of E75.242 (NPC) during the study period. Objective 2 expands upon Objective 1, including (a) patients from Objective 1 and (b) patients with documented miglustat use (NDC 43975–0310 or 10,148–0201) who did not have any claim with Gaucher disease (ICD-10 E75.22) or GM1 gangliosidosis (ICD-10 E75.1) during the study period. For the third objective, published NPC incidence (1 per 89,000 live births) and expected mortality estimates were applied to the 2018 United States birth rate (11.6 per 1000) and population size (326.7 million). Results A total of 308 million unique individuals were represented in the database. Of these, 294 individuals had an NPC diagnosis, yielding an identified NPC prevalence of 0.95 per million people in the United States. 305 individuals were diagnosed with NPC and/or were treated with miglustat without having a diagnosis for either Gaucher or GM1 gangliosidosis, yielding an NPC diagnosed or treated prevalence of 0.99 per million people in the United States. Based on the published literature, there are an estimated 42 new NPC cases per year. Applying this number to the distribution of NPC type (based on age of neurologic symptom onset) and corresponding mortality estimates generates an estimated 943 prevalent cases of NPC, or 2.9 cases of NPC per million people in the United States. Conclusions NPC is an ultra-rare, progressive neurodegenerative disease with approximately 1 per million people in the United States diagnosed with or treated off-label for NPC. Given that NPC is often misdiagnosed or undiagnosed, the estimated prevalence from the epidemiology calculations (2.9 per million) approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.

In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1−/− mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1−/− and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1−/− mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1−/− mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1−/− mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1−/− mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1−/− mice was almost completely reduced only in the female groups.

A series of N-alkylated deoxynojirimycin (DNJ) derivatives connected to a terminal tertiary amine at the alkyl chains of various lengths were prepared. These novel synthetic compounds were assessed for preliminary glucosidase inhibition and anticancer activities in vitro. Potent and selective inhibition was observed among them. Compound 7d (IC50 = 0.052 mM) showed improved and selective inhibitory activity against ?-glucosidase compared to DNJ (IC50 = 0.65 mM). In addition, analysis of the kinetics of enzyme inhibition by using Lineweaver-Burk plots indicated that 7d inhibited ?-glu-cosidase in a competitive manner, suggesting that 7d was expected to bind to the active site of ?-glucosidase. Compounds 8b and 8c were found to be moderate and selective inhibitors of ?-glucosidase. Nevertheless, none of compounds inhib-ited the growth of B16F10 melanoma cells.

1-Deoxynojirimycin (1-DNJ), the main active component found in4% hydro-alcoholic extract was prepared fromAge mean ± SD was equal to 54.79 ± 9.203 (38-69) years. There was no significant difference between intervention and placebo groups considering FBS (p=0.633) but was for HbA1c% (p=0.0011), before treatment. After three months, both FBS and HbA1c% were significantly reduced in patients underThis clinical trial and virtual analysis showed that a hydro-alcoholic extract of

A new determination method of 1-deoxynojirimycin (1-DNJ) in mulberry leaves based on ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed. Dried and crushed mulberry leaves’ sample was extracted by MeCN-water solvent, purified by graphitized carbon black (GCB) and primary secondary amine (PSA) to remove organic acids and pigments, and then analyzed after attenuation and filtration. The calibration curve showed linearity in the concentration range of 10–500 ng/mL, with the correlation coefficient of 0.998. Recoveries of spiked 1-DNJ at three fortification levels ranged from 94.6% to 96.4%, with relative standard derivation below 1.2%. Additionally, the matrix effect was assessed as negligible. Compared with methods by gas chromatography (GC) and liquid chromatography (LC) via real sample detection, the proposed method acquired better stability and detection efficiency. These results proved that this method has advantages of simple operation, complete purification, small pretreatment loss, good precision and accuracy, and high determination specificity, which is suitable for massive monitoring and precise quantitation of 1-DNJ in mulberry leaves.

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat. Fundación Biomédica Galicia Sur | Ref. OT-02-CNF Xunta de Galicia | Ref. CN2012 / 184

To assess the utility of globotriaosylsphingosine (lyso-GbA post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-GbNo significant correlations were identified between changes in lyso-GbAlthough used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb

Nojirimycin (NJ) is a compound in which the oxygen of the ring is replaced with an NH group in the D-glucose structure. NJ, which has a structure similar to D-glucose, is a powerful glucosidase inhibitor and an interesting compound. However, no anti-inflammatory effects of NJ have been reported. Therefore, to investigate its anti-inflammatory effect, the production and expression of inflammatory cytokines, as well as inflammatory mediators, such as iNOS and COX-2, were measured in LPS-stimulated RAW264.7 macrophages. In addition, the effects on the representative inflammatory signaling pathways, the suppression of NF-κ B, and the activation of MAPK were studied. The production of iNOS, COX-2, and inflammatory cytokines (PGE₂, IL-6, IL-1β, and TNF-α) after NJ treatment was significantly inhibited. In addition, NJ showed anti-inflammatory effects through suppression of LPS-induced NF-κ B activation. D-Glucose is structurally similar to NJ. The effects of these substances on RAW264.7 macrophages were evaluated. NJ reduced nitric oxide (NO) levels, whereas D-glucose had no significant effect. Overall, the results suggested that NJ is a potential anti-inflammatory compound.

Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived macrophages (MDMΦs). Given the important role played by DCs in innate immune defense against DENV, the antiviral effects of three deoxynojirimycin (DNJ) derivatives (NN-DNJ, EOO-DNJ and 2THO-DNJ) and a deoxygalactonojirimycin (DGJ) negative control were evaluated in DENV-infected primary human monocyte-derived immature DCs (imDCs). DNJ- but not DGJ-derivatives elicited antiviral activity in DENV-infected imDCs, similar to that observed in MDMΦs. The DNJ-derivatives inhibited DENV secretion in a dose-dependent manner. Endoplasmic reticulum (ER) α-glucosidase I inhibition by DNJ-derived iminosugars, at concentrations of 3.16 μM, correlated with a reduction in the specific infectivity of virions that were still secreted, as well as a reduction in DENV-induced tumour necrosis factor alpha secretion. This suggests iminosugar-mediated ER α-glucosidase I inhibition may give rise to further benefits during DENV infection, beyond the reduction in viral secretion associated with ER α-glucosidase II inhibition.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach., Graphical Abstract