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Application and function of 1-deoxynojirimycin (DNJ) in medical field

    1, 1-Deoxynojirimycin overview:

    DNJ is a piperidine alkaloid whose chemical name is 3,4, 5-trihydroxy-2-light methyltetrahydropyridine, short for 1-de-Oxynojirimycin. Nojirimycin was first obtained from Streptomyces by Inoue et al. as an antibiotic, and DNJ was obtained by nojirimycin hydrogenation. There are two main sources of DNJ: plant and microbial. Plant sources include: mulberry leaves and mulberry root bark, plantaris, hyacinth, Psammophyllaceae. Microbial sources include Streptomyces palioides and Bacillus.

    1. Functions and uses of DNJ:

    DNJ is a potent α -glucosidase inhibitor with better absorption than acarbose. Sulfonylureas are better than sulfonylureas in inhibiting the conversion of human sugar, reducing fasting blood glucose and increasing postprandial blood glucose, while the possibility of hypoglycemia and other side effects is much lower than other hypoglycemic drugs, so it is safer.

    2.1 DNJ can reduce blood glucose and is used in the treatment of diabetes

    All cells in the body use glucose as an energy source. The sugar in the blood circulation is almost all glucose. The blood glucose value of healthy people is 80-100m/dL, which rises to 110-140mg/dL about 0.5~1 hour after eating, and restores to the original blood glucose value after 2 hours. If insulin secretion is insufficient or its activity is not strong, it will make the glucose absorbed and absorbed from food stay in the blood, which is fully utilized and discharged in the urine, forming diabetes. The clinical symptoms of diabetes are “three more and one less” (polydipsia, polydipsia, polyuria, weight loss).

    2.1.1 Inhibitory effect of DNJ on α -glucosidase

    The inhibitory effect of DNJ on A-glucosidase in different animals was different, and the IC50 of DNJ on sucrase and maltosinase were 6.6-16×10-8m and 7.4-63×10-8, respectively. DNJ showed competitive inhibition of A – glucosidase, which usually acted on or near the substrate binding site, and competed with the substrate to bind to the enzyme.

    2.1.2 Effects of DNJ on blood glucose of rats fed with carbohydrate

    Yoshiake Yoshikuni studied the effects of DNJ on blood glucose levels in rats fed with different carbohydrates. The results showed that 60mg/kg DNJ completely inhibited the increase in blood glucose levels after eating when 2g/kg sucrose was added simultaneously. DNJ at 20mg/kg significantly reduced blood glucose levels and lasted for 90 min. At low doses (6mg/kg), DNJ delayed the peak of blood glucose without affecting the peak height. In starch-fed rats, DNJ delayed the appearance and reduced the height of the peak. The higher the dose of DNJ was, the lower the peak height of blood glucose was. The inhibitory effect of DNJ on blood glucose in maltose fed rats was similar to the dose effect of starch fed rats.

    2.1.3 Hypoglycemic mechanism of DNJ

    Dietary carbohydrates, such as starch, are hydrolyzed into the stomach by the action of saliva a-amylase, and about 70% of the portion of the stomach that has not yet been mixed with saliva is still hydrolyzed. Then into the duodenum, under the action of pancreatic a-amylase continue to add water decomposition, the formation of sucrose, maltose and other disaccharides. When disaccharides are transported to the small intestine, they are hydrolyzed into monosaccharides such as glucose and fructose by a-glycosidase on the surface of microciliary membranes in the upper part of the small intestine, which are absorbed into the human body through the intestinal wall, resulting in a sharp increase in glucose concentration in the blood. When food is taken together with DNJ, food also reaches the small intestine and is decomposed into disaccharide, and DNJ also enters the small intestine and binds with a-glycosidase in it. Since the affinity between DNJ and A-glycosidase is greater than that between disaccharide and A-glycosidase, DNJ blocks the binding of disaccharide and A-glycosidase. A-glycosidase does not decompose disaccharides, so that disaccharides cannot be hydrolyzed into glucose and are sent directly to the intestine. As a result of DNJ, the amount of glucose entering the blood is reduced, thus lowering the blood sugar level.

    2.2 Inhibitory effect of DNJ on virus activity *

    The inhibitory effect of DNJ on molony mouse leukemia virus (MoLV) showed that DNJ had significant anti-retroviral activity * with IC50 of 1.2-.2.5 μg/ mL, and the inhibitory effect increased with the increase of DNJ dose. Glycosylation steps such as transfer of polysaccharide precursor to new peptide and subsequent glucose modification during glycoprotein formation are necessary for HIV envelope processing and folding.

    2.3 Inhibitory effect of DNJ on tumor metastasis

    TsulomuTsuruoka et al. used mouse β-16 lung black cell tumor as A model to study the anti-tumor metastasis activity of nojirimycin A-related derivatives and their analoges *, and pointed out that DNJ was nojirimycin structural analog, and its inhibition rate on tumor metastasis was 80.5%. The possible relationship between the anti-tumor metastasis activity and the anti-glycosidase activity and the anti-a-glucosidase activity was elucidated. The inhibitory mechanism of DNJ on lung tumor metastasis might be that DNJ produced immature carbohydrate chains on the surface of tumor cells by inhibiting the activity of glycosidase, which weakened the ability of tumor metastasis. These tumor cells are attacked by the host’s immune system and cannot bind to the host cell.

    2.4 Inhibitory effect of DNJ on A-glucose amylase

    DNJ is a strong inhibitor of glucoamylase. The IC50 of GLUCoamylase inhibition by DNJ was 14μg/ mL. The active * site of A-glucose amylase consists of multiple subsites, each of which binds to a glucose residue of the substrate with a certain affinity. The inhibitory activity of DNJ on A. Niger amylase was related to the subsite structure of the enzyme. DNJ binds to the 1 subsite of the enzyme activity * site. Most or all of the substrates bind to the enzyme in a reversible manner, but bind to the subsite 1 with DNJ.

    2.5DNJ was used as a carrier for enzyme synthesis of high purity malt picking

    Industrial production of medicinal high purity maltose usually uses β -amylase and debranched enzyme to hydrolyze starch. The disadvantages of this hydrolysis process lie in that the reversible reaction caused by debranched enzyme makes it difficult to carry out the reaction under the condition of high concentration of starch. In addition, it is difficult to obtain high purity maltose due to the similar physical and chemical properties of glucose, maltose, maltoprolose and other maltooligosaccharides in the product. In the past, many methods such as ion exchange resin and live carbon column were used to purify maltose. These methods are inefficient for the separation of maltose from intermediate products such as glucose and maltose oligosaccharides. However, when DNJ was used to produce high purity maltose, only maltose was the intermediate product produced by this method, so it was easy to separate maltose.

    In conclusion, as an inhibitor of A-glucosidase, DNJ’s various functions provide a theoretical basis for its application in medicine. However, since the natural content of DNJ in various organisms is very low, how to improve the content of DNJ to obtain more natural DNJ will become a direction of future development and research.

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