PAL enzymatic biotherapy: hope for phenylketonuria July 26, 2018 Source: China Science News Author: Yangshun Kai Nowadays, a group of children who do not eat human fireworks - children with phenylketonuria cause more and more attention in society. Previously, Qinghai Province called for the inclusion of phenylketonuria in medical insurance, and Heilongjiang Province also decided to include phenylketonuria in the scope of special treatment management for urban and rural residents' basic medical insurance clinics. What is phenylketonuria? Phenylketonuria is an autosomal recessive disorder and a common amino acid metabolic disorder. At present, the incidence of phenylketonuria in China is about 1/16,500, and the number of children exceeds 100,000. According to reports, the disease has no symptoms before the child is 3 years old, but after 3 years old, there will be symptoms of short, mental retardation. Phenylketonuria is a Phe molecule in neonates that lacks a mutation in the phenylalanine (Phe) hydroxylase gene and does not eliminate the toxic effects in the blood, so that the accumulated Phe cannot be converted to tyrosine like a normal baby. This results in high Pheemia in the child, and Phe and its ketoacid accumulate and are excreted in large amounts from the urine. The child is usually normal at birth, but symptoms begin to appear at 3 to 6 months of age. Early neurological abnormalities such as excitement, hyperactivity, or lethargy may occur, which may manifest as a significant delay in mental development, and severe muscle tone may occur. Consternation and so on. In addition, it may be accompanied by a decrease in pigmentation, dry skin, and a special urine odor in the urine. The reason is that the high level of Phe in the blood causes brain damage; if the phenylketonuria is not screened early, timely treatment of the screened children will bring a series of problems to the family and society, which is not conducive to the population composition of our country. Prenatal and postnatal care. PAL enzymatic biological therapy attracts attention The traditional treatment of phenylketonuria is the use of dietary therapy, that is, the intake of special rice and milk powder containing very low or no L-Phe in children, generally a child's monthly dietary cost of 2,000 yuan, which is undoubtedly for the family Brought a heavy economic burden. At present, a more active and effective alternative therapy than diet therapy, PAL enzymatic biotherapy, has become a topic of concern for Chinese and foreign medical scientists. Phenylalanine ammonia lyase (PAL) is widely found in plants and certain microorganisms, as well as a few simple prokaryotic microbial organisms. PAL biocatalyzes the non-oxidative deamination of Phe to produce cinnamic acid and ammonia. Since the presence of PAL has not been found in eubacteria and mammals to date, this suggests that the high activity and high yield of PAL enzyme preparations of certain microorganisms can be used to promote the biocatalytic removal of amino groups from Phe to form non-toxic cinnamic acid and ammonia. A new treatment for phenylketonuria with PAL enzymatic therapy. Over the past 20 years, life scientists at home and abroad have carried out extensive research and application on microorganisms, especially red yeast PAL, including the unremitting exploration and progress in research and development of PAL biocatalytic frontier technology for the treatment of phenylketonuria. The key moment of the door. Previous researchers conducted a series of studies on PAL-controlled L-Phe levels in children with phenylketonuria, including a series of studies on the route of drug administration, clinical enzymatic test, and safety evaluation. The pharmacological animal model test also proved that the PAL organism The effectiveness of catalyzing the reduction of L-Phe levels. In the spring of 1999, a collaborative research team from the United States and Canada published a paper in the top scientific journal of the National Academy of Sciences (PNAS), saying that Canada has developed a method for producing PAL in large quantities by inserting the PAL enzyme gene into bacteria. This includes large-scale cultivation of the bacteria, isolation of cell material, and a process of separating and purifying the PAL enzyme preparation on a large scale. In the same period, Liu Jingzhong and others from Peking Union Medical College Hospital also used the plant material parsley as the donor of PAL gene, and constructed the successful PAL genetic engineering bacteria with E. coli expression system. Scientists also used Lactococcus lactis as genetically engineered bacteria to transform Lactococcus lactis by electroporation with parsley PAL cDNA, expressing PAL activity, but not high vigor. This also indicates that the domestic PAL/PKU enzymatic treatment project has been initiated. PAL enzyme stability is further enhanced Since 1988, the author's laboratory team has started research on microbial PAL enzymes and biotechnology under the support of the National Natural Science Foundation of China. The author team selected the high PAL activity Rhodobacter sphaeroides CIBASA1401 from the soil samples collected in the Mango Garden in western Yunnan by means of enrichment culture/physicochemical mutagenesis/antagonistic plate selection. The selected red yeast strain has unique PAL characteristics, and some enzymatic properties indicate that the PAL enzyme activity is stored at 4 degrees Celsius for one week without any preservative and protective agent, and the remaining enzyme activity is 95%; Week 63%, minus 20 degrees Celsius 82% for two weeks; the enzyme activity is almost completely lost after the PAL enzyme is kept at 60 degrees Celsius for 1 hour, but the PAL enzyme is below 50 degrees Celsius, especially at the optimum reaction temperature and lower temperature. Has a higher stability. The ability of the strain to reversely catalyze the synthesis of L-Phe by its PAL has been successfully used in the first industrial scale production of L-Phe products in China for 100 tons, ending the history of the inability to produce Phe in China for a long time and filling the domestic gap. Naturally, this is associated with the high PAL activity and high stability characteristics of the red yeast. With the use of the red yeast strain CIBAS A1401 for the development of PAL/PKU projects is a logical development, and the conditions for independent innovation are mature. In recent years, the PAL derived from Rhodospora erythropolis has been chemically modified by PEG (polyvinyl alcohol), and the PAL derivative preparation obtained by oral administration has been orally administered with various PAL dosage forms. The results show that most of the high and low dose experimental groups can effectively reduce blood Phe. Level 60%. This indicates that the use of PAL chemically derived preparations from Rhodospora erythropolis and Chlorella is effective in treating PKU via oral non-mammalian enzyme proteins. It can be seen that the application of PAL as a candidate biochemical enzyme preparation for the treatment of PKU is because the PAL enzymatic method does not require a cofactor for the hydrolysis of Phe; although PAL proteolysis and immunogenicity are obstacles to the enzymatic replacement therapy, In the past few years, through the efforts of the academic circles, they have been solved one by one. A US company has signed a contract for a clinical trial in a selected community in California. Finally, the author calls on the younger generation of science and technology workers who are struggling in the frontiers of life sciences and life engineering in China to face the 100,000 children of PKU in China and work hard to innovate the PAL enzymatic biological treatment PKU with Chinese characteristics. In an unspeakable burden on thousands of families, the so-called "biocatalytic manifestation of power, Lectra is a good prospect." (The author is a researcher at the Chengdu Institute of Biology, Chinese Academy of Sciences) 《Journal of the Chinese Academy of Sciences》 (2018-07-26 6th edition frontier)
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