CN109045033A - New application of the niacinamide in terms of preventing salivary gland radiation insult - Google Patents

New application of the niacinamide in terms of preventing salivary gland radiation insult Download PDF

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Publication number
CN109045033A
CN109045033A CN201810794853.5A CN201810794853A CN109045033A CN 109045033 A CN109045033 A CN 109045033A CN 201810794853 A CN201810794853 A CN 201810794853A CN 109045033 A CN109045033 A CN 109045033A
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nam
radiation
salivary gland
insult
cell
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CN201810794853.5A
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CN109045033B (en
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向彬
王馨悦
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Second Hospital of Dalian Medical University
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Second Hospital of Dalian Medical University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses new application of the niacinamide in terms of preventing salivary gland radiation insult, belong to pharmaceutical sanitary field.The present invention finally specifies that NAM can effectively prevent salivary gland radiation insult by cell and zoopery.NAM in the present invention can be prepared into the drug of prevention salivary gland radiation insult, provide a kind of new method for the damage of clinical treatment radioactivity salivary gland.

Description

New application of the niacinamide in terms of preventing salivary gland radiation insult
Technical field
The present invention relates to new application of the niacinamide in terms of preventing salivary gland radiation insult, belong to pharmaceutical sanitary field.
Background technique
Niacinamide (Nicotinamide, NAM) is also known as niacinamide, is the amide compound of niacin, is vitamin B3 The component part of Coenzyme I and Coenzyme I I in a kind of derivative and human energy metabolism, shown in structure such as formula (I):
In clinical practice, NAM be used for pellagra, stomatitis, glossitis prevention and treatment, and treatment coronary heart disease, vital myocarditis, The arrhythmia cordis that rheumatic heart disease and a small number of digitalis poisonings etc. occur together.Currently, existing patent CN106715455A (China) Describing nicotinamide riboside class medicine can be used for treating the subject for suffering from or being susceptible to suffer from mitochondrial disease or illness, or for increasing Suffer from or be susceptible to suffer from the insulin sensitivity of the subject of insulin resistance, metabolic syndrome, diabetes or its complication, the disease Disease or illness will benefit from increased nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide, NAD) horizontal.Patent CN101601679A (China) describes drug or health care of the NAM mononucleotide in preparation prevention and treatment cerebral apoplexy Application in food, illustrating NAM mononucleotide itself is the endogenic Protective substances of body, has very high drug safety.
Salivary gland radiation insult is the common complication of head and neck neoplasm radiotherapy.Clinical manifestation be radiation therapy delivery during and After radiotherapy, there is serious mouth parched symptom in patient, influences the normal physiological functions such as normal language, the sense of taste, feed, substantially reduces The quality of life of patient.The damage of salivary gland caused by head and neck neoplasm radiotherapy how is coped with, is clinical problem urgently to be resolved One of.In recent years, the degree of being showing improvement or progress day by day with radiotherapy technology, salivary gland radiation insult is alleviated, and clinician also exists Seek some other means to protect the function of salivary gland as far as possible, as the application of artificial saliva, salivary gland transfer operation are opened Exhibition etc., but these means fundamentally change salivary gland exposure after function reduction the phenomenon that.It has been reported that in animal experiments Salivary gland radiation insult is treated by the way of gene transfer, obtains certain curative effect, but its effectiveness is ofer short duration, and in a short time It is difficult to apply in clinic.
Summary of the invention
To solve prior art problem, the present invention provides a kind of niacinamide (NAM) and prevents salivary gland radiation insult in preparation Drug in application, and have good effect.
Radiation insult of the present invention is radiation insult caused by radiotherapy (radiotherapy).
Radiation insult of the present invention is radiation insult caused by interior radiation and fluconazole ear drops.Internal radiotherapy is Internal (internal) radiotherapy is that radioactive source is placed in a kind of intracorporal side for the treatment of of body in a variety of manners (including oral or implantation) Formula, such as radioiodine therapy;Fluconazole ear drops are external (external) radiotherapy, are that clinically usually said radiation is controlled It treats, is that radioactive source is placed in a kind of extracorporeal therapeutic modality.
The present invention using the rat primary submandibular gland cell of originally culture and Wistar rat as model, through experimental studies have found that NAM has good prevention radiation insult effect in salivary gland cell and tissue, that is, it is thin to be effectively improved salivary gland caused by radioactive ray The decline of born of the same parents' vigor, gland tissue structure is destroyed and Apoptosis etc., and can reduce in cellular level discovery NAM radiation-induced The reduction of acinar cells NAD level.These results of study show that NAM can improve the energetic supersession of irradiated cell, are clinical pre- Anti- salivary gland radiation injury provides a kind of new method.
The dosage form of the drug of prevention salivary gland radiation insult of the invention can be tablet, capsule, pill, emulsion, injection Agent, syrup, oral solution, granule or patch.
(1) in cellular level, NAM (50-200 μM) can prevent rat submandibular gland cell radiation injury.
(2) in tissue and organ level, NAM (500mg/kg) can prevent the damage of rat radioactivity salivary gland.
The vigor of originally culture rat submandibular gland cell can be improved in NAM pretreatment of the present invention, reduces saliva after radiation injury NAD synthesizes rate-limiting enzyme Nampt (nicotinamide in liquid gland cell Phosphoribosyltransferase, NAMPT) reduction, improve cellular NAD level.To prompt NAM to promote carefully Born of the same parents' Mitochondria oxidative phosphorylation metabolism and series are using NAD as key protein (such as SIRT1/ of the regulation mitochondria of substrate PGC-1 α etc.) metabolic activity.Meanwhile the present invention also has found that NAM pretreatment can be improved rat submandibular gland in animal model The ability of radiation injury is resisted, NAM pretreatment has protective effect to submandibular organization's morphosis in histological level, mitigates Radiation injury, and significantly mitigate the apoptosis of radiation-induced submandibular gland acinar cells.
Beneficial effects of the present invention:
The present invention finally specifies that NAM can effectively prevent salivary gland radiation insult by cell and zoopery.The present invention In NAM can be prepared into prevention salivary gland radiation insult drug, for clinical treatment radioactivity salivary gland damage provide one kind New method.The present invention proposes that the drug containing NAM can generate following effect to the salivary gland of radiation insult:
1. improving acinar cells survival rate after radiation;
2. preventing salivary organization's radiation injury;
3. mitigating the radiogenic Apoptosis of salivary gland.
Detailed description of the invention
Influence of Fig. 1 .NAM to radiation injury submandibular gland cell form and cell density.
Influence of Fig. 2 .NAM to radiation injury submandibular gland cell vigor.
Influence of Fig. 3 .NAM to NAMPT protein expression level in radiation injury submandibular gland cell.
Influence of Fig. 4 .NAM to radiation injury submandibular gland cell NAD level.
Influence of Fig. 5 .NAM to radiation injury rat submandibular gland tissue morphology.
Influence of Fig. 6 .NAM to radiation insult rat submandibular gland cell apoptosis, wherein A is cellular morphology figure, B TUNEL The quantitative figure of method detection.
Specific embodiment
Following nonlimiting examples can with a person of ordinary skill in the art will more fully understand the present invention, but not with Any mode limits the present invention.
Radiation insult in following embodiments is radiation insult caused by fluconazole ear drops.
The experimental study of embodiment 1:NAM prevention suckling mouse submandibular gland cell radiation insult
1. purpose
NAM is inquired into the preventive and therapeutic effect of rat submandibular gland cell radiation injury.
2. materials and methods
The present embodiment uses the originally culture suckling mouse submandibular gland cell of third generation logarithmic growth phase, is randomly divided into blank group (Control, abridge Cont), simple NAM group (NAM), simple radiation group (IR) and NAM pretreated group (NAM+IR), with RS 2000 biology X-ray irradiation instrument row 5GyX-ray irradiation (before irradiation, NAM intervention group (simple NAM group and NAM pretreated group) 30min is pre-processed with 50 μM, 200 μM of NAM respectively, wherein 50 μM of NAM pre-process 30min are as follows: with 50 μM of niacinamide preincubates Originally culture suckling mouse submandibular gland cell 30min, 200 μM of NAM pre-process 30min are as follows: with 200 μM of primary trainings of niacinamide preincubate Support suckling mouse submandibular gland cell 30min;Control group (blank group and simple radiation group) is given only the PBS buffer solution of same volume). (1) 200 μM of NAM of dosage pre-process 30min, each group after irradiation 6h, 12h, with 48h carry out morphological observation for 24 hours, and Cell viability is detected with Prestoblue cell viability assay kit;(2) 50 μM of NAM pretreatments of dosage 30min detects the expression of NAMPT albumen in cell;(3) 50 μM of NAM of dosage pre-process 30min, detect group of cells NAD is horizontal.
3. result
(1) influence of Fig. 1 .NAM to radiation injury submandibular gland cell form and cell density.Bar=50 μm.Shape under light microscopic State observation discovery: NAM pretreated group cell growth state is good, and cellular morphology is close with density with normal cell.
(2) influence of Fig. 2 .NAM to radiation injury submandibular gland cell vigor.* P < 0.05 is compared with blank control group;#P< 0.05 compared with simple irradiation group.Cell viability experiment display: NAM significantly promotes the cell viability of acinar cells after radiation, To demonstrate the direct effect that NAM promotees salivary gland cell survival after ionization radiation injury.
(3) influence of Fig. 3 .NAM to NAMPT protein expression level in radiation injury submandibular gland cell.Cellular immunofluorescence As a result prompt: NAM significantly increases the expression of submandibular gland cell NAMPT albumen after radiation, shows NAM to radiation injury salivary gland The protective effect of cell is related with NAMPT protein upregulation.
(4) influence of Fig. 4 .NAM to radiation injury submandibular gland cell NAD level.* P < 0.05 is compared with blank control group;# P < 0.05 is compared with simple irradiation group.NAD testing result is shown: submandibular gland cell NAD is horizontal after NAM has significantly raised radiation, Show that NAM may be related to the mitochondrial approach that NAD is mediated to the protective effect of radiation injury cell.
4. conclusion
NAM can effectively mitigate the damage radiated to submandibular gland cell, and mechanism is that NAM promotes NAMPT synthesis, improve cell NAD is horizontal, the mitochondrial mediated so as to improve NAD.
Embodiment 2:NAM prevents the experimental study of rat submandibular gland tissue radiation damage
1. purpose
NAM is inquired into the preventive and therapeutic effect of submandibular organization's radiation insult.
2. materials and methods
This research uses 24 Wistar rats (weight 180-230g, male and female are unlimited), is randomly divided into blank group (Control, abridge Cont), simple NAM group (NAM), simple radiation group (IR) and NAM pretreated group (NAM+IR), with RS 2000 biology X-ray irradiation instrument row 20GyX-ray irradiation (irradiates preceding half an hour, (simple NAM group and NAM are pre- for NAM intervention group Processing group) through stomach-filling NAM500mg/kg is given, control group (blank group and simple radiation group) is given only isometric physiological saline). After 7 days, Xia Qu submandibular organization is anaesthetized, makes paraffin section, row HE dyeing, the change of light microscopic observation submandibular organization form Change, TUNEL method detects the apoptosis in situ of group of cells.
3. result
(1) influence of Fig. 5 .NAM to radiation injury rat submandibular gland tissue morphology.Om observation discovery: tailored radiation Group rat submandibular gland body of gland atrophy, vacuolated change, karyopycnosis;The rat submandibular gland tissue for giving NAM is small compared with tailored radiation group gland Impeller structure understands that acinus structural integrity is similar to normal submandibular organization's structure.
(2) influence of Fig. 6 .NAM to radiation insult rat submandibular gland cell apoptosis, wherein A is cellular morphology figure, and B is The quantitative figure of TUNEL method detection.* P < 0.05 is compared with blank control group;#P < 0.05 is compared with simple irradiation group.TUNEL result is aobvious Show: apoptotic cell quantity significantly increases (87 ± 9.07) compared with blank control group in tailored radiation group rat submandibular gland tissue, and gives The salivary gland apoptotic cell for giving NAM is substantially reduced (19.4 ± 4.97).
4. conclusion
NAM can effectively prevent salivary gland radiation injury, and resisting radiogenic Apoptosis may be its mechanism.
For any person skilled in the art, without departing from the scope of the technical proposal of the invention, all Many possible changes and modifications are made to technical solution of the present invention using the technology contents of the disclosure above, or are revised as equivalent The equivalent embodiment of variation.Therefore, anything that does not depart from the technical scheme of the invention, according to the technical essence of the invention to Any simple modifications, equivalents, and modifications that upper embodiment is done should all still fall within the range of technical solution of the present invention protection It is interior.

Claims (5)

1. application of the niacinamide in the drug of preparation prevention salivary gland radiation insult.
2. application according to claim 1, which is characterized in that the radiation insult is to radiate damage caused by radiotherapy Wound.
3. application according to claim 1, which is characterized in that the radiation insult is that interior radiation and/or outer radiation are controlled Radiation insult caused by treatment.
4. according to right to go 1 described in application, which is characterized in that the niacinamide is for preventing salivary gland radiation insult Dosage is 500mg/kg.
5. application described in any one of -4 according to claim 1, which is characterized in that the prevention salivary gland radiation insult Drug dosage form be tablet, capsule, pill, emulsion, injection, syrup, oral solution, granule or patch.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109745563A (en) * 2019-01-09 2019-05-14 复旦大学 SIRT1 inhibitor is for preventing and treating radioactive injury of mouth
WO2023282283A1 (en) * 2021-07-07 2023-01-12 明治ホールディングス株式会社 Composition for improving oral environment

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CN107362362A (en) * 2017-07-20 2017-11-21 复旦大学 Application of the SIRT1 inhibitor in radioactive intestines problem is prevented and treated
WO2018129039A1 (en) * 2017-01-04 2018-07-12 President And Fellows Of Harvard College Modulating nudix homology domain (nhd) with nicotinamide mononucleotide analogs and derivatives of same

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109745563A (en) * 2019-01-09 2019-05-14 复旦大学 SIRT1 inhibitor is for preventing and treating radioactive injury of mouth
CN109745563B (en) * 2019-01-09 2021-04-16 复旦大学 SIRT1 inhibitor for preventing and treating oral cavity injury caused by radiation
WO2023282283A1 (en) * 2021-07-07 2023-01-12 明治ホールディングス株式会社 Composition for improving oral environment

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