WO2018169153A1 - Composition, containing potassium-competitive acid blocker as active ingredient, for treatment and prevention of leaky gut syndrome - Google Patents
Composition, containing potassium-competitive acid blocker as active ingredient, for treatment and prevention of leaky gut syndrome Download PDFInfo
- Publication number
- WO2018169153A1 WO2018169153A1 PCT/KR2017/010349 KR2017010349W WO2018169153A1 WO 2018169153 A1 WO2018169153 A1 WO 2018169153A1 KR 2017010349 W KR2017010349 W KR 2017010349W WO 2018169153 A1 WO2018169153 A1 WO 2018169153A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- composition
- leaky gut
- gut syndrome
- cab
- Prior art date
Links
- 229940126535 potassium competitive acid blocker Drugs 0.000 title claims abstract description 22
- 208000011580 syndromic disease Diseases 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 title claims abstract description 11
- 239000004480 active ingredient Substances 0.000 title claims abstract description 4
- 230000002265 prevention Effects 0.000 title claims description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 23
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 5
- 239000003112 inhibitor Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- PWILYDZRJORZDR-MISYRCLQSA-N (7r,8r,9r)-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-8-ol Chemical compound C1([C@@H]2[C@@H](O)[C@@H](C3=C(C4=NC(C)=C(C)N4C=C3)N2)OCCOC)=CC=CC=C1 PWILYDZRJORZDR-MISYRCLQSA-N 0.000 claims description 3
- GHVIMBCFLRTFHI-UHFFFAOYSA-N 8-[(2,6-dimethylphenyl)methylamino]-n-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide Chemical compound C=1C(C(=O)NCCO)=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C GHVIMBCFLRTFHI-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 230000002860 competitive effect Effects 0.000 claims description 3
- 230000027119 gastric acid secretion Effects 0.000 claims description 3
- 229950010119 linaprazan Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229950004825 soraprazan Drugs 0.000 claims description 3
- 229950003825 vonoprazan Drugs 0.000 claims description 3
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 claims description 3
- 210000004211 gastric acid Anatomy 0.000 claims 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 24
- 229940126409 proton pump inhibitor Drugs 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 210000001035 gastrointestinal tract Anatomy 0.000 description 14
- 230000035699 permeability Effects 0.000 description 13
- 229960000905 indomethacin Drugs 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 102000000591 Tight Junction Proteins Human genes 0.000 description 8
- 108010002321 Tight Junction Proteins Proteins 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 230000000968 intestinal effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 6
- 239000000612 proton pump inhibitor Substances 0.000 description 6
- 230000006378 damage Effects 0.000 description 5
- 230000003870 intestinal permeability Effects 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 229950000859 revaprazan Drugs 0.000 description 5
- LECZXZOBEZITCL-UHFFFAOYSA-N revaprazan Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 LECZXZOBEZITCL-UHFFFAOYSA-N 0.000 description 5
- 210000000813 small intestine Anatomy 0.000 description 5
- 108010034143 Inflammasomes Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 210000001578 tight junction Anatomy 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 2
- 229960004770 esomeprazole Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960005019 pantoprazole Drugs 0.000 description 2
- 102000007268 rho GTP-Binding Proteins Human genes 0.000 description 2
- 108010033674 rho GTP-Binding Proteins Proteins 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 206010070545 Bacterial translocation Diseases 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 102000004162 Claudin-1 Human genes 0.000 description 1
- 108090000600 Claudin-1 Proteins 0.000 description 1
- 102000004056 Claudin-2 Human genes 0.000 description 1
- 108090000580 Claudin-2 Proteins 0.000 description 1
- 206010056979 Colitis microscopic Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- 102000003940 Occludin Human genes 0.000 description 1
- 108090000304 Occludin Proteins 0.000 description 1
- 102000006270 Proton Pumps Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000007375 bacterial translocation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 101150047356 dec-1 gene Proteins 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 210000005027 intestinal barrier Anatomy 0.000 description 1
- 230000007358 intestinal barrier function Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000004341 lymphocytic colitis Diseases 0.000 description 1
- 210000005004 lymphoid follicle Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000008275 microscopic colitis Diseases 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/4353—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/4353—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
Definitions
- each tissue was scored on the basis of villi loss, ulceration, inflammation, and the like, when viewed pathologically as an animal tissue, and the results are shown in FIG. 6.
- severe vili loss and inflammation were observed, with similar findings in the group receiving PPI.
- the group receiving P-CAB showed more improvement in vili loss and inflammation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a composition capable of usefully preventing and treating leaky gut syndrome or non-steroidal anti-inflammatory drug (NSAID)-induced leaky gut syndrome, the composition containing potassium-competitive acid blocker (p-cab) as an active ingredient.
Description
본 발명은 장 누수 증후군 치료 및 예방용 조성물에 관한 것으로서, 더욱 상세하게는 특히 비스테로이드성 항염제(NSAID)에 의해서 유발되는 장 누수 증후군을 유용하게 예방 및 치료할 수 조성물에 관한 것이다. The present invention relates to a composition for treating and preventing bowel leak syndrome, and more particularly, to a composition capable of usefully preventing and treating bowel leak syndrome caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
인체의 장관은 장내 세균의 저장소로서 점막 장벽기능(intestinal barrier), 면역글로불린 분비 기능, 대식세포계 등을 포함한 일련의 방어체계를 이루고 있다. 장관 내 장점막층은 장내에 존재하는 다양한 세균 및 독소 등이 혈류로 유입되는 것을 차단하는 방어벽 역할을 하며 상피세포층에 단단히 결합되어 있다. 즉 장점막은 외부물질을 차단하는 장벽인 동시에 이들을 통과, 흡수시키는 이중적인 기능을 가진다.The intestine of the human body is a reservoir of intestinal bacteria and forms a series of defenses, including an intestinal barrier, an immunoglobulin secretion function, and a macrophage system. Intestinal mucosa acts as a barrier to block the influx of various bacteria and toxins in the intestine and is tightly bound to the epithelial cell layer. In other words, the mesangial membrane is a barrier that blocks foreign substances and has a dual function of passing and absorbing them.
장점막세포는 일정한 세포 사이의 간극을 유지하다가 소화 흡수 과정이 일어나는 동안 어떠한 자극이나 손상이 가해지면서 세포 사이의 틈으로 고분자 물질이 왕복할 수 있는 장점막 투과성이 증가되는 현상이 나타나게 된다. 이때 장벽의 기능을 제대로 하지 못하여 혈액 내 고분자 물질이 장관내 관강으로 누수되거나 관강 내의 고분자 물질이 직접 혈액으로 들어가는 현상이 초래되는데 이를 ¨새는 장〃 즉 ¨leaky gut〃의 상태라고 말한다. 이때 나타나는 증상을 총괄하여 장 누수 증후군(leaky gut syndrome: LGS)이라고 하며 노화, 알레르기, 다발성 외상, 류마티스 관절염, 염증성 대장질환, 만성피로 증후군, 과민성 증후군 등의 다양한 임상적 상태로 나타난다. 또한 장점막 투과성의 증가나 장점막의 손상으로 인해 병원체, 항원, 부패물질 등이 장점막 내로 유입되어 염증반응이 일어나고 내독소가 혈류로 유입되어 장내세균 전위(bacterial translocation), 장관내독소혈증(intestinal endotoxemia) 등을 야기하여 각종 염증반응 및 면역 반응이 나타나게 된다.The mesothelial membrane cells maintain a gap between the cells, and during the digestive absorption process, some irritation or damage is applied to increase the permeability of the mesenteric membrane to allow the polymer material to reciprocate into the gaps between the cells. At this time, the function of the barrier does not function properly, and the high molecular material in the blood leaks into the intestinal lumen or the high molecular material in the lumen directly enters the blood, which is called ¨a leaky gut, or ¨leaky gut〃. The symptoms that appear at this time are collectively referred to as leaky gut syndrome (LGS) and appear in various clinical conditions such as aging, allergy, multiple trauma, rheumatoid arthritis, inflammatory bowel disease, chronic fatigue syndrome, and irritable syndrome. In addition, pathogens, antigens, and decay substances enter into the membranes of the gut due to increased permeability or damage to the membranes, causing inflammatory reactions, endotoxins entering the bloodstream, and bacterial translocation, intestinal endotoxemia. To cause various inflammatory and immune responses.
이와 같은 장 누수 증후군은 다양한 원인에 의해 발생할 수 있으나 특히 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID))에 의해서도 유발되는 것으로 알려져 있다. Intestinal leak syndrome may be caused by various causes, but is also known to be caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
본 발명자들의 실험 결과에 의하면 NSAID로써 인도메타신(Indomethacin)을 투여하였을 때 정상적인 소장의 투과성(Permeability)가 증가하면서 세포 침윤(cellular infiltration) 및 융모(villi)의 손실(loss) 등을 볼 수 있으며 이는 시간이 경과함에 따라 림프여포(lymphoid follicle)를 형성하고 위장관 궤양(intestinal ulcer)를 유도하며 이는 곧 천공(perforation) 등을 거쳐 복막염(peritonitis)이 유도된다(도 1 참조). According to the experimental results of the present inventors, when indomethacin is administered as an NSAID, permeability of the small intestine increases and cellular infiltration and loss of villi are observed. Over time, it forms lymphoid follicles and induces gastrointestinal ulcers, which induce peritonitis through perforation and the like (see FIG. 1).
이와 같은 현재 임상적인 최선의 선택으로는 양성자 펌프 억제제(Proton Pump Inhibitor(PPI))를 사용하는 것으로 알려져 있으나, 최근의 연구결과들에 의하면 Proton pump inhibitor가 오히려 NSAID에 의한 장 누수 증후군(leaky gut syndrome)을 증가시키는 것으로 알려져 있는데, 대표적 proton pump inhibitor인 에소메프라졸(esomeprazole)을 투여한 경우 소장 투과도를 측정하였을 때 시간이 경과함에 따라 십이지장 투과도가 유의성 있게 증가되는 결과를 보임에 따라 proton pump inhibitor가 미세 장염(microscopic colitis)이나 림프구성 장염(lymphocytic colitis) 등을 유도한다(Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase, Mullin et al., Aliment Pharmacol Ther. 2008 Dec 1;28(11-12):1317-25 참조).Proton Pump Inhibitors (PPIs) are known to be the current best clinical choice, but recent studies have shown that proton pump inhibitors may lead to NSAID-induced leaky gut syndrome. In the case of administration of the representative proton pump inhibitor esomeprazole, the duodenal permeability was significantly increased with time when the small intestine permeability was measured. Induce microscopic colitis or lymphocytic colitis (Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase, Mullin et al., Aliment Pharmacol Ther. 2008 Dec 1; 28 (11-12): 1317 -25).
실제로 본 발명자들의 실험에서도 Indomethacin 투여에 의하여 소장 조직 전체에 걸쳐서 출혈(bleeding) 및 부종(edema) 등을 확인할 수 있었으며 이때 proton pump inhibitor를 함께 투여한 경우 상태가 호전되기보다는 오히려 악화되는 듯한 결과를 확인하였다.Indeed, in our experiments, bleeding and edema were observed throughout the small intestine tissues by the administration of Indomethacin, and when the proton pump inhibitor was administered together, the condition appeared to worsen rather than improve. It was.
따라서 NSAID에 의한 위장관 투과도(Intestinal permeability)의 증가가 proton pump inhibitor의 투여에 의하여 오히려 더욱 증가되는 것을 보여줌으로써 새로운 약제나 물질탐색이 장 누수 증후군(Leaky gut syndrome)을 해결하기 위해 절대적으로 필요한 상황임을 알 수 있다. Therefore, the increase in intestinal permeability by NSAIDs is shown to be increased by the administration of proton pump inhibitors, suggesting that new drug or substance discovery is absolutely necessary to resolve leaky gut syndrome. Able to know.
따라서 본 발명이 해결하고자 하는 과제는 비스테로이드성 항염제(NSAID)에 의해 유발되는 장 누수 증후군(Leaky gut syndrome)을 해결할 수 있는 유용한 조성물을 제공하는 것이다.Therefore, the problem to be solved by the present invention is to provide a useful composition that can solve the leaky gut syndrome caused by non-steroidal anti-inflammatory drugs (NSAID).
상기 기술적 과제를 달성하기 위하여 본 발명은,The present invention to achieve the above technical problem,
칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)를 유효성분을 함유하는 장 누수 증후군(leaky gut syndrome) 치료 및 예방용 조성물을 제공한다.Provided is a composition for the treatment and prevention of leaky gut syndrome, comprising a potent potassium-competitive acid blocker (Ptas) as an active ingredient.
본 발명에 있어서, 상기 상기 장 누수 증후군(leaky gut syndrome)이 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID))에 의해 유발되는 것일 수 있다.In the present invention, the leaky gut syndrome may be caused by a nonsteroidal anti-inflammatory drug (NSAID).
본 발명에 있어서, 상기 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)이 레바프라잔(Revaprazan), 보노프라잔(Vonoprazan), 리나프라잔( Linaprazan) 및 소라프라잔(Soraprazan)으로 이루어진 군에서 선택되는 어느 하나 이상인 것이 바람직하다.In the present invention, the potassium competitive gastric acid secretion inhibitor (Potassium-Competitive Acid Blocker, p-cab) is Revaprazan (Revaprazan), Bonophrazan (Vonoprazan), Linaprazan (Soraprazan) It is preferably at least one selected from the group consisting of.
본 발명에 의하면 장 누수 증후군(leaky gut syndrome)을, 특히 SANID에 의해 유발되는 장 누수 증후군(leaky gut syndrome)을 치료 및 예방하는데 유용한 조성물에 제공된다.According to the present invention there is provided a composition useful for treating and preventing the leaky gut syndrome, in particular the leaky gut syndrome caused by SANID.
도 1은 Indomethacin 투여에 따른 소장의 변화를 나타낸 결과 도면이다.1 is a result showing the change in the small intestine according to the administration of Indomethacin.
도 2는 세포와 세포 사이의 저항성을 확인하기 위하여 TEER을 측정하여 그 결과 도면이다.Figure 2 is a result of measuring the TEER in order to confirm the resistance between the cell and the cell.
도 3은 위장관 투과도(Intestinal permeability)와 관련 있는 tight junction protein들에는 어떤 영향이 있는지 확인하고자 western blotting을 시행한 결과 도면이다.3 is a result of western blotting to determine the effect of tight junction proteins associated with gastrointestinal permeability (Intestinal permeability).
도 4는 tight junction 과 관련성이 높은 Molecular switch인 Rho-GTPase의 활성도를 확인한 결과 도면이다.4 is a result confirming the activity of Rho-GTPase, a Molecular switch highly related to tight junction.
도 5는 장 손상에 대한 Gross leisons 확인한 결과 도면이다.5 is a diagram illustrating the results of gross leisons on intestinal damage.
도 6은 동물 조직으로 이용하여 병리학적으로 보았을 때 각 조직을 융모 손실(villi loss), 궤양(ulceration), 염증(inflammation) 기준으로 점수화한 결과 도면이다.6 is a result of scoring each tissue by villus loss, ulceration, and inflammation criteria when viewed as a pathology using animal tissue.
도 7은 실험동물 조직을 이용하여 염증과 관련한 인자들을 확인한 결과 도면이다.7 is a result of confirming the factors related to inflammation using experimental animal tissue.
도 8은 위장관 투과도(Intestinal permeability)에 영향일 미치는 inflammasome 과 관련된 인자들을 확인한 결과 도면이다.FIG. 8 shows the results of identifying factors related to inflammasome that may affect gastrointestinal permeability.
도 9는 위장관 투과도(Intestinal permeability)의 endpoint인 tight junction과 관련한 인자들을 확인한 결과 도면이다. 9 is a result of confirming the factors related to tight junction as an endpoint of the gastrointestinal permeability (Intestinal permeability).
이하 본 발명을 상세하게 설명하기로 하며, 이하의 설명에서 사용되는 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID)), 위산분비억제제(Potassium-Competitive Acid Blocker(P-CAB)), 양성자 펌프 억제제(Proton Pump Inhibitor(PPI))는 예시를 위한 것뿐이며 설명에서 사용되지 않은 다른 약물을 사용하더라도 유사한 결과 및 결론을 도출할 수 있음은 당연하다.Hereinafter, the present invention will be described in detail, and nonsteroidal anti-inflammatory drugs (NSAIDs), gastric acid secretion inhibitors (Ptascab), and proton pumps used in the following description. Proton Pump Inhibitors (PPIs) are for illustration only and it is natural that similar results and conclusions can be drawn using other drugs not used in the description.
본 발명자들은 NSAID와 함께 PPI 투여 시의 위장관 투과도(Intestinal permeability)의 변화를 살펴보고 이때 PPI 대신 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker(P-CAB))을 투여 시에 어떠한 영향이 있는지를 확인하여 본 발명의 유효성 및 효과를 입증하였다.The present inventors examined the change in gastrointestinal permeability when administering PPI with NSAID, and the effect of administration of potassium-competitive acid blocker (P-CAB) instead of PPI. Confirmation proves the effectiveness and effect of the present invention.
우선 세포실험으로는 Human colon carcinoma cells인 Caco-2 세포를 이용하였고 TEER기법(Trans-epithelial Electrical Resistance), RT-PCR, Westernblotting 등을 이용하였습니다. 또한 NSAID로는 인도메타신(Indomethacin) PPI로는 판토프라졸(Pantoprazole), P-CAB으로는 레바프라잔(Revaprazan)을 사용하였다. First of all, we used Caco-2 cells, human colon carcinoma cells, and TEER technique (Trans-epithelial Electrical Resistance), RT-PCR, Westernblotting. In addition, pantoprazole was used as an indomethacin PPI and revaprazan was used as a P-CAB.
우선 세포와 세포 사이의 저항성을 확인하기 위하여 TEER을 측정하여 그 결과를 도 2에 나타냈으며, 세포와 세포 사이의 저항성을 측정함으로써 저항성이 높을수록 세포 사이의 간극이 Strong하게 연결됨을 의미합니다. First, TEER was measured to check resistance between cells, and the results are shown in FIG. 2. By measuring resistance between cells, the higher the resistance, the stronger the gap between cells.
도 2의 결과를 보면 Indomethacin(IND)을 처리 한 후 세포 저항성이 현저하게 감소함을 볼 수 있으며 이때 PPI를 처리하여도 동일하게 세포 저항성이 감소되었음을 확인할 수 있습니다. 그러나 이때 P-CAB 처리 세포를 보시면 세포저항성이 유의적으로 증가함을 볼 수 있었습니다. In the results of Figure 2 it can be seen that after the treatment of Indomethacin (IND), the cell resistance is significantly reduced, and at this time, the cell resistance is also reduced even if the PPI treatment. However, the P-CAB treated cells showed a significant increase in cell resistance.
이어서 이 위장관 투과도(Intestinal permeability)와 관련 있는 tight junction protein들에는 어떤 영향이 있는지 확인하고자 western blotting을 시행하였고 그 결과를 도 3에 나타냈는데, 도 3을 보면 대표적인 tight junction protein인 ZO-2, occludin-1, claudin-1에서 IND 처리에 의하여 정상보다 그 발현이 감소해 있었으며 이때 PPI 처리시 더욱 발현이 감소하거나 또는 변화가 없었지만 이때 P-CAB의 처리 세포는 정상과 비교하여 비슷하거나 더 높은 수준으로 발현하는 것을 알 수 있었습니다. Subsequently, western blotting was performed to confirm the effect on the tight junction proteins related to the gastrointestinal permeability and the results are shown in FIG. 3. FIG. 3 shows the representative tight junction proteins ZO-2 and occludin. -1, claudin-1 showed decreased expression than normal by IND treatment, but there was no decrease or change in PPI treatment, but P-CAB treated cells were similar or higher than normal. It was found to manifest.
또한 이러한 tight junction 과 관련성이 높은 Molecular switch인 Rho-GTPase의 활성도를 확인하여 그 결과를 도 4에 나타냈는데, 도 4를 보면 IND 처리에 의하여 증가된 active Rho의 발현이 PPI 처리에 의하여 변화가 없음을 확인하였지만 이 때 P-CAB의 처리에 의하여 그 발현이 감소함을 확인하였습니다. In addition, the result of confirming the activity of Rho-GTPase, a Molecular switch that is highly related to such tight junction, is shown in FIG. 4, which shows that the expression of active Rho increased by IND treatment is not changed by PPI treatment. At this time, it was confirmed that the expression was reduced by the treatment of P-CAB.
이상의 세포실험 결과를 바탕으로 동물실험을 진행하였다. Animal experiments were conducted based on the results of the above cell experiments.
동물은 SD RAT을 이용하였고 NSAID로써 Indomethacin을 경구 투여하였고 이와 함께 PPI로는 Pantoprazole을 정맥주사하였으며, P-CAB으로는 Revaprazan을 경구 투여하였으며, 투여 후 48시간 후에 Sacrifice 하여 gross와 pathologic index를 측정하고 molecular work을 진행하였다. Animals were treated with SD RAT, oral administration of Indomethacin as NSAID, and intravenous injection of Pantoprazole with PPI, oral administration of Revaprazan with P-CAB. Sacrifice was performed 48 hours after administration to measure gross and pathologic index and Work was progressed.
도 5로 나타낸 결과를 보면 gross에서 IND 투여에 의하여 소장에 출혈과 부종 등을 관찰할 수 있었으며 이때 PPI를 투여한 그룹에서도 동일한 소견을 얻을 수 있었다. 하지만 이때 P-CAB을 투여한 그룹에서는 상태가 호전되어 보이는 Gross를 확인할 수 있었다. As shown in FIG. 5, bleeding and edema were observed in the small intestine by IND administration in gross, and the same findings were obtained in the PPI-administered group. At this time, however, Gross was found to improve in the group administered with P-CAB.
또한 동물 조직으로 이용하여 병리학적으로 보았을 때 각 조직을 융모 손실(villi loss), 궤양(ulceration), 염증(inflammation) 등의 기준으로 점수화 하였고 그 결과를 도 6에 나타냈는데, IND을 단독으로 투여한 그룹에서는 심각한 vili loss, inflammation 등을 확인할 수 있으며 이때 PPI를 함께 투여한 그룹에서도 비슷한 양상의 소견을 보였습니다. 하지만 P-CAB을 투여한 그룹에서는 이러한 vili loss, inflammation 등이 좀 더 호전되는 결과를 보여주었다. In addition, each tissue was scored on the basis of villi loss, ulceration, inflammation, and the like, when viewed pathologically as an animal tissue, and the results are shown in FIG. 6. In one group, severe vili loss and inflammation were observed, with similar findings in the group receiving PPI. However, the group receiving P-CAB showed more improvement in vili loss and inflammation.
이상의 실험동물 조직을 이용하여 염증과 관련한 인자들을 확인하여 그 결과를 도 7에 나타냈는데, 그 결과 대표적인 pro-inflammatory cytokine 들의 발현이 IND처리 그룹과 PPI 병행 처리 그룹에서 높은 발현을 보였으며 이와 비교하여 P-CAB 처리 그룹에서는 그 발현이 감소함을 확인할 수 있었다. Inflammation-related factors were identified using the above-described experimental animal tissues, and the results are shown in FIG. 7. As a result, the expression of representative pro-inflammatory cytokines showed high expression in the IND treatment group and the PPI treatment group. In the P-CAB treatment group it was confirmed that its expression is reduced.
또한 위장관 투과도(Intestinal permeability)에 inflammasome의 활성이 영향을 미친다는 보고 등을 참고하여 inflammasome 과 관련된 인자들을 확인하여 그 결과를 도 8에 나타냈는데, 그 결과를 보면 IND 처리그룹에서 증가된 각 인자의 발현들이 오히려 PPI와 병행 처리시 그 발현이 더욱 증가되어 있음을 보였지만 이때 P-CAB 처리그룹에서는 그 발현 또한 감소되어 있음을 확인할 수 있었다. In addition, the factors related to inflammasome were identified by referring to the report that inflammasome activity affects gastrointestinal permeability, and the results are shown in FIG. 8. Although expressions were shown to be more increased in parallel treatment with PPI, the expression was also reduced in the P-CAB treatment group.
마지막으로 위장관 투과도(Intestinal permeability)의 endpoint인 tight junction과 관련한 인자들을 확인하여 그 결과를 도 9에 나타냈는데, 그 결과를 보면 IND 처리에 의하여 tight junction protein의 발현이 감소되어 있음을 확인하였고 이때 PPI를 병행처리그룹에서는 그 발현이 ind 처리 그룹과 비슷하거나 오히려 더욱 감소되어 있음을 보였지만 이때 P-CAB처리 그룹에서는 Occluin-1, claudin-2 등의 발현이 증가됨을 확인할 수 있었다. Finally, the factors related to tight junction, an endpoint of intestinal permeability, were identified and the results are shown in FIG. 9. The results confirmed that the expression of tight junction protein was decreased by IND treatment. In the parallel treatment group, the expression of the ind treatment group was shown to be similar or even more reduced, but the expression of Occluin-1 and claudin-2 was increased in the P-CAB treatment group.
이상의 결과를 요약하면 NSAID에 의하여 위장관(Intestinal permeability)가 증가함을 확인할 수 있었고 이 때 PPI의 사용은 별다른 호전효과를 보이지 않았지만 P-CAB의 사용이 오히려 NSAID에 의해 유도된 Permeability 증가 및 intestinal damage를 완화시키는 효과를 보여주었고 이러한 효과들은 inflammasome을 비롯한 염증 mediator를 감소시키고 tight junction protein을 preserve 하는 효과에 기인함을 알 수 있었다. Summarizing the above results, it was confirmed that the gastrointestinal tract (Intestinal permeability) is increased by NSAID. At this time, the use of PPI showed no improvement effect, but the use of P-CAB increased the permeability and intestinal damage induced by NSAID. The effect was alleviated, and these effects were attributed to the reduction of inflammatory mediators including inflammasome and preservation of tight junction protein.
결론적으로 NSAID에 의한 위장관 손상(Intestinal damage)에서 오는 장 누수 증후군(leaky gut syndrome)에서 PPI의 투여는 오히려 상태를 더욱 악화시킴을 보여줌으로써 PPI 대신 P-CAB의 사용이 장 누수 증후군(leaky gut syndrome)에 효과적으로 예방 및 치료함을 알 수 있다.In conclusion, the use of P-CAB instead of PPI may lead to a worsening of the condition in the case of leaky gut syndrome resulting from NSAID Intestinal damage. ) Can be effectively prevented and treated.
상술한 설명에서는 P-CAB으로 레바프라잔(Revaprazan)을 예를 들어 설명을 하였으나 NSAID에 의한 장 누수 증후군(leaky gut syndrome)에 유용한 것은 P-CAB으로 본 발명이 속하는 기술 분야에 널리 알려진 것이라면 특별한 제한 없이 사용가능하며, 그 예로는 보노프라잔(Vonoprazan), 리나프라잔( Linaprazan), 소라프라잔(Soraprazan) 등을 들 수 있다. In the above description, Revaprazan has been described as an example of P-CAB, but it is useful for the leaky gut syndrome caused by NSAIDs if P-CAB is widely known in the art to which the present invention belongs. It can be used without limitation, and examples thereof include Vonoprazan, Linaprazan, Soraprazan and the like.
Claims (3)
- 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)를 유효성분을 함유하는 장 누수 증후군(leaky gut syndrome) 치료 및 예방용 조성물.Composition for the treatment and prevention of leaky gut syndrome containing potassium competitive gastric acid secretion inhibitor (Potassium-Competitive Acid Blocker, p-cab) as an active ingredient.
- 제 1항에 있어서, 상기 장 누수 증후군(leaky gut syndrome)이 비스테로이드성 항염제(nonsteroidal anti-inflammatory drug, NSAID))에 의해 유발되는 것을 특징으로 하는 장 누수 증후군(leaky gut syndrome) 치료 및 예방용 조성물.The method of claim 1, wherein the leaky gut syndrome is caused by a nonsteroidal anti-inflammatory drug (NSAID). Composition.
- 제 1항 또는 제 2항에 있어서, 상기 칼륨 경쟁적 위산분비억제제(Potassium-Competitive Acid Blocker, p-cab)이 레바프라잔(Revaprazan), 보노프라잔(Vonoprazan), 리나프라잔( Linaprazan) 및 소라프라잔(Soraprazan)으로 이루어진 군에서 선택되는 어느 하나 이상인 것을 특징으로 하는 장 누수 증후군(leaky gut syndrome) 치료 및 예방용 조성물.The method of claim 1 or 2, wherein the potassium competitive gastric acid inhibitor (Potassium-Competitive Acid Blocker, p-cab) is Levaprazan, Vonoprazan, Linaprazan and Sora Prazan (Soraprazan) composition for the treatment and prevention of leaky syndrome (leaky gut syndrome), characterized in that any one or more selected from the group consisting of.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170033118A KR20180107341A (en) | 2017-03-16 | 2017-03-16 | Composition for the treatment and prevention of Leaky Gut Syndrome comprising Potassium-Competitive Acid Blocker as active component |
| KR10-2017-0033118 | 2017-03-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018169153A1 true WO2018169153A1 (en) | 2018-09-20 |
Family
ID=63522412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2017/010349 WO2018169153A1 (en) | 2017-03-16 | 2017-09-20 | Composition, containing potassium-competitive acid blocker as active ingredient, for treatment and prevention of leaky gut syndrome |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20180107341A (en) |
| WO (1) | WO2018169153A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100010412A1 (en) | 2021-04-26 | 2022-10-26 | Anseris Farma S R L | COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL AND METABOLIC SYNDROME RELATED TO INTESTINAL PERMEABILITY ALTERATIONS. |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11202104258TA (en) * | 2018-11-02 | 2021-05-28 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010056078A1 (en) * | 2000-02-11 | 2001-12-27 | Norton Healthcare Limited | Novel method for treating gut disorders using polyanionic polyglycosides |
| KR20070057663A (en) * | 2005-12-01 | 2007-06-07 | 주식회사유한양행 | Composition for the prevention or treatment of gastrointestinal mucosa damage |
| US8183211B2 (en) * | 2000-05-19 | 2012-05-22 | University Of Maryland, Baltimore | Pharmaceutical compositions for inhibiting intestinal permeability |
| US20150057349A1 (en) * | 2012-03-30 | 2015-02-26 | Nestec S.A. | 4-oxo-2-pentenoic acid and the health of the digestive tract |
| US20150258151A1 (en) * | 2012-12-07 | 2015-09-17 | Albert Einstein College Of Medicine Of Yeshiva University | Gut barrier dysfunction treatment and prevention |
-
2017
- 2017-03-16 KR KR1020170033118A patent/KR20180107341A/en not_active Ceased
- 2017-09-20 WO PCT/KR2017/010349 patent/WO2018169153A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010056078A1 (en) * | 2000-02-11 | 2001-12-27 | Norton Healthcare Limited | Novel method for treating gut disorders using polyanionic polyglycosides |
| US8183211B2 (en) * | 2000-05-19 | 2012-05-22 | University Of Maryland, Baltimore | Pharmaceutical compositions for inhibiting intestinal permeability |
| KR20070057663A (en) * | 2005-12-01 | 2007-06-07 | 주식회사유한양행 | Composition for the prevention or treatment of gastrointestinal mucosa damage |
| US20150057349A1 (en) * | 2012-03-30 | 2015-02-26 | Nestec S.A. | 4-oxo-2-pentenoic acid and the health of the digestive tract |
| US20150258151A1 (en) * | 2012-12-07 | 2015-09-17 | Albert Einstein College Of Medicine Of Yeshiva University | Gut barrier dysfunction treatment and prevention |
Non-Patent Citations (1)
| Title |
|---|
| CHA CANCER PREVENTION RESEARCH CENTER, CHA CANCER INSTITUTE, CHA UNIVERSITY ET AL.: "Indomethacin-induced Leaky Gut Syndrome Aggravated by Pantoprazole, but Not by Revaprazan: PPI Aggravated, but p-CAB Relieved NSAID-induced Intestinal Permeability", THE 10TH INTERNATIONAL GASTROINTESTINAL CONSENSUS SYMPOSIUM, vol. 4, 18 February 2017 (2017-02-18), pages 104 - 4 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100010412A1 (en) | 2021-04-26 | 2022-10-26 | Anseris Farma S R L | COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL AND METABOLIC SYNDROME RELATED TO INTESTINAL PERMEABILITY ALTERATIONS. |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20180107341A (en) | 2018-10-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hu et al. | The gut microbiota contributes to the development of Staphylococcus aureus-induced mastitis in mice | |
| Friedrich et al. | HDAC inhibitors promote intestinal epithelial regeneration via autocrine TGFβ1 signalling in inflammation | |
| König et al. | Human intestinal barrier function in health and disease | |
| Dai et al. | Sodium butyrate ameliorates high-concentrate diet-induced inflammation in the rumen epithelium of dairy goats | |
| Bücker et al. | Aerolysin from Aeromonas hydrophila perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells | |
| Zhang et al. | Cathelicidin-BF, a novel antimicrobial peptide from Bungarus fasciatus, attenuates disease in a dextran sulfate sodium model of colitis | |
| Choi et al. | Enhanced wound healing by recombinant Escherichia coli Nissle 1917 via human epidermal growth factor receptor in human intestinal epithelial cells: therapeutic implication using recombinant probiotics | |
| Barbara et al. | Corrigendum: Inflammatory and microbiota-related regulation of the intestinal epithelial barrier | |
| WO2018169153A1 (en) | Composition, containing potassium-competitive acid blocker as active ingredient, for treatment and prevention of leaky gut syndrome | |
| Wang et al. | Distinct roles of intracellular heat shock protein 70 in maintaining gastrointestinal homeostasis | |
| CN117070389A (en) | Enterococcus faecium strain for improving intestinal barrier function and application thereof | |
| IL265761B2 (en) | Tralipressin compounds for oral use for the treatment of ascites | |
| Kum et al. | Protective role of Akt2 in Salmonella enterica serovar typhimurium-induced gastroenterocolitis | |
| Hung et al. | Acetate, a gut bacterial product, ameliorates ischemia-reperfusion induced acute lung injury in rats | |
| Yan et al. | Intestine‐Decipher Engineered Capsules Protect Against Sepsis‐induced Intestinal Injury via Broad‐spectrum Anti‐inflammation and Parthanatos Inhibition | |
| Tomlinson et al. | Interactions between lipopolysaccharide and the intestinal epithelium | |
| Liu et al. | Mechanism of ulcerative colitis-aggravated liver fibrosis: the activation of hepatic stellate cells and TLR4 signaling through gut-liver Axis | |
| Wang et al. | The protective effect of l-theanine on the intestinal barrier in heat-stressed organisms | |
| Tian et al. | Oral delivery of mouse β-Defensin 14 (mBD14)-producing Lactococcus lactis NZ9000 attenuates experimental colitis in mice | |
| Osman et al. | Serosal but not mucosal endotoxin exposure increases intestinal permeability in vitro in the rat | |
| Qin et al. | Arbutin alleviates intestinal colitis by regulating neutrophil extracellular traps formation and microbiota composition | |
| Notebaert et al. | In vivo imaging of NF‐κB activity during Escherichia coli‐induced mammary gland infection | |
| CN114392264A (en) | Pharmaceutical composition and application thereof in treating ulcerative colitis | |
| Margutti et al. | Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions | |
| Zhang et al. | Thonningianin A ameliorated renal interstitial fibrosis in diabetic nephropathy mice by modulating gut microbiota dysbiosis and repressing inflammation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17900644 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 17900644 Country of ref document: EP Kind code of ref document: A1 |