WO2022246586A1 - Utilisation d'un extrait d'huile riche en curcuminoïde pour le traitement d'une lésion pulmonaire aiguë - Google Patents

Utilisation d'un extrait d'huile riche en curcuminoïde pour le traitement d'une lésion pulmonaire aiguë Download PDF

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WO2022246586A1
WO2022246586A1 PCT/CN2021/095393 CN2021095393W WO2022246586A1 WO 2022246586 A1 WO2022246586 A1 WO 2022246586A1 CN 2021095393 W CN2021095393 W CN 2021095393W WO 2022246586 A1 WO2022246586 A1 WO 2022246586A1
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oil
lps
group
atg
curcuminoid
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Tzung-Yan LEE
Hen-Hong Chang
Wei-Han CHIANG
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Lee Tzung Yan
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine

Definitions

  • the present disclosure in general relates to the field of disease treatment. More particularly, the present disclosure relates to novel use of a curcuminoid-rich oil extract in the treatment of acute lung injury (ALI) , such as acute respiratory distress syndrome (ARDS) .
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) with an overall mortality rate of about 43%remains the leading cause of death in intensive care.
  • Pathological features of the disease include diffuse alveolar capillary injury and increased lung permeability associated with a strong inflammatory response. These changes underlie clinical symptoms characterized by acute onset, severe hypoxemia and proteinaceous pulmonary edema.
  • various treatment strategies such as using glucocorticoids, ketoconazole, lysophylline, alprostadil, inhaled nitric oxide (NO) or supplemented surfactant.
  • therapeutic pharmacological interventions have so far failed to improve the clinical outcome of ALI /ARDS.
  • the only obvious improvement for ARDS patient survival has been the implementation of a minimally invasive ventilation policy with low tidal volume.
  • Curcuma longa a member of the ginger family (Zingiberaceae) , has rhizomes below the ground. Curcuma longa has been used for thousands of years as a remedy in folk medicine for the cure of a wide variety of illnesses, such as inflammation, infectious diseases, and gastric, hepatic, and blood disorders. Curcuminoids such as curcumin are natural polyphenol compounds derived from Curcuma longa, their biological activities have been extensively investigated, including for their role as nutraceuticals with potential against cancer, diabetes and inflammation.
  • the present disclosure aims at a novel use of a curcuminoid-rich extract of Curcuma longa produced by the method of the present disclosure, in which the curcuminoids in the thus produced curcuminoid-rich extract has more than 5-folds of bisdemethoxycurcumin as compared to that in the extract produced by an existing known method.
  • the present curcuminoid-rich oil extract is found to suppress the expression of proteins associated with ALI in young, aged, and farnesoid X receptor (FXR) deficient subjects, thus the present curcuminoid-rich oil extract is useful as a medicament or a dietary supplement for the treatment of ALI (e.g., ARDS) .
  • the present disclosure is directed to a novel use of a curcuminoid-rich oil extract produced by the present disclosure, in which the curcuminoid-rich oil extract is found to suppress the expression of proteins associated with ALI, thus are useful as medicaments or dietary supplements for the treatment of ALI (e.g., acute respiratory distress syndrome, ARDS) .
  • ALI acute respiratory distress syndrome
  • the curcuminoid-rich oil extract comprises curcuminoids dissolved in an oil, and the curcuminoids consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30% (wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the curcuminoid-rich oil extract is produced by a method, which includes steps of extracting dried Curcuma longa powders with an oil, thereby producing a curcuminoid-rich oil extract, in which the curcuminoids consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30%(wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the extraction is performed by, (i) mixing the dried Curcuma longa powders with the oil; and (ii) double boiling the oil mixture of the step (i) under ultra-sound vibrations.
  • the oil suitable for mixing with dried Curcuma longa powders in the step (i) is an edible vegetable oil.
  • exemplary edible vegetable oil includes, but is not limited to, coconut oil, corn oil, canola oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, sunflower oil, sesame oil, soybean oil, and nut oil.
  • the dried Curcuma longa powders is extracted with olive oil.
  • the double boiling in the step (ii) is performed by heating the oil mixture sequentially at 50°C for 30 min, 60°C for 30 min, and 80°C for 30 min; in which each heating is accompanied with the ultra-sound vibrations about 25-35 kHz in frequency.
  • the dried Curcuma longa powders are prepared by, (a) cutting the rhizome of a fresh Curcuma longa into slices; (b) drying the slices of the step (a) at 55°C; and (c) grounding the dried slices of the step (b) into powders via a ball-miller.
  • the curcuminoid-rich oil extract thus produced comprises curcuminoids dissolved in the oil, in which the curcuminoids consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30%(wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the subject suitable for receiving the curcuminoid-rich oil extract produced by the present method is a mammal; preferably, a human.
  • extract encompasses crude extracts as well as processed or refined extract.
  • crude extracts are prepared by a simple extraction in which dried root powders of the selected plant are brought into contact with an extractant (i.e., an oil) in the presence of heat, and optionally in combination of ultrasound vibrations.
  • an extractant i.e., an oil
  • the thus-produced crude extract is subjected to one or more separation and/or purification steps to obtain purified, processed or refined extracts.
  • the extract may be in liquid form, such as a solution, a concentrate, or a distillate.
  • weight percentage refers to the weight percentage of an ingredient (e.g., the bisdemethoxycurcumin, demethoxycurcumin, or curcumin of the present curcuminoid-rich extract) in a mixture containing the ingredient.
  • the weight percentage (wt %) is calculated as the weight of the ingredient divided by the total weight of the mixture expressed in percentage and/or decimal.
  • the term “treat, ” “treating” and “treatment” are interchangeable, and encompasses partially or completely preventing, ameliorating, mitigating and/or managing a symptom, a secondary disorder or a condition associated with ALI.
  • the term “treating” as used herein refers to application or administration of the of the present disclosure to a subject, who has a symptom, a secondary disorder or a condition associated with ALI, with the purpose to partially or completely prevent, alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, and/or reduce incidence of one or more symptoms, secondary disorders or features associated with ALI.
  • Treatment may be administered to a subject who exhibits only early signs of such symptoms, disorder, and/or condition for the purpose of decreasing the risk of developing the symptoms, secondary disorders, and/or conditions associated with ALI.
  • Treatment is generally “effective” if one or more symptoms or clinical markers associated with ALI are reduced.
  • a treatment is “effective” if the progression of a symptom, disorder or condition is reduced or halted.
  • an effective amount designate the quantity of a component which is sufficient to yield a desired response.
  • the effective amount is also one in which any toxic or detrimental effects of the component are outweighed by the therapeutically beneficial effects.
  • An effective amount of an agent is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered or prevented, or the disease or condition symptoms are ameliorated.
  • the effective amount may be divided into one, two, or more doses in a suitable form to be administered at one, two or more times throughout a designated time period.
  • Effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient (e.g., the patient's body mass, age, or gender) , the type of mammal or animal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives. Effective amount may be expressed, for example, in grams, milligrams or micrograms or as milligrams per kilogram of body weight (mg/Kg) .
  • the effective amount can be expressed in the concentration of the active component (e.g., bisdemethoxycurcumin, demethoxycurcumin, or curcumin of the present curcuminoid-rich oil extract) , such as molar concentration, mass concentration, volume concentration, molality, mole fraction, mass fraction and mixing ratio.
  • the active component e.g., bisdemethoxycurcumin, demethoxycurcumin, or curcumin of the present curcuminoid-rich oil extract
  • HED human equivalent dose
  • FDA US Food and Drug Administration
  • subject and patient are used interchangeably herein, and are intended to mean an animal including the human species that is treatable by the curcuminoid-rich oil extract and/or method of the present invention.
  • subject or patient intended to refer to both the male and female gender unless one gender is specifically indicated. Accordingly, the term “subject” or “patient” comprises any mammal, which may benefit from the curcuminoid-rich oil extract or the treatment method of the present disclosure.
  • a “subject” or “patient” include, but are not limited to, a human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse, dog, cat, bird and fowl.
  • the subject is a human.
  • the present disclosure is directed to a novel use of a curcuminoid-rich oil extract, which is found to suppress the expression of proteins associated with ALI; thus the present curcuminoid-rich oil extract is useful as a medicament or a dietary supplement for the treatment of ALI (e.g., acute respiratory distress syndrome, ARDS) .
  • ALI acute respiratory distress syndrome
  • the curcuminoid-rich oil extract comprises curcuminoids dissolved in an oil, and the curcuminoids consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30% (wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the curcuminoid-rich oil extract comprises curcuminoids dissolved in an oil, in which the curcuminoids consist of about 26.7% (wt%) of bisdemethoxycurcumin, about 28.8% (wt%) of demethoxycurcumin, and about 44.5% (wt%) of curcumin.
  • curcuminoid-rich oil extract is produced by procedures described in working example of the present disclosure. Specifically, the rhizome of a fresh Curcuma longa is cut into slices about 0.2 cm in thickness, which are dried at 55°C, and then grounded into powders, such as with the aid of a ball-miller. Additionally or alternatively, the grounded powders may be filtered through a filter about 400 meshes to give Curcuma longa powders independently less than 38 ⁇ m in diameter.
  • the thus produced dried Curcuma longa powders are mixed with an edible vegetable oil in a weight (g) to volume (L) ratio of 10: 1 to 1: 10, such as 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1, 9: 2, 9: 3, 9: 4, 9: 5, 9: 6, 9: 7, 9: 8, 9: 10, 8: 3, 8: 5, 8: 6, 8: 7, 8: 9, 8: 10, 7: 2, 7: 3, 7: 4, 7: 5, 7: 6, 7: 8, 7: 9, 7: 10, 6: 4, 6: 5, 6: 7, 6: 8, 6: 9, 6: 10, 5: 2, 5: 3, 5: 4, 5: 6, 5: 7, 5: 8, 5: 9, 5: 10, 4: 1, 4: 3, 4: 5, 4: 6, 4: 7, 4: 8, 4: 9, 4: 10, 3: 1, 3: 7, 3: 8, 3: 10, 2: 9, 2: 7, 1: 7, 1: 8, 1: 9, and 1: 10; preferably, in a weight (g) to volume (L) ratio of 10:
  • Exemplary edible vegetable oil suitable for use in the present method includes, but is not limited to, coconut oil, corn oil, canola oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, sunflower oil, sesame oil, soybean oil, and nut oil.
  • the dried Curcuma longa powders is extracted with olive oil.
  • the oil mixture is double boiled first at 50°C for 30 min, then at 60°C for 30 min, and finally 80°C for 30 min, respectively; with each heating being conducted in the presence of ultra-sound vibrations about 25-35 kHz in frequency, such as about 28 kHz.
  • the step of “double boiling” referred to heating the oil mixture of dried Curcuma longa powders and oil (e.g., olive oil) indirectly, that is, by placing the mixture in a first container, which is placed over a second container pre-filled with sufficient amount of water, then applied direct heat to the second container until the temperature in the second container reached a pre-designated temperature (e.g., 50, 60 or 80°C) , which is then maintained for a pre-described period (e.g., 30 min) .
  • a pre-designated temperature e.g., 50, 60 or 80°C
  • a pre-described period e.g. 30 min
  • ultrasound wave vibrations about 25-35 kHz, such as 25, 26, 27, 28, 30, 31, 32, 33, 34 and 35 kHz are applied to the first container during the entire double boiling period.
  • the thus produced oil extract was termed “ATG-235 solution” in the present disclosure.
  • the ATG-235 solution is rich in curcuminoids, in which the curcuminoids in the ATG-235 solution consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30% (wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the ATG-235 solution consisted of about 26.7% (wt%) of bisdemethoxycurcumin, about 28.8% (wt%) of demethoxycurcumin, and about 44.5% (wt%) of curcumin; while the curcuminoids in the Curcuma longa extract produced by a known conventional process consist 5.7% (wt%) of bisdemethoxycurcumin, 24.1% (wt%) of demethoxycurcumin, and 70.8% (wt%) of curcumin.
  • ATG-235 solution produced by the present method is rich in bisdemethoxycurcumin and low in curcumin, with bisdemethoxycurcumin being about 5-folds more than that produced by the known method, and curcumin being about half of that produced by the known method.
  • the present curcuminoid-rich extract or the ATG-235 solution may be formulated with one or more appropriate pharmaceutically acceptable carriers or excipients, and may be formulated into dosage forms suitable for oral and parenteral administration.
  • the ATG-235 solution of the present disclosure may be administered alone or in combination with other known pharmaceutically active agent to treat ALI.
  • One of skilled person in the art is familiar with the various dosage forms that are suitable for use in each route.
  • the ATG-235 solution of the present disclosure is formulated into a liquid dosage form for parenteral administration, such as injection, which includes, but is not limited to, subcutaneous, intramuscular, intraperitoneal and intravenous injection.
  • parenteral administration such as injection
  • the ATG-235 solution may be formulated in oily or aqueous vehicles, and may contain formulatory agents and/or flavoring agents. They may be presented in sterile ampoules or vials.
  • the ATG-235 solution of the present disclosure is formulated into liquid dosage forms for oral administration.
  • the liquid dosage formulations may also be filled into soft gelatin capsules.
  • the liquid may include a solution, suspension, emulsion, micro-emulsion, precipitate or any desired liquid media carrying the active ingredients of the present ATG-235 solution.
  • the liquid may be designed to improve the solubility of the active ingredients of the present ATG-235 solution to form a drug-containing emulsion or disperse phase upon release.
  • the present curcuminoid-rich oil extract or ATG-235 solution is orally or parenterally administered to a subject suffering from ALI in a single dose or in multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more doses) .
  • the subject suitable for receiving the curcuminoid-rich oil extract produced by the present method is a mammal; preferably, a human.
  • the subject is a mouse.
  • about 1-100 mg/Kg body weight per dose of the present curcuminoid-rich oil extract is administered to the subject; preferably, about 10-90 mg/Kg body weight per dose of the present ATG-235 solution is administered to the subject; more preferably, 50-70 mg of the present ATG-235 solution per Kg body weight per dose is sufficient to elicit a therapeutic effect on muscle atrophy in the subject.
  • the effective amount of the present ATG-235 solution suitable for use in a human subject may be in the range of 0.08-8 mg/Kg body weight per dose for human; preferably, 0.8-8 mg/Kg body weight per dose.
  • the curcuminoid-rich oil extract of the present disclosure is administered to the subject daily for at least 7 days; for example, being administered to the subject daily for 7, 8, 9, 10, 11, 12, 13, 14, or more day. In one specific example, the curcuminoid-rich oil extract of the present disclosure is administered to the subject daily for 14 days.
  • the skilled artisan or clinical practitioner may adjust the dosage or regime in accordance with the physical condition of the patient or the severity of the diseases.
  • the present curcuminoid-rich oil extract can be applied to the subject, alone or in combination with additional therapies that have some beneficial effects on the prevention or treatment of ALI.
  • the present curcuminoid-rich oil extract can be applied to the subject before, during, or after the administration of the additional therapies.
  • the subject treatable by the present curcuminoid-rich oil extract and/or method is a mammal, for example, human, mouse, rat, guinea pig, hamster, monkey, swine, dog, cat, horse, sheep, goat, cow, and rabbit.
  • the subject is a human.
  • LPS Lipopolysaccharide
  • ALI acute lung injury
  • mice Male C57BL/6J young and aged mice (4 and 18 months old) , and young Nr1h4 knock-out mice (FXR KO, B6.129 x 1 (FVB) -Nr1h4 tm1Gonz /J Stock No: 007214, 4 months old) were kept in an environment having 12-hour light/dark cycle, average temperature about 25 ⁇ 1.0 °C, and humidity about 60-70%, with ad libitum access to food and water. All protocols were approved by the Committee of Animal Protection and Uses.
  • mice were randomly assigned into 12 groups (5 mice per group) , which were (1) young normal control group (4 months old) ; (2) young LPS treatment group (4 months old) ; (3) young LPS + ATG-235 treatment group; (4) young LPS +theophylline (Th) treatment group; (5) aged group (18 months old) ; (6) aged LPS treatment group; (7) aged LPS + ATG-235 treatment group; (8) aged LPS + theophylline (Th) treatment group; (9) FXR KO mice (4 months old) , (10) FXR KO mice (4 months old) + LPS group; (11) FXR KO mice (4 months old) + LPS + ATG-235 treatment group; and (12) XR KO mice (4 months old) +LPS + theophylline (Th) treatment group.
  • mice were intraperitoneally (ip) injected with PBS or LPS (3 mg/Kg) for 7 days, followed by orally feeding with olive oil, the ATG-235 solution of Example 1 (2 mL/Kg) , or theophylline (10 mg/Kg) for 14 days. All animals were sacrificed for further study 15 days after the last dose of LPS.
  • mice were sacrificed and the brain tissues were immediately harvested and fixed in metaformaldehyde (4%) , followed by embedding in paraffin. The paraffin embedded tissues were then sliced into sections about 5 ⁇ m in thickness. Before immunostaining, tissue samples were deparaffinized by washing in xylene and graded alcohol series. The endogenous peroxidase activity was blocked by hydrogen peroxidase treatment. Tissue samples were then washed with distilled water and transferred to Tris-buffered saline (0.5% 20, pH 7.4, (TBS-T) ) containing 5%normal goat serum for 30 minutes.
  • TBS-T Tris-buffered saline
  • tissue samples were incubated with anti-IL-1 ⁇ , anti-p65 NF- ⁇ B, anti-p38 mitogen-activated protein kinase (MAPK) , anti-Myeloperoxidase (MPO) , anti-NLR family pyrin domain containing 3 (NLRP3) , anti-caspase 1, anti-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 ⁇ ) , anti-TFAM (transcription factor A, mitochondrial) , anti-myelin regulatory factor-1 (MRF-1) , anti-SIRT1, and MITOTRACKER TM or reactive oxygen species (ROS) staining agent at room temperature for 2 hours.
  • MRF-1 messenger kinase
  • MRF-1 anti-myelin regulatory factor-1
  • MITOTRACKER TM reactive oxygen species
  • Tissue samples were further incubated with the secondary antibody ( 488, 633, anti-mouse or anti-rabbit secondary antibody) at room temperature for 1 hour. All antibodies were diluted in 2%non-immune goat serum, in which the serum was dissolved in PBS (PBST) . Tissue samples were incubated with 3, 30-diaminobenzidine (DAB) for 5-10 minutes, and hematoxylin or 4′, 6-diamidino-2-phenylindole (DAPI) was used for nuclear staining.
  • the secondary antibody 488, 633, anti-mouse or anti-rabbit secondary antibody
  • BALF bronchoalveolar lavage fluid
  • Bronchoalveolar lavage fluid was obtained by lavage the lungs of mice by passing 1 mL of PBS solution through the trachea.
  • BAL cells were centrifuged (at 500 x g, 4°C, 10 min) to sediment, the sediment was resuspended, and the total number of white blood cells was calculated in a Goyaev chamber.
  • the cytological composition of BALF was examined by an optical microscope equipped with an oil immersion lens. The number of monocytes /macrophages, neutrophils, eosinophils and lymphocytes per 200 cells was counted and observed in at least 5 fields. The relative cell number of each cell population was expressed as a percentage of the total cell number.
  • the levels of non-cellular contents such as TNF- ⁇ , IL-1 ⁇ , and IL-6 in BALF were also determined by ELISA.
  • the roots of fresh Curcuma longa were cut into thin slices respectively about 0.2 cm in thickness. Dried the root slices in an oven of 55°C, then grounded the dried slices into powders via use of a ball-miller. Filtered the grounded powders through a filter of 400 meshes, thereby producing a dried, filtered Curcuma longa powders independently ⁇ 38 ⁇ m in diameter.
  • Example 2 ATG-235 solution ameliorated LPS-induced ALI in young mice
  • mice (4 months old) were intraperitoneally injected with LPS (3 mg/Kg) to induce symptoms of ALI, then treated with oral administration of ATG-235 solution (2 mL/kg) or theophylline (Th) (10 mg/Kg) .
  • ATG-235 solution (2 mL/kg) or theophylline (Th) (10 mg/Kg) .
  • the pulmonary architecture of the mice was evaluated by histological analysis, infiltration of cells was observed microscopically, while cytokine production and the expressions of proteins associated with ALI were analyzed by immuno-blotting. Results are depicted in FIGs 1 to 5.
  • the HE-stained histopathological features of lungs revealed that LPS induced haemorrhagic and erythematous conditions, interalveolar septal thickening, and pulmonary interstitial edema, which were symptoms of ALI. Surprisingly, the distortion of the pulmonary architecture was significantly suppressed in the ATG-235 or Th-treated mice (FIG 1, (A) and (B) ) .
  • the histological scores for the evaluation of pulmonary architecture are summarized in Table 1.
  • LPS treatment also caused infiltration of cells (i.e., neutrophils, macrophages, and etc) , cytokine production (i.e., TNF- ⁇ , IL-1 ⁇ , and IL-6) and enhanced expression of inflammation proteins (i.e., MAPK, NF- ⁇ B, and IL-1 ⁇ ) , which were independently attenuated by the treatment of the ATG-235 solution or Th (FIGs 2 and 3) .
  • cells i.e., neutrophils, macrophages, and etc
  • cytokine production i.e., TNF- ⁇ , IL-1 ⁇ , and IL-6
  • enhanced expression of inflammation proteins i.e., MAPK, NF- ⁇ B, and IL-1 ⁇
  • Example 3 ATG-235 solution ameliorated LPS-induced ALI in aged mice
  • mice were challenged with LPS in induce ALI, and then treated with ATG-235 solution or Th in accordance with procedures described in in Example 2, except aged mice (18 months old) , and not young mice (4 months old) , were used. Results are depicted in FIGs 6 to 10.
  • HE-stained histopathological features of LPS-treated lungs of the aged mice also exhibited haemorrhagic and erythematous conditions, interalveolar septal thickening, and pulmonary interstitial edema, which were symptoms of ALI.
  • the distortion of the pulmonary architecture was also significantly suppressed by the administration of ATG-235 solution or Th (FIG 6, (A) and (B) ) .
  • mice not treated with LPS compared to the control mice (i.e., mice not treated with LPS) , administration of ATG-235 solution or Th to LPS-treated mice led to a significant reduction in the weight ratio of the wet and dried lungs of the mice, an indication that LPS-induced lung infiltration was alleviated (FIG 6, (C) ) . Most importantly, the present ATG-235 solution appeared to be more potent than Th, which served as the positive control.
  • LPS induced infiltration of cells i.e., neutrophils, macrophages, and etc
  • production of cytokines i.e., TNF- ⁇ , IL-1 ⁇ , and IL-6
  • enhanced expression of inflammation proteins i.e., MAPK, NF- ⁇ B, and IL-1 ⁇
  • MAPK, NF- ⁇ B, and IL-1 ⁇ were independently attenuated by the treatment of the ATG-235 solution or Th (FIGs 7 and 8) .
  • the present ATG-235 solution appeared to be more potent than Th.
  • the levels of enzymes that regulated mitochondria biogenesis including PGC1 ⁇ , TFAMA, NRF-1, and SIRT1 were reduced by LPS treatment, however, application of the ATG-235 solution successfully restored the level of each enzymes to a level similar to that of the control mice (i.e., LPS untreated mice) , an indication of improved function of mitochondria. Further, the ATG-235 solution was more potent than that of Th. (FIG 10)
  • Example 4 ATG-235 solution ameliorated LPS-induced ALI in farnesoid X receptor (FXR) deficient mice
  • mice were challenged with LPS to induce ALI and then treated with ATG-235 solution or Th in accordance with procedures described in Example 2, except FXR deficient mice (4 months old) instead of the young mice (4 months) were used in the present example.
  • FXR is a nuclear receptor encoded by the NR1H4 gene in humans, and is expressed at high levels in liver and intestines. Results are depicted in FIGs 11 to 15.
  • LPS induced infiltration of cells i.e., neutrophils, macrophages, and etc
  • production of cytokines i.e., TNF- ⁇ , IL-1 ⁇ , and IL-6
  • enhanced expression of inflammation proteins i.e., MAPK, NF- ⁇ B, and IL-1 ⁇
  • the present disclosure provides a novel use of a curcuminoid-rich oil extract (i.e., the ATG-235 solution) for the treatment of a subject suffering from ALI (e.g., ARDS) , in which the curcuminoids dissolved in the oil consist of 25-30% (wt%) of bisdemethoxycurcumin, 25-30% (wt%) of demethoxycurcumin, and 40-50% (wt%) of curcumin.
  • the present curcuminoid-rich oil extract may serve as a therapeutic agent for preventing and/or treating ALI thereby enhances the life span and life quality of the ALI subjects.

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Abstract

Est divulguée ici, une nouvelle utilisation d'un extrait d'huile riche en curcuminoïde pour le traitement d'une lésion pulmonaire aiguë (ALI), telle qu'un syndrome de détresse respiratoire aiguë (SDRA). Selon des modes de réalisation préférés de la présente divulgation, l'extrait d'huile riche en curcuminoïdes comprend des curcuminoïdes dissous dans une huile comestible, les curcuminoïdes étant constitués de 25 à 30 % (% en poids) de bisdéméthoxycurcumine, de 25 à 30 % (en poids) de déméthoxycurcumine, et de 40 à 50 % (en poids) de curcumine.
PCT/CN2021/095393 2021-05-24 2021-05-24 Utilisation d'un extrait d'huile riche en curcuminoïde pour le traitement d'une lésion pulmonaire aiguë WO2022246586A1 (fr)

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