A phase-2, multi-centre, prospective, randomized, standard-of-care plus placebo-controlled, patient and central evaluator blinded, parallel arm, clinical study to evaluate safety, tolerability and efficacy of the recommended phase-2 dose of AUP1602-C in two dosing frequencies as a topical treatment for non-healing neuro-ischemic diabetic foot ulcers - AT-W-CLI-2022-04

Start Date21 Jul 2023

Sponsor / Collaborator

Aurealis Oy

NCT06111183 / RecruitingPhase 2

Phase-2, Multi-centre, Prospective, Randomized, Standard-of-care Plus Placebo-controlled, Patient and Central Evaluator Blinded, Parallel Arm, Clinical Study to Evaluate Safety, Tolerability and Efficacy of the AUP1602-C as Treatment for Non-healing Neuro-ischemic DFU

This is a phase 2 study performed in diabetic foot ulcer (DFU) patients with chronic non-healing, neuro-ischemic wounds to investigate the safety, tolerability and efficacy of AUP1602-C.

Start Date21 Jul 2023

Sponsor / Collaborator

Aurealis Oy

NCT04281992 / CompletedPhase 1/2

A Phase 1/2A Clinical Study to Evaluate the Safety, Tolerability and Efficacy of Single and Repeated Doses of AUP1602-C as Topical Treatment of Diabetic Foot Ulcers

This is a two-part phase 1/2A study performed in diabetic foot ulcer (DFU) patients with chronic non-healing wounds to investigate the safety and efficacy of AUP1602-C.

Start Date28 Jan 2020

Sponsor / Collaborator

Aurealis Oy

100 Clinical Results associated with M-CSF x bFGF

100 Translational Medicine associated with M-CSF x bFGF

0 Patents (Medical) associated with M-CSF x bFGF

Literatures (Medical) associated with M-CSF x bFGF

21 Nov 2023·Bioscience, Biotechnology, and Biochemistry

Resveratrol inhibits basic fibroblast growth factor-induced macrophage colony-stimulating factor synthesis via the PI3-kinase/Akt pathway in osteoblasts

Article

Author: Hioki, Tomoyuki ; Tachi, Junko ; Kuroyanagi, Gen ; Iida, Hiroki ; Kozawa, Osamu ; Matsushima-Nishiwaki, Rie ; Tokuda, Haruhiko

ABSTRACTResveratrol is a natural polyphenol found in grapes and beneficial for human health. Resveratrol regulates basic fibroblast growth factor (bFGF)-induced osteoprotegerin synthesis through Akt pathway in osteoblast-like MC3T3-E1 cells. In this study, we investigated resveratrol effects on bFGF-induced macrophage colony-stimulating factor (M-CSF) synthesis in MC3T3-E1 cells. bFGF significantly stimulated release and mRNA expression of M-CSF, which was reduced by resveratrol and SRT1720, sirtuin 1 (SIRT1) activator. Inauhzin, SIRT1 inhibitor, reversed inhibitory effects of resveratrol on bFGF-induced mRNA expression of M-CSF. Deguelin, Akt inhibitor, and LY294002, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced bFGF-induced M-CSF synthesis. Inauhzin reversed inhibitory effects of resveratrol on bFGF-induced Akt phosphorylation. Suppressive effect of resveratrol on bFGF-induced osteoprotegerin mRNA expression was confirmed in the identical samples using in experiment of M-CSF mRNA expression. Therefore, resveratrol reduces bFGF-induced M-CSF synthesis in addition to osteoprotegerin synthesis by inhibiting PI3-kinase/Akt pathway and suppressive effects are mediated through SIRT1 activation in osteoblasts.

01 Jan 2023·Health Science Reports

A cross‐sectional study comparing the inflammatory profile of menstrual effluent vs. peripheral blood

Article

Author: Avrutsky, Maria I. ; Blumenthal, Paul D. ; Naseri, Sara ; Rosenberg‐Hasson, Yael ; Maecker, Holden T.

AbstractBackground and AimsCytokine profiles of peripheral blood and other bodily fluids provide diagnostic indicators for assessing inflammatory processes. Menstrual effluent may provide a noninvasive source of biological material for monitoring cytokine levels in blood and in endometrial tissues. This pilot study investigated the potential of measuring cytokines in menstrual effluent, and compared the cytokine profiles of menstrual versus peripheral blood.MethodsSeven healthy donors (aged ≥18 and ≤45 years) collected menstrual effluent on day 2 of menses. Matched peripheral blood samples were collected by venous blood draw on the same day. Levels of 62 cytokines were measured in all samples by 62‐plex Luminex assay.ResultsPeripheral blood and menstrual effluent cytokine profiles were tenuously correlated (r2 = 0.26, p < 0.0001), with higher levels detected in menstrual effluent for 48/62 cytokines. Thirty five cytokines were significantly elevated in menstrual effluent compared to peripheral blood samples (IL‐8, CCL2, CCL4, LIF, IL‐1RA, IL‐6, IL‐1β, HGF, CCL3, FGF‐2, TNF‐α, VEGF‐A, IL‐1α, CXCL1, IL‐9, IL‐10, EGF, CXCL5, CSF3, EOTAXIN, TGF‐α, TRAIL, CXCL10, VEGF‐D, IL‐12P40, CXCL9, IL‐18 RESISTIN, IL‐22, IL‐21, CSF1, IFN‐γ, IL‐17A, CXCL12, IL‐12p70). Two cytokines (LEPTIN, CSF2) were expressed at significantly lower levels in menstrual effluent compared to peripheral blood. Linear regression of individual cytokines found low predictive power (linear regression p > 0.05) for 53/62 cytokines in menstrual effluent versus peripheral blood. Levels of TGF‐β (r2 = 0.87, p = 0.002) and CCL7 (r2 = 0.63, p = 0.033) were significantly positively correlated between matched menstrual and peripheral blood samples.ConclusionIn this group of study participants, the cytokine profile of menstrual effluent was quantitatively distinct from peripheral blood, and also characterized by higher levels of inflammatory signaling. This pattern of comparative menstrual blood cytokine profiles points to a need for further studies to evaluate the relationship between peripheral and menstrual blood cytokines in broader populations including both healthy and diseased states.

03 Oct 2022·AutophagyQ1 · BIOLOGY

A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence

Q1 · BIOLOGY

Article

Author: Ye, Jiang-Feng ; Li, Da-Jin ; Zhao, Jian-Yuan ; Zhou, Wen-Jie ; Li, Ming-Qing ; Mei, Jie ; Yang, Hui-Li ; Shi, Jia-Wei ; Zhang, Tao ; Wang, Jian ; Lai, Zhen-Zhen

Massive infiltrated and enriched decidual macrophages (dMφ) have been widely regarded as important regulators of maternal-fetal immune tolerance and trophoblast invasion, contributing to normal pregnancy. However, the characteristics of metabolic profile and the underlying mechanism of dMφ residence remain largely unknown. Here, we observe that dMφ display an active glycerophospholipid metabolism. The activation of ENPP2-lysophosphatidic acid (LPA) facilitates the adhesion and retention, and M2 differentiation of dMφ during normal pregnancy. Mechanistically, this process is mediated through activation of the LPA receptors (LPAR1 and PPARG/PPARγ)-DDIT4-macroautophagy/autophagy axis, and further upregulation of multiple adhesion factors (e.g., cadherins and selectins) in a CLDN7 (claudin 7)-dependent manner. Additionally, poor trophoblast invasion and placenta development, and a high ratio of embryo loss are observed in Enpp2^±, lpar1^-/- or PPARG-blocked pregnant mice. Patients with unexplained spontaneous abortion display insufficient autophagy and cell residence of dMφ. In therapeutic studies, supplementation with LPA or the autophagy inducer rapamycin significantly promotes dMφ autophagy and cell residence, and improves embryo resorption in Enpp2^± and spontaneous abortion mouse models, which should be dependent on the activation of DDIT4-autophagy-CLDN7-adhesion molecules axis. This observation reveals that inactivation of ENPP2-LPA metabolism and insufficient autophagy of dMφ result in resident obstacle of dMφ and further increase the risk of spontaneous abortion, and provides potential therapeutic strategies to prevent spontaneous abortion.Abbreviations: ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; Atg5: autophagy related 5; ATG13: autophagy related 13; BECN1: beclin 1; CDH1/E-cadherin: cadherin 1; CDH5/VE-cadherin: cadherin 5; CFSE: carboxyfluorescein succinimidyl ester; CLDN7: claudin 7; CSF1/M-CSF: colony stimulating factor 1; CSF2/GM-CSF: colony stimulating factor 2; Ctrl: control; CXCL10/IP-10: chemokine (C-X-C) ligand 10; DDIT4: DNA damage inducible transcript 4; dMφ: decidual macrophage; DSC: decidual stromal cells; ENPP2/ATX: ectonucleotide pyrophosphatase/phosphodiesterase 2; Enpp2^±: Enpp2 heterozygous knockout mouse; ENPP2i/PF-8380: ENPP2 inhibitor; EPCAM: epithelial cell adhesion molecule; ESC: endometrial stromal cells; FGF2/b-FGF: fibroblast growth factor 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPCPD1: glycerophosphocholine phosphodiesterase 1; HE: heterozygote; HIF1A: hypoxia inducible factor 1 subunit alpha; HNF4A: hepatocyte nuclear factor 4 alpha; HO: homozygote; ICAM2: intercellular adhesion molecule 2; IL: interleukin; ITGAV/CD51: integrin subunit alpha V; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11b: integrin subunit alpha X; ITGB3/CD61: integrin subunit beta 3; KLRB1/NK1.1: killer cell lectin like receptor B1; KRT7/cytokeratin 7: keratin 7; LPA: lysophosphatidic acid; LPAR: lysophosphatidic acid receptor; lpar1^-/-: lpar1 homozygous knockout mouse; LPAR1i/AM966: LPAR1 inhibitor; LY6C: lymphocyte antigen 6 complex, locus C1; LYPLA1: lysophospholipase 1; LYPLA2: lysophospholipase 2; Lyz2: lysozyme 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MARVELD2: MARVEL domain containing 2; 3-MA: 3-methyladenine; MBOAT2: membrane bound O-acyltransferase domain containing 2; MGLL: monoglyceride lipase; MRC1/CD206: mannose receptor C-type 1; MTOR: mechanistic target of rapamycin kinase; NP: normal pregnancy; PDGF: platelet derived growth factor; PLA1A: phospholipase A1 member A; PLA2G4A: phospholipase A2 group IVA; PLPP1: phospholipid phosphatase 1; pMo: peripheral blood monocytes; p-MTOR: phosphorylated MTOR; PPAR: peroxisome proliferator activated receptor; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; PPARGi/GW9662: PPARG inhibitor; PTPRC/CD45: protein tyrosine phosphatase receptor type, C; Rapa: rapamycin; RHEB: Ras homolog, mTORC1 binding; SA: spontaneous abortion; SELE: selectin E; SELL: selectin L; siCLDN7: CLDN7-silenced; STAT: signal transducer and activator of transcription; SQSTM1: sequestosome 1; TJP1: tight junction protein 1; VCAM1: vascular cell adhesion molecule 1; WT: wild type.

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