tretinoin and Ischemia

Large vessel thrombosis is a very rare clinical presentation of acute leukemia which is usually revealed by hemorrhagic complications or thrombosis of small vessels. We present here the case of a patient with previously undiagnosed acute myeloid leukemia who was referred to our hospital with symptoms of acute ischemia of the left lower limb. Occlusion of the left popliteal artery due to a leucostasis was noted and successfully treated with emergency surgical thromboembolectomy and chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arterial Occlusive Diseases; Cytarabine; Daunorubicin; Emergencies; Femoral Artery; Humans; Ischemia; Leg; Leukemia, Promyelocytic, Acute; Leukostasis; Male; Popliteal Artery; Remission Induction; Thrombectomy; Tretinoin

Objectives: The current work investigated the effect of Wharton jelly mesenchymal stem cells (WJ-MSCs) pretreated with all-trans-retinoic acid (ATRA) on renal ischemia in rats and the possible role of oxidative stress, apoptotic and Wnt/β-Catenin signaling pathways, and inflammatory cytokines in their effects. Methods: The study included 90 male Sprague Dawley rats that were allocated to five groups (n = 18 rats): (I) Sham-operated group (right nephrectomy was performed); (II) Ischemia/reperfusion injury (IRI) group, a sham group with 45-min renal ischemia on the left kidney; (III) ATRA group, an ischemic group with an intravenous (i.v.) administration of ATRA 10 µM, 10 min post-surgery); (IV) WJ-MSCs group, an IRI group with an i.v. administration of 150 µL containing 7 × 106 WJ-MSCs, 10 min post-surgery; (V) WJ-MSCs + ATRA group, an IRI group with an i.v. administration of 150 µL of 7 × 106 WJ-MSCs pretreated with 10 µM ATRA. At the end of the experiments, serum creatinine, BUN micro-albuminuria (MAU), urinary protein, markers of redox state in the left kidney (MDA, CAT, SOD, and GSH), and the expression of Bax, IL-6, HIF-1α, Wnt7B, and β-catenin genes at the level of mRNA as well as for immunohistochemistry for NFkB and β-Catenin markers were analyzed. Results: The current study found that 45-min of renal ischemia resulted in significant impairment of kidney function (evidenced by the increase in serum creatinine, BUN, and urinary proteins) and deterioration of the kidney morphology, which was associated with a significant increase in redox state (evidenced by an increase in MDA and a decrease in GSH, SOD, and CAT), and a significant increase in inflammatory and apoptotic processes (evidenced by an increase in Bax and IL-6, NFkB, Wnt7B, β-catenin and HIF-1α) in kidney tissues (p < 0.05). On the other hand, treatment with ATRA, WJ-MSCs, or a combination of both, caused significant improvement in kidney function and morphology, which was associated with significant attenuation of oxidative stress, apoptotic markers, and inflammatory cytokines (IL6 and NFkB) with the upregulation of HIF-1α and β-catenin in kidney tissues (p < 0.05). Moreover, the renoprotective effect of WJ-MSCs pretreated with ATRA was more potent than WJ-MSCs alone. Conclusions: It is concluded that preconditioning of WJ-MSCs with ATRA may enhance their renoprotective effect. This effect could be due to the upregulation of the beta-catenin/Wnt pathway and attenuation of apoptosis, infla

Topics: Animals; bcl-2-Associated X Protein; beta Catenin; Creatinine; Cytokines; Interleukin-6; Ischemia; Kidney; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tretinoin; Wharton Jelly

Endothelial progenitor cells (EPCs) play a critical role in neovascularization, which enhances proliferation under all-trans retinoic acid (ATRA) treatment. However, the effects of ATRA on the skin flap survival in diabetic flap ischemia remains unknown.. Ischemic random skin flaps were made in 40 diabetic Sprague-Dawley rats with 20 normal rats used as control in this study. At 7 days postoperatively, the surviving area of each skin flap was measured. Immunofluorescence staining was used to analyze capillary density and EPCs recruited to the flaps. The expression of ANG2 and VEGF was determined by Western blotting. Circulating EPC number was determined by flow cytometry. In vitro tube formation experiment was used to analyze the function of EPCs.. The flap survival rate and capillary density of ATRA-treated flap were significantly increased. Fluorescence-activated cell sorting (FACS) analysis demonstrated a marked increase in systemic CD34+/Flk-1+ EPCs in ATRA-treated rat. The expression of ANG2 and VEGF was increased in diabetic flap tissues under ATRA administration. Furthermore, ATRA administration restored the impaired function of diabetic EPCs in tube formation.. ATRA could notably exert preventive effects against skin flap necrosis and promote neovascularization in diabetic rats, which may partially through elevating the expression of ANG2 and VEGF, and augmenting EPC mobilization.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Ischemia; Male; Mice; Neovascularization, Physiologic; Postoperative Complications; Rats; Rats, Sprague-Dawley; Surgical Flaps; Tretinoin

Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

Topics: Animals; Cell Death; Cell Differentiation; Cell Proliferation; Cell Survival; Drug Carriers; Humans; Ischemia; Mice; Nanoparticles; Neovascularization, Physiologic; Neural Stem Cells; Neurogenesis; Polymers; Stroke; Tretinoin

A 37-year-old patient was transferred to Haematology from the ENT Emergency Department where he had been admitted due to tonsillitis. He displayed anaemia and leukopenia and had agranulocytosis in the study. A day later the patient had blast crisis, and was diagnosed with myeloid acute leukaemia. Due to blast crisis the patient experienced sudden back pain, with oliguria and renal function deterioration followed by anaemia, in the context of haemolysis consistent with thrombotic microangiopathy, and as such, we were consulted. We began treatment with plasmapheresis and on the following day we performed haemodialysis (we carried out a total of 12 sessions of plasmapheresis until haemolysis disappeared). Five days later there was respiratory failure, and the patient was consequently transferred to the Intensive Care Unit, where he continued treatment with plasmapheresis and haemodialysis. The patient remained anuric thereafter, requiring haemodialysis, with no sign of renal recovery. Once platelet levels normalised with haematology chemotherapy, a percutaneous renal biopsy was performed, which confirmed the diagnosis of cortical necrosis. Finally, the patient underwent renal replacement therapy by regular haemodialysis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Hemolytic-Uremic Syndrome; Humans; Idarubicin; Ischemia; Kidney; Kidney Cortex Necrosis; Leukemia, Promyelocytic, Acute; Male; Plasma; Plasmapheresis; Renal Dialysis; Respiratory Insufficiency; Tonsillitis; Tretinoin

Dopamine receptor agonists are protective in different models of neurodegeneration by both receptor-dependent and -independent mechanisms. We used SH-SY5Y cells, differentiated into neuron-like type, to evaluate if cabergoline, a dopamine D2 receptor agonist endowed with anti-oxidant activity, protects the cells against ischemia (oxygen-glucose deprivation model). Cabergoline protected the cells from ischemia-induced cell death in a concentration-dependent manner (EC(50)=1.2 microM), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and fluorescein diacetate-propidium iodide staining. This effect, observed even when the drug was added after oxygen-glucose deprivation, was not mediated by either dopamine D2 receptor activation or anti-apoptotic Bcl-2 protein over-expression (Western blotting analysis), but was linked to a reduction in cellular free radical loading (2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining) and membrane lipid peroxidation (thiobarbituric acid-reacting test). In conclusion, cabergoline protects in vitro neurons against ischemia-induced cell death, suggesting its possible use in the therapy of other neurodegenerative diseases in addition to Parkinson's disease.

Topics: Animals; Antioxidants; Cabergoline; Cell Death; Cell Hypoxia; Cell Line, Transformed; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ergolines; Free Radical Scavengers; Free Radicals; Gene Expression; Genes, bcl-2; Glucose; Haloperidol; Humans; Ischemia; Neurons; Thiobarbituric Acid Reactive Substances; Time Factors; Tretinoin; Vitamin E

Localized large vessel thrombosis in acute leukaemia is rare, haemorrhagic complications being more common.. We present a patient with acute promyelocytic leukaemia (APL) presenting with an acutely ischaemic lower limb. Large vessel thrombosis is a rare presentation of APL. We reviewed the literature on the coagulopathy of APL and discuss the pathology and current treatment options.. Disordered haemostasis is typical of acute promyelocytic leukaemia (FAB M3) and relates to the intrinsic properties of the blast cells as well as thrombocytopenia from bone marrow involvement. Expression of procoagulants, stimulation of cytokines and alterations in endothelial cell anticoagulant properties initiate a disseminated intravascular coagulation (DIC) resulting in the typical clinical and laboratory findings in APL. The promyelocytes are characterized by the balanced reciprocal translocation between chromosomes 15 and 17. All-trans-retinoic acid (ATRA) induces differentiation in these cells, revolutionizing the treatment of APL.. Unexpected limb ischaemia in a young, apparently healthy patient might be the presenting symptom of an underlying haematological disorder such as APL. A thorough haematological investigation should be performed prior to contemplating surgery. New treatment strategies based on knowledge of the molecular biology of APL has improved the prognosis of patients suffering from APL.

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Arterial Occlusive Diseases; Cysteine Endopeptidases; Cytarabine; Daunorubicin; Female; Gangrene; Humans; Intermittent Claudication; Ischemia; Leg; Leukemia, Promyelocytic, Acute; Middle Aged; Neoplasm Proteins; Neoplastic Stem Cells; Popliteal Artery; Remission Induction; Smoking; Thioguanine; Thrombophilia; Thromboplastin; Thrombosis; Toes; Tretinoin

Topics: Adult; Antineoplastic Agents; Drug Eruptions; Female; Humans; Ileal Diseases; Ileum; Ischemia; Leukemia, Promyelocytic, Acute; Necrosis; Skin; Tretinoin; Vasculitis

Nerve growth factor (NGF), which has been shown to act as a morphological and neurochemical differentiating factor in PC12 cells, also protects PC12 cells from the toxicity of serum withdrawal and ischemia. By using a previously established in vitro model of ischemia, which incorporates the combination of anoxia with glucose deprivation (Boniece and Wagner: J Neurosci 13:4220-4228, 1993), we have been able to study the signal transduction pathways upon which NGF-induced survival is dependent. Here we demonstrate that inhibitors of the N-kinase and NGF-induced neuritogenesis, 6-thioguanine and 2-aminopurine, prevent the protective effects of NGF, while they have little, if any, effect on the protection conferred by epidermal growth factor (EGF) or dbcAMP. This suggests that only NGF acts by a mechanism that depends strongly on the N-kinase. Furthermore, the methyltransferase inhibitor 5'-deoxy-5'-methylthioadenosine (MTA), which also inhibits NGF-induced neuritogenesis, inhibits the protective effect of NGF but not the protective effects of EGF or dbcAMP. Thus, the neuroprotective effect of NGF requires some of the same signal transduction steps used by NGF to promote differentiation and neurite formation. Furthermore, we found that exposure of PC12 cells to retinoic acid, which promotes the differentiation and inhibits the growth of PC12 cells, also improves cell survival during ischemia. In addition, a combination of NGF and retinoic acid was more effective than either agent alone. It is likely that these two agents confer protection by independent pathways.

Topics: 2-Aminopurine; Animals; Cyclic AMP; Ischemia; Methyltransferases; Nerve Growth Factors; PC12 Cells; Phosphotransferases; Rats; Thioguanine; Tretinoin