tretinoin and Hyperglycemia

Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Dexamethasone; Disease-Free Survival; Female; Follow-Up Studies; Humans; Hyperglycemia; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Multiple Myeloma; Pilot Projects; Recombinant Proteins; Treatment Outcome; Tretinoin

The aim of the present study is to explore the effect of retinoic acid (RA) on cardiac injury induced by gestational diabetes mellitus (GDM). GDM mice were given 3 mg/kg RA once daily until the 19th day of pregnancy or the 7th day of post-partum. Compared to normal control and normal pregnant control mice, GDM mice before and after delivery showed significantly cardiac injury. RA treatment attenuated cardiac injury as evidenced by decreased heart mass and left ventricular mass, mRNA expressions of ANP and BNP, and cardiac fibrosis compared with that in GDM mice. The protective effect of RA on GDM cardiomyopathy was related to the decreased MDA content and ROS generation, the increased GSH-Px and SOD content as well as the reduced TNF-α and IL-1β content and inhibition of NF-κB signaling. In addition, RA treatment delayed the continuous rise of blood glucose before delivery and decreased the higher level of glucose after delivery. In conclusion, RA treatment could increase the activity of the antioxidant enzyme and suppress the oxidative stress, inflammation response, and activation of NF-κB signaling, thereby improving blood glucose level and cardiac injury of GDM mice before and after delivery.

Topics: Animals; Antioxidants; Diabetes, Gestational; Disease Models, Animal; Female; Heart Injuries; Heart Ventricles; Hyperglycemia; Inflammation; Interleukin-1beta; Male; Mice; NF-kappa B; Oxidative Stress; Pregnancy; Reactive Oxygen Species; Signal Transduction; Tretinoin; Tumor Necrosis Factor-alpha

Embryonic exposure to excess circulating fuels is proposed to underlie diabetic embryopathy. To isolate the effects of hyperglycemia from the many systemic anomalies of diabetes, we infused 4 mg/min glucose into the left uterine artery of non-diabetic pregnant rats on gestation days (GD) 7-9. Right-sided embryos and dams exhibited no glucose elevation. Embryos were assessed on GD13, comparing the left versus right uterine horns. Hyperglycemic exposure increased rates of embryopathy, resorptions, and worsened embryopathy severity. By contrast, saline infusion did not affect any of these parameters. To assess for possible embryopathy susceptibility bias between uterine horns, separate dams were given retinoic acid (25mg/kg, a mildly embryopathic dose) systemically on GD7.5. The resultant embryopathy rates were equivalent between uterine horns. We conclude that hyperglycemia, even in the absence of systemic maternal diabetes, is sufficient to produce in vivo embryopathy during organogenesis.

Topics: Animals; Diabetes Mellitus, Experimental; Female; Fetal Diseases; Glucose; Hyperglycemia; Organogenesis; Pregnancy; Pregnancy Outcome; Rats; Rats, Sprague-Dawley; Teratogenesis; Tretinoin

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6, and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

Topics: Animals; Apoptosis; Bexarotene; Cytokines; Cytoprotection; Gene Expression Regulation; Hyperglycemia; I-kappa B Kinase; Male; Myocytes, Cardiac; NF-kappa B; Phosphorylation; Protein Phosphatase 2; Rats; Rats, Zucker; Signal Transduction; Tetrahydronaphthalenes; Tretinoin

The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased expression of RARα and RXRα has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARα and RXRα remain unclear. Using neonatal cardiomyocytes, we found that ligand-induced promoter activity of RAR and RXR was significantly suppressed by HG. HG promoted protein destabilization and serine-phosphorylation of RARα and RXRα. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARα and RXRα. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H(2)O(2) stimulation suppressed the expression and ligand-induced promoter activity of RARα and RXRα. HG promoted phosphorylation of ERK1/2, JNK and p38 MAP kinases, which was abrogated by an ROS inhibitor. Inhibition of JNK, but not ERK and p38 activity, reversed HG effects on RARα and RXRα. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARα and RXRα. Ligand-induced promoter activity of RARα and RXRα was also suppressed by overexpression of MEKK1. HG-induced cardiomyocyte apoptosis was potentiated by activation of JNK, and prevented by all-trans retinoic acid and inhibition of JNK. Silencing the expression of RARα and RXRα activated the JNK pathway. In conclusion, HG-induced oxidative stress and activation of the JNK pathway negatively regulated expression/activation of RAR and RXR. The impaired RAR/RXR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to hyperglycemia induced cardiomyocyte apoptosis.

Topics: Alitretinoin; Animals; Animals, Newborn; Apoptosis; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Glucose; HEK293 Cells; Humans; Hyperglycemia; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 7; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Cardiac; Oxidants; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha; RNA Interference; Signal Transduction; Time Factors; Transcriptional Activation; Transfection; Tretinoin

Diabetes mellitus (DM) is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARα and RXRα, activation of apoptotic signaling and cell apoptosis was observed in high glucose (HG) treated neonatal and adult cardiomyocytes and diabetic hearts in Zucker diabetic fatty (ZDF) rats. HG-induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARα and RXRα, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARα and RXRα are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT(1) R); but, not AT(2) R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT(1) R, and angiotensin II (Ang II) synthesis were inhibited by RARα agonists and promoted by silencing RARα. Activation of RXRα, downregulated the expression of AT(1) R; and RXRα silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARα and RXRα has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Newborn; Apoptosis; Blood Glucose; Cells, Cultured; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hyperglycemia; Hypoglycemic Agents; Male; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rats, Zucker; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptors, Retinoic Acid; Renin-Angiotensin System; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha; RNA Interference; RNA, Messenger; Signal Transduction; Time Factors; Tretinoin

9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose reporter proteins. In view of the fact that 9CRA and ATRA are endogenous in crustaceans and a retinoic acid X-receptor exists in crabs, we investigated whether 9CRA and ATRA also plays a role in glucose homeostasis in freshwater crab, Oziotelphusa senex senex. Injection of 9CRA into intact crabs significantly increased the hemolymph glucose level in a dose-dependent manner. Such 9CRA-induced hyperglycemia was apparently mediated by the CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. In support of this, administration of 9CRA in to crabs resulted in reduced hyperglycemic activity of eyestalks and elevated titers of CHH in hemolymph. ATRA injection did not cause any changes in hemolymph glucose and CHH levels. The results provide the first evidence that 9-cis-retinoic acid, but not all-trans-retinoic acid, is involved in the regulation of glucose homeostasis and apparently mediated by the eyestalk hormone CHH.

Topics: Animals; Arthropod Proteins; Blood Glucose; Brachyura; Endocrine Glands; Eye; Fresh Water; Hemolymph; Hyperglycemia; Invertebrate Hormones; Male; Nerve Tissue Proteins; Tissue Extracts; Tretinoin

Diabetes is a risk factor for neuronal dysfunction. Impairment in signaling mechanisms that regulate differentiation of neurons is hypothesized to be one of the main causes of neuronal dysfunction. Retinoic acid, a physiologically active retinoid synthesized from vitamin A, regulates neuronal differentiation during embryonic development and is required for maintenance of plasticity in differentiated neurons. To date, little is known about the molecular events underlying hyperglycemia-induced complications in the central nervous system (CNS). Here, we provide evidence, in a diabetes rat model, of hyperglycemia-induced oxidative stress along with apoptotic stress in developing cortical neurons isolated from 16-day-old rat embryos. We also demonstrate impaired retinoic acid signaling that is involved in neuronal differentiation. Retinoic acid-induced neurite outgrowth and expression of neuronal markers were reduced in this model. The activation of small-molecular weight G-protein, Rac1, that mediates these effects was also reduced. Retinoic acid applied at a physiological concentration significantly decreased hyperglycemia-induced oxidative stress and thus supported the antioxidant defense system. These results suggest that diabetes-induced neuronal complications during pregnancy might be due to impaired retinoic acid signaling, and exogenously administered retinoic acid may be useful against CNS complications associated with diabetes.

Topics: Animals; Apoptosis; Cell Differentiation; Cerebral Cortex; Diabetes Mellitus, Experimental; Female; Hyperglycemia; Neurons; Oxidative Stress; Pregnancy; Pregnancy Complications; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tretinoin

We recently showed in mice that maternal diabetes increases embryonic susceptibility to caudal regression induced by vitamin A metabolite retinoic acid. Here we tested whether in the maternal diabetic milieu hyperglycaemia is the critical factor responsible for mediating this increased susceptibility.. Non-diabetic pregnant mice were made hyperglycaemic by subcutaneous injections of glucose at regular intervals. Conversely, diabetic pregnant mice were treated with phlorizin to induce renal glucosuria and thus reduce blood glucose concentrations. Pregnant mice were treated with retinoic acid and the extent of caudal regression in mouse embryos, measured in terms of the ratio of tail length to crown-rump length was assessed. Embryos were also examined for Wnt-3a expression and cell death.. Embryos of mice treated with glucose had a greater extent of caudal regression induced by retinoic acid than saline-treated controls, with enhanced down-regulation of Wnt-3a expression and exacerbated cell death specifically at the caudal end of the embryo. Embryos of diabetic mice treated with phlorizin had a similar extent of caudal regression to embryos of non-diabetic mice after treatment with retinoic acid.. Hyperglycaemia increases embryonic susceptibility to caudal regression induced by retinoic acid, with the underlying cellular and molecular changes closely mimicking those that occur in maternal diabetes. Reduction of blood glucose concentrations in diabetic mice completely abolishes this increased susceptibility to retinoic acid. These results suggest that in maternal diabetes hyperglycaemia is the critical factor responsible for potentiating the teratogenic effect of retinoic acid.

Topics: Animals; Blood Glucose; Disease Susceptibility; Embryo, Mammalian; Embryonic Development; Female; Glucose; Hyperglycemia; Mice; Pregnancy; Pregnancy in Diabetics; Teratogens; Tretinoin

9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose transporter proteins. In view of the fact that both 9CRA and ATRA are endogenous to the fiddler crab, Uca pugilator, that a retinoid X receptor exists in this fiddler crab and that activities of insulin-like and insulin-like growth factor-like peptides have been reported for crustaceans, we investigated whether 9CRA and ATRA also play a role in glucose homeostasis in U. pugilator. Neither 9CRA nor ATRA was found to produce hypoglycemic effects at a dose of 10 microg/g live mass. However, 9CRA, but not ATRA, induced hyperglycemia. Such 9CRA-induced hyperglycemia was apparently mediated by the eyestalk hormone CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. ATRA was found to have an inhibitory effect on the recovery of blood glucose concentration following ATRA administration. Discussion on the possible mechanisms for the actions of 9CRA and ATRA was presented.

Topics: Animals; Arthropod Proteins; Blood Glucose; Brachyura; Eye; Homeostasis; Hyperglycemia; Invertebrate Hormones; Nerve Tissue Proteins; Ophthalmologic Surgical Procedures; Tretinoin