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Introduction: Acute promyelocytic leukemia (APL) is the most malignant form of acute myeloid leukemia (AML) with short survival without treatment. All trans retinoic acid (ATRA) is a vitamin A metabolite and plays an important role in the treatment of APL. Hypercalcemia is a rare side effect of ATRA. Case Report: A 67-year-old female patient was investigated due to widespread bruising and pancytopenia. The patient was diagnosed with APL and remission was achieved by administering idarubicin together with ATRA in the induction treatment. The patient has hypocalcemia due to acquired hypoparathyroidism, and it was observed that the calcium level increased with the initiation of fluconazole 200 mg/day for antifungal prophylaxis together with ATRA in the consolidation treatment. It was observed that the calcium value reached 13 mg/dL by increasing the fluconazole to 400 mg/day treatment dose due to oral mucositis. Management and Outcome: The development of hypercalcemia has been reported in previous case reports when ATRA is used together with voriconazole, fosfluconazole, itraconazole, and posaconazole, which inhibit cytochrome P450 enzymes. In this case, it is the first in the literature that a patient with hypocalcemia due to acquired hypoparathyroidism developed hypercalcemia after fluconazole and ATRA were used together. Discussion: Since hypercalcemia may develop while azole drugs are administered during ATRA treatment, it is important to monitor calcium levels to prevent complications of hypercalcemia. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukaemia is a highly curable sub type of acute myeloid leukaemia and about 90% of these patients have good chance of survival with current all transretinoic acid based arsenic tri oxide or chemotherapy. However, a rare complication, pseudotumour cerebri may arise following All Trans Retinoic Acid (ATRA) therapy, which may provide obstacle to continue this promising therapy. We present the case report of a young female patient with acute promyelocytic leukaemia treated with Arsenic trioxide (ATO) and ATRA that subsequently develop abrupt onset of lateral rectus palsy and decreased visual acuity due to pseudotumour cerebri. We treated the patient with acetazolamide and kept her at frequent follow up. There was significant improvement of her lateral rectus palsy as well as visual acuity following treatment with acetazolamide that allowed us to continue the primary All Trans Retinoic Acid (ATRA) based treatment. [ABSTRACT FROM AUTHOR]

An 18-year-old female presented with sudden onset bilateral vision loss. Extensive retinal hemorrhages were seen in both eyes. Systemic examination lead to a diagnosis of acute promyelocytic leukemia. The patient was treated with all trans retinoic acid (ATRA) and other medications in the induction phase. Bilateral disc edema was noted during the second consolidation cycle with ATRA. Complete resolution of bilateral disc edema was attained in three weeks' time after discontinuing ATRA. [ABSTRACT FROM AUTHOR]

Network pharmacology is an emerging field which is currently capturing interest in drug discovery and development. Chronic kidney conditions have become a threat globally due to its associated lifelong therapies. Nephrotic syndrome (NS) is a common glomerular disease that is seen in paediatric and adult population with characteristic manifestation of proteinuria, oedema, hypoalbuminemia, and hyperlipidemia. It involves podocyte damage with tubulointerstitial fibrosis and glomerulosclerosis. Till date there has been no specific treatment available for this condition that provides complete remission. Repurposing of drugs can thus be a potential strategy for the treatment of NS. Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA). Epigenetic drugs act by binging about changes in gene expression without altering the DNA sequence. The changes include DNA methylation or histone modifications. The targets for the two drugs ATRA and VPA were collated from ChEMBL and Binding DB. All the genes associated with NS were collected from DisGeNET and KEGG database. Interacting proteins for the target genes were acquired from STRING database. The genes were then subjected to gene ontology and pathway enrichment analysis using a functional enrichment software tool. A drug-target and drug-potential target-protein interaction network was constructed using the Cytoscape software. Our results revealed that the two drugs VPA and ATRA had 65 common targets that contributed to kidney diseases. Out of which, 25 targets were specifically NS associated. Further, our work exhibited that ATRA and VPA were synergistically involved in pathways of inflammation, renal fibrosis, glomerulosclerosis and possibly mitochondrial biogenesis and endoplasmic reticulum stress. We thus propose a synergistic potential of the two drugs for treating chronic kidney diseases, specifically NS. The outcomes will undoubtedly invigorate further preclinical and clinical explorative studies. We identify network pharmacology as an initial inherent approach in identifying drug candidates for repurposing and synergism.

Introduction: Acute promyelocytic leukemia (APL) is a distinct leukemia which can be treated with differentiating agents alone.Treatment without chemotherapy decreases the cost of treatment and the need for supportive care. Here we present analysis of APL patients treated with arsenic trioxide (ATO)-all trans retinoic acid (ATRA) without chemotherapy in our hospital. Patients and Methods: Forty three patients with newly diagnosed APL were treated with arsenic trioxide(ATO ) and All trans retinoic acid (ATRA) during induction treatment. For consolidation ATRA 45 mg /m2 for two weeks every four weeks was administered for twenty eight weeks. ATO was administered for four cycles, with a cycle length of eight weeks. The drug was administered at 0.15 mg/kg/d for five days per week for four weeks during each cycle.Patients were followed up with once in three month hemogram and once in six month reverse-transcriptase polymerase chain reaction (RT-PCR) for two years and yearly thereafter. Results: The morphologic complete remission (CR) rate was 86.04%.The most common cause of remission failure was early death due to bleeding. None of the low risk patients died during induction therapy. The most important prognostic factor for early mortality was a high white blood cell (WBC) count at presentation. The median overall survival (OS) has not been reached.The two year OS was 83.4% and the three year OS was 74.8%.The estimated five year survival was 74.8%. At a median follow up of 42.6 months the estimated five year survival in the low-intermediate risk group was 93.3% and 59.1% in the high risk group Conclusion: ATO –ATRA can be considered as a treatment option for frontline treatment of all risk APL patients in resource poor settings.The results can be better with better supportive care to prevent early mortality and by salvaging patients who relapse.

Arsenic trioxide (ATO) combined with all trans retinoic acid (ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia (APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients' compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel (PPSG) loaded with ATO and ATRA was developed. ATO+ATRA-PPSG (AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO+ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application.

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB. [ABSTRACT FROM AUTHOR]

Background: The majority of patients with acute promyelocytic leukemia (APL) manifest a specific chromosomal translocation t(15;17)(q22;q21), characterized by the fusion of RARA and PML genes. However, a proportion of APL cases are due to variant translocations, being t(11;17) (q23;q21) the most common amongst them. With the major exception of ZBTB16-RARA t(11;17) APL, these variant APL cases present similar morphological features as classic APL and are characterized by a lack of differentiation response to retinoids. Case summary: We describe the case of variant APL with the ZBTB16-RARA fusion gene, showing a distinct morphology of classical APL, characterized by crystalline intracytoplasmic inclusions in both peripheral blood (PB) and bone marrow (BM) patients' blasts. Our patient was treated with two courses of intensive chemotherapy, initiating maintenance treatment with all-trans retinoic acid (ATRA) on day twenty-eight of the second course. Our patient achieved complete remission (CR) once the intensive chemotherapy was combined with ATRA.Conclusions: This is the second case described of APL with t(11;17) that showed crystalline intracytoplasmic inclusions. The finding of these morphological features may suggest the presence of a variant translocation with RARA, being that both cases described are related to the presence of t(11;17). Despite induction treatment with intensive chemotherapy that included a seven-day continuous treatment with cytarabine (200 mg/m2), plus daily idarubicin (12 mg/m2) during the first three days, our patient did not achieve complete remission (CR) until scheduled 3 + 7 regimen combined with ATRA treatment was established. This observation suggests that ATRA may be partially effective in some ZBTB16-RARA APLs. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a devastating disease with unknown treatment. All‐trans retinoic acid (ATRA) attenuates bleomycin‐induced lung fibrosis by different mechanistic pathways. However, the role of retinoid receptors in lung fibrosis is still unclear. Forskolin (FSK), a potent inhibitor for the revolutionary hedgehog (Hh) signalling pathway, has a promising antifibrotic effect on other organs such as the liver. This study investigates the interplay between the retinoid receptors modulation and the Hh signalling pathway in bleomycin (BLM)‐induced pulmonary fibrosis. Rats were randomised and administrated a single dose of 7.5 mg/kg of BLM alone and with ATRA, FSK and both of them. The effects of FSK and ATRA on lung functions, oxidative stress markers (malondialdehyde [MDA], glutathione [GSH], superoxide dismutase [SOD] and catalase [CAT]), retinoid markers (retinoic acid receptors [RAR] and rexinoid X receptors [RXR]) and Hh signalling markers (patched homolog 1 [Ptch‐1], Smoothened [Smo] and glioblastoma‐2 [Gli‐2]) were assessed. In single therapies, ATRA and FSK ameliorated BLM‐induced lung fibrosis. On the contrary, a combination of both drugs synergistically reversed the effect of BLM‐induced lung fibrosis, as indicated by the enhancement of lung functions and the decrease of the α‐smooth muscle actin (α‐SMA) expression and collagen deposition. Additionally, FSK and ATRA ameliorated oxidative stress and inflammation, reduced transforming growth factor β1 (TGF‐β1) levels and reversed the effect of BLM on the mRNA expression of Ptch‐1, Smo and Gli‐2. FSK inhibited the Hh pathway and also activated protein kinase A (PKA) that is, in part, involved in phosphorylation of RAR/RXR heterodimer (a key step in retinoid receptor activation). The present results suggest that a combination of FSK and ATRA has a promising therapeutic value for lung fibrosis management. [ABSTRACT FROM AUTHOR]

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is second only to COVID-19 as the top infectious disease killer worldwide. Multi-drug resistant TB (MDR-TB) may arise because of poor patient adherence to medications due to lengthy treatment duration and side effects. Delivering novel host directed therapies (HDT), like all trans retinoic acid (ATRA) may help to improve drug regimens and reduce the incidence of MDR-TB. Local delivery of ATRA to the site of infection leads to higher bioavailability and reduced systemic side effects. ATRA is poorly soluble in water and has a short half-life in plasma. Therefore, it requires a formulation step before it can be administered in vivo. ATRA loaded PLGA nanoparticles suitable for nebulization were manufactured and optimized using a scalable nanomanufacturing microfluidics (MF) mixing approach (MF-ATRA-PLGA NPs). MF-ATRA-PLGA NPs demonstrated a dose dependent inhibition of Mtb growth in TB-infected A549 alveolar epithelial cell model while preserving cell viability. The MF-ATRA-PLGA NPs were nebulized with the Aerogen Solo vibrating mesh nebulizer, with aerosol droplet size characterized using laser diffraction and the estimated delivered dose was determined. The volume median diameter (VMD) of the MF-ATRA-PLGA NPs was 3.00 ± 0.18 μm. The inhaled dose delivered in adult and paediatric 3D printed head models under a simulated normal adult and paediatric breathing pattern was found to be 47.05 ± 3 % and 20.15 ± 3.46 % respectively. These aerosol characteristics of MF-ATRA-PLGA NPs supports its suitability for delivery to the lungs via inhalation. The data generated on the efficacy of an inhalable, scalable and regulatory friendly ATRA-PLGA NPs formulation provides a foundation on which further pre-clinical testing can be built. Overall, the results of this project are promising for future research into ATRA loaded NPs formulations as inhaled host directed therapies for TB. [Display omitted] [ABSTRACT FROM AUTHOR]

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.

Background: The majority of patients with acute promyelocytic leukemia (APL) manifest a specific chromosomal translocation t(15;17)(q22;q21), characterized by the fusion of RARA and PML genes. However, a proportion of APL cases are due to variant translocations, being t(11;17) (q23;q21) the most common amongst them. With the major exception of ZBTB16-RARA t(11;17) APL, these variant APL cases present similar morphological features as classic APL and are characterized by a lack of differentiation response to retinoids. Case summary: We describe the case of variant APL with the ZBTB16-RARA fusion gene, showing a distinct morphology of classical APL, characterized by crystalline intracytoplasmic inclusions in both peripheral blood (PB) and bone marrow (BM) patients’ blasts. Our patient was treated with two courses of intensive chemotherapy, initiating maintenance treatment with all-trans retinoic acid (ATRA) on day twenty-eight of the second course. Our patient achieved complete remission (CR) once the intensive chemotherapy was combined with ATRA.Conclusions: This is the second case described of APL with t(11;17) that showed crystalline intracytoplasmic inclusions. The finding of these morphological features may suggest the presence of a variant translocation with RARA, being that both cases described are related to the presence of t(11;17). Despite induction treatment with intensive chemotherapy that included a seven-day continuous treatment with cytarabine (200 mg/m2), plus daily idarubicin (12 mg/m2) during the first three days, our patient did not achieve complete remission (CR) until scheduled 3 + 7 regimen combined with ATRA treatment was established. This observation suggests that ATRA may be partially effective in some ZBTB16-RARA APLs.

Introduction: Pulmonary emphysema is characterized by destruction of alveoli leading to inadequate oxygenation, disability and frequently death. This destruction was understood so far as irreversible. Published data has shown that ATRA (All Trans Retinoic Acid) reverses elastase-induced emphysema in rats. However, the molecular mechanisms governing regeneration process are so far unknown. Objective: To examine the therapeutic potential of ATRA on various molecular pathways and their coordination towards governance of alveolar epithelial regeneration in emphysematous rats. Methods: Emphysema was induced by elastase versus saline in Sprague-Dawley rats. On days 26–37, rats received daily intraperitoneal injections with ATRA (500 μg/kg b.w.) versus olive-oil. Lungs were removed at day 38 for histopathology and investigation of relative mRNA and protein expressions. Results: Histopathological analysis has shown that losses of alveoli were recovered in therapy (EA) group. Moreover, expressions of markers genes for alveolar cell proliferation, differentiation and EMT events at mRNA and protein levels were significantly increased in EA group than emphysema group (ES). Upon validation at genomics level, expressions of components of Notch, Hedgehog, Wnt, BMP and TGFβ pathways were significantly attenuated in EA group when compared with ES and were well comparable with the healthy group. Conclusion: Therapeutic supplementation of ATRA rectifies the deregulated Notch, Hedgehog, Wnt, BMP and TGFβ pathways in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema. Nevertheless, elaborated studies are to be conducted.

The zebrafish embryo (ZE) model provides a developmental model well conserved throughout vertebrate embryogenesis, with relevance for early human embryo development. It was employed to search for gene expression biomarkers of compound-induced disruption of mesodermal development. We were particularly interested in the expression of genes related to the retinoic acid signaling pathway (RA-SP), as a major morphogenetic regulating mechanism. We exposed ZE to teratogenic concentrations of valproic acid (VPA) and all-trans retinoic acid (ATRA), using folic acid (FA) as a non-teratogenic control compound shortly after fertilization for 4 h, and performed gene expression analysis by RNA sequencing. We identified 248 genes specifically regulated by both teratogens but not by FA. Further analysis of this gene set revealed 54 GO-terms related to the development of mesodermal tissues, distributed along the paraxial, intermediate, and lateral plate sections of the mesoderm. Gene expression regulation was specific to tissues and was observed for somites, striated muscle, bone, kidney, circulatory system, and blood. Stitch analysis revealed 47 regulated genes related to the RA-SP, which were differentially expressed in the various mesodermal tissues. These genes provide potential molecular biomarkers of mesodermal tissue and organ (mal)formation in the early vertebrate embryo. • ATRA and VPA retinoic acid pathway perturbation alter mesodermal-tissue development. • Transcriptomic changes were found for 7 mesodermal tissues. • 47 potential gene expression maldevelopment biomarkers were found. • 13 were considered potential early biomarkers of general mesodermal maldevelopment. • Some were considered novel potential early biomarkers of specific mesoderm organs. [ABSTRACT FROM AUTHOR]

Objective: Several studies have reported that retinoic acid (RA) might be used to treat malignancies. The effects of RA are mediated by the RA receptor (RAR), and RARα/RARβ especially acts as a tumor suppressor. However, little is known about its role in human endometrial cancer. Materials and Methods: In this study, we examined the effects of all-trans RA (ATRA) on progression of human endometrial cancer cell line, RL95-2 and Hec1A. We then examined the expression ofRARα andRARβ in 50 endometrial cancer tissues by usingimmunohistochemistry. Results: We found inhibitory effects ofATRAon cell proliferation, apoptosis, and migration in RL95-2 cells, but not in Hec1A cells. RARα or RARβ knockdown individually could not cancel out the inhibition of cell proliferation by ATRA in RL95-2 cells, but simultaneous knockdown of RAR> and RARA could block its effect on proliferation. RARα and RARβ knockdown dose dependently reduced the inhibition of migration by ATRA, but the effect was more pronounced with RARA knockdown than with RARα knockdown. We confirmed that RARA gene was directly regulated by ATRA in microarray and real-time reverse transcription polymerase chain reaction. Furthermore, theRARβ agonist (BMS453) significantly suppressed proliferation of RL95-2 cells. In immunohistochemical analysis, RAR> expression was positively correlated with tumor grade, and RARβ showed the opposite tendency in endometrial cancer. Conclusions: Retinoic acid might have multiple antitumor effects, and RARβ may be a potent therapeutic target in RA treatment for endometrial cancers. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of all trans retinoic acid (ATRA) and suberoylanilide hydroxamic acid (SAHA) on the apoptosis of MCF-7 and to investigate whether the combination of the two drugs have synergistic effect Methods: Human breast cancer cell line MCF-7 was cultured in vitro. When the cells entered the logarithmic growth phase, a certain concentration of ATRA (or) SAHA was added into the petridishes. Flow cytometry was used to detect the apoptosis of the cells. Results: Compared with the control group, the early apoptosis rate was higher in the single drug groups and combined group. But the early apoptosis rate of the combined group was lower than that of the single drug group at 24 h, and the early apoptosis rate of 48 h and 72 h in combined group was higher than that in ATRA group but lower than SAHA group. The difference was statistically significant (P<0.05). The rate of death and late apoptotic cells in the combination group was higher than that in the single drug groups and the control group, the difference was statistically significant (P<0.05). Conclusions: ATRA and SAHA can promote the apoptosis of breast cancer cells ATRA combined with SAHA induced apoptosis of cells is more intense than the single drug groups. [ABSTRACT FROM AUTHOR]

Gastroenteritis is a global burden; it’s the major cause of morbidity and mortality both in adults and children of developing countries. Salmonella is one of the leading causes of bacteria-mediated gastroenteritis and due to its increasing multidrug antibiotic resistance; Salmonella- mediated gastroenteritis is difficult to control. Retinoic acid, the biologically active agent of vitamin A has an anti-inflammatory effect on experimental colitis. In this study we have shown All trans retinoic acid (ATRA) treatment down regulates Salmonella -mediated colitis in a murine model. Macroscopic signs of inflammation such as decrease in body weight and cecum weight, shorter length of proximal colon and pathological score of colitis were observed less in ATRA treated mice than in a vehicle control group. ATRA treatment not only reduced pro-inflammatory cytokine responses, such as TNF-α, IL-6, IL-1β, IFN-γ and IL-17 production but also increased IL-10 response in the supernatant of intestinal tissue. Results also suggested that ATRA treatment enhances the number of FoxP3-expressing T regulatory cells in MLN and also decreases bacterial load in systemic organs. We concluded that ATRA treatment indeed reduces Salmonella Typhimurium-mediated gastroenteritis in mice, suggesting it could be an important part of an alternative therapeutic approach to combat the disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of all-trans retinoic acid(ATRA) as adjuvant treatment on the level of serum erythropoietin(Erythropoietin, EPO), ferritin, folic acid and vitamin B12 in the patients with acute promyelocytic leukemia(APL).Methods: All clinical data of 50 cases with APL- were retrospective collected in our hospital from June 2011 to June 2015. According to the different treatment methods, all the patients were divided into two groups, group A, and B. The level of serum ferritin, EPO, folic acid and vitamin B12 was compared between two groups after treatment. Results: There was no significant difference between the two groups of in the level of serum EPO and ferritin before treatment(P>0.05); after treatment, the level of each index was obviously improved(P 0.05). The case number that the serum EPO, ferritin, folic acid and vitamin B12 returned to normal level in group B was more than that of group A, all had statistically significant difference, P<0.05. Conclusions: All-trans retinoic acid can improve the abnormality of serum EPO, ferritin, folic acid and vitamin B12 in the adjuvant treatment of patients with APL, and has a certain curative effect for this disease. [ABSTRACT FROM AUTHOR]

Although tumor-associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down-regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down-regulation of GADD45α. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA-transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene-transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Objectives: Acute promyelocytic leukemia (APL) is the only acute leukemia amenable to targeted therapy. However, there is limited Indian data on APL. We aimed to analyze data of APL patients treated with all trans retinoic acid (ATRA) and anthracycline based chemotherapy.Materials and Methods: A total of 34 cases of APL were treated at our center over 4 years. Induction chemotherapy consisted of a combination of ATRA and daunorubicin.Results: Most of our patients were intermediate risk (50%) followed by high risk (41.17%). Induction mortality was 14.7%. We observed a high incidence of febrile neutropenia (91%) and 50% of our patients developed ATRA syndrome. Four patients (11.76%) relapsed during follow-up (median - 15 months, range: 13-33 months). There was no correlation between risk status and death or relapse or ATRA syndrome. Median event free survival (EFS) duration was not reached however mean duration was 38.45 ± 3.84 months. Median overall survival (OS) duration was also not reached at 53 months of follow-up. The 4 year OS and EFS were 75.45% and 64.5% respectively. On multivariate analysis, only disseminated intravascular coagulation (DIC) significantly correlated with a poor OS and EFS.Discussion: Our data reflects that APL remains a highly curable malignancy with good response to ATRA plus anthracycline based chemotherapy even with a greater number of high and intermediate risk patients. Only DIC during induction chemotherapy bore an impact on survival in our patients. [ABSTRACT FROM AUTHOR]

Background Damaging effects that chronic ethanol exposure causes to the brain and the neurons are well documented. Ethanol and its toxic metabolites increase the oxidative stress in brain. Chronic exposure to ethanol leads to upregulation of N-methyl D-aspartate receptors (NMDAR) and also activates Kruppel like factor 11 (KLF11) mediated death cascade and thereby neurodegeneration. Objective Ethanol depletes vitamin A stores. But supplementation of vitamin A exacerbates ethanol induced toxicity since alcohol and its metabolites are competitive inhibitors of the enzymes involved in the metabolism of vitamin A. Hence, in this study we investigated the impact of co-administration of ethanol and all trans retinoic acid (ATRA), active metabolite of vitamin A, on ethanol induced alterations to the brain. Materials and methods Male Sprague Dawley rats, adolescent, were grouped as follows and maintained for 90 days. I – Control, II – Ethanol (4 g/kg b.w.), III – ATRA (100 µg/kg b.w.), IV – Ethanol (4 g/kg b.w.), +ATRA (100 µg/kg b.w.). Oxidative stress and the mRNA expression of various receptors for the neurotransmitter involved in glutamergic, serotonergic and gabaergic pathways were studied in the brain homogenate. Results Ethanol treatment was shown to decrease brain weight and it was increased on ATRA treatment. Increase in oxidative stress due to ethanol treatment was also brought down on ATRA administration. Ethanol induced upregulation of NMDAR and KLF11 was also downregulated on ATRA supplementation. The alterations in the levels of neurotransmitters and the expression of their receptors due to ethanol treatment also were ameliorated on ATRA supplementation. Conclusion Our results show that ATRA supplementation mitigates the ethanol induced alterations in the brain by reducing oxidative stress in the brain with concurrent suppression of NMDAR and KLF11 expression leading to enhanced catabolism of neurotransmitters. [ABSTRACT FROM AUTHOR]

Purpose: Current strategies implementing drug-eluting polymer stent coatings fail to fully address the lasting effects of endothelial suppression which ultimately result in delayed reendothelialization and thrombogenic complications. The present study investigates the in vitro hemocompatibility of all-trans retinoic acid loaded poly (1,8-octanediol-co-citrate) coatings (AtRA-POC coatings) for advanced intravascular stent technology. The ability of these materials in supporting endothelial restoration via migration and proliferation while inhibiting smooth muscle cell growth is also explored., Methods: Using in vitro models, the hemocompatibility of AtRA-loaded POC-coated cobalt chromium (CoCr) vascular stents was evaluated in terms of platelet and inflammatory activity. Platelet activity was quantified by platelet adhesion and platelet activation, further supported by SEM visualization. Inflammatory activity was quantified by the production of proinflammatory cytokines by THP1 monocytes. Lastly, in vitro wound healing and an 5-Ethynyl-2'deoxyuridine (EdU) and pico green DNA assays were used in quantitating endothelial and smooth muscle cell migration and proliferation., Results: Experimental examinations of platelet adhesion and activation demonstrate significant reductions in the platelet response to POC coated AtRA loaded stents when compared to bare CoCr stents. Such findings reveal AtRA-POC coatings to have significantly improved hemocompatibility compared to that of bare metal stents and at least as good as POC alone. Similarly, in reference to LPS-stimulated controls, Human monocyte-like THP1 cells in culture with AtRA-POC-CoCr stents for 24 hours showed reduced detection of proinflammatory cytokines, comparable to that of bare CoCr and untreated controls. This result supports AtRA-POC coatings as possessing limited immunological potential. Observations from in vitro endothelial and smooth muscle cell investigations demonstrate the ability of the drug AtRA to allow cell processes involved in restoration of the endothelium while inhibiting smooth muscle cell processes., Conclusion: This study demonstrates AtRA loaded POC coatings are hemocompatible, noninflammatory, and provide a promising strategy in enhancing vascular stent techniques and clinical integration. Possessing hemocompatibility and immunological compatibility that is at least as good as bare metal stents as clinical standards support the use of AtRA-POC coatings for vascular applications. Additionally, selectively reducing smooth muscle cell proliferation while supporting endothelial cell proliferation and migration further demonstrates the potential of these materials in significantly improving the state of vascular stent technology in the area of stent thrombosis and neointimal hyperplasia., Competing Interests: Conflicts of interest/Competing interests: Author, Josephine Allen holds a position on the editorial board of Regenerative Engineering and Translational Medicine Journal. The other authors have no relevant financial or non-financial interests to disclose.

Background & Aims: The function of cytoplasmic AFP as a regulatory factor in the growth of tumor cells has been well defined. However, its precise mechanism of action and its clinical significance remain to be worked out. Methods: Specimens from HCC patients were analyzed by using immunohistochemistry, co-immunoprecipitation (CoIP), and chromatin immunoprecipitation (ChIP) assays to evaluate the role of AFP in RAR signaling-mediated carcinogenesis. Quantitative real-time reverse transcription PCR, Western blotting, confocal microscopy, CoIP, GST pull-down, siRNA, gene transfection, and ChIP assays were also used for analysis of cell lines. Results: RAR is able to interact with cytoplasmic AFP and binds to the element of the regulatory region of the Fn14 gene in the neoplastic tissue of HCC patients. An assay of hepatocyte cell lines of differing AFP expression showed that cytoplasmic AFP is able to block ATRA-induced nuclear translocation of RAR and expression of the Fn14 gene. Knockdown of AFP in siRNA-transfected HepG2 and Bel7402 cells led to greater binding of RAR to its response element. The expression of the Fn14 gene was therefore up regulated as reflected by increases in mRNA and protein levels. Conversely, transfection of HLE and L02 cells (AFP negative) with the afp gene resulted in apparent reduction of RAR binding to DNA and Fn14 protein. Conclusions: Demonstration of the involvement of cytoplasmic AFP in RAR-mediated expression of the Fn14 gene strongly indicates AFP plays a signal molecule-like role in the regulation of hepatocellular carcinoma growth. [Copyright &y& Elsevier]

Abstract: We have previously shown in HK-2 cells that ATRA (all-trans-retinoic acid) up-regulates HIF-1α (hypoxia-inducible factor-1α) in normoxia, which results in increased production of renal protector VEGF-A (vascular endothelial growth factor-A). Here we investigated the role of COXs (cyclooxygenases) in these effects and we found that, i) ATRA increased the expression of COX-1 and COX-2 mRNA and protein and the intracellular levels (but not the extracellular ones) of PGE2. Furthermore, inhibitors of COX isoenzymes blocked ATRA-induced increase in intracellular PGE2, HIF-1α up-regulation and increased VEGF-A production. Immunofluorescence analysis found intracellular staining for EP1-4 receptors (PGE2 receptors). These results indicated that COX activity is critical for ATRA-induced HIF-1α up-regulation and suggested that intracellular PGE2 could mediate the effects of ATRA; ii) Treatment with PGE2 analog 16,16-dimethyl-PGE2 resulted in up-regulation of HIF-1α and antagonists of EP1-4 receptors inhibited 16,16-dimethyl-PGE2- and ATRA-induced HIF-1α up-regulation. These results confirmed that PGE2 mediates the effects of ATRA on HIF-1α expression; iii) Prostaglandin uptake transporter inhibitor bromocresol green blocked the increase in HIF-1α expression induced by PGE2 or by PGE2-increasing cytokine interleukin-1β, but not by ATRA. Therefore only intracellular PGE2 is able to increase HIF-1α expression. In conclusion, intracellular PGE2 increases HIF-1α expression and mediates ATRA-induced HIF-1α up-regulation. [Copyright &y& Elsevier]

Abstract: Carotenoids play a pivotal role in prevention of many degenerative diseases mediated by oxidative stress including neurodegenerative diseases like Alzheimer’s Disease (AD). The involvement of retinoids in physiology, AD pathology and their therapeutic role in vitro and in vivo has been extensively studied. This review focuses on the role of carotenoids like retinoic acid (RA), all trans retinoic acid (ATRA), lycopene and β-carotene in prevention of AD symptoms primarily through inhibition of amyloid beta (Aβ) formation, deposition and fibril formation either by reducing the levels of p35 or inhibiting corresponding enzymes. The role of antioxidant micronutrients in prevention or delaying of AD symptoms has been included. This study emphasizes the dietary supplementation of carotenoids to combat AD and warrants further studies on animal models to unravel their mechanism of neuroprotection. [Copyright &y& Elsevier]

Arsenic trioxide (ATO) synergistically promotes all trans retinoic acid (ATRA)-induced differentiation of PML–RARα negative HL-60 myeloblastic leukemia cells. In PML–RARα positive myeloid leukemia cells, ATO is known to cause degradation of PML–RARα with subsequent induced myeloid differentiation. We found that ATO by itself does not cause differentiation of the PML–RARα negative HL-60 cells, but enhances ATRA's capability to cause differentiation. ATO augmented ATRA-induced RAF/MEK/ERK axis signaling, expression of CD11b and p47PHOX, and inducible oxidative metabolism. ATO enhanced ATRA-induced population growth retardation without evidence of apoptosis or enhanced G1/G0 growth arrest. Compared to ATRA-treated cells, the ATRA plus ATO-treated cells progressed more slowly through the cell cycle as detected by a slower rate of accumulation in G2/M following nocodazole treatment. Hoechst/PI staining showed that low-dose ATO did not induce apoptosis. In summary, our results indicate that ATO in conjunction with ATRA is of potential chemotherapeutic use in PML–RARα negative leukemias. [ABSTRACT FROM AUTHOR]

Abstract: Work is presented on the role of cAMP-dependent protein phosphorylation in post-translational processing and biosynthesis of complex I subunits in mammalian cell cultures. PKA-mediated phosphorylation of the NDUFS4 subunit of complex I promotes in cell cultures in vivo import/maturation in mitochondria of the precursor of this protein. The import promotion appears to be associated with the observed cAMP-dependent stimulation of the catalytic activity of complex I. These effects of PKA are counteracted by activation of protein phosphatase(s). PKA and the transcription factor CREB play a critical role in the biosynthesis of complex I subunits. CREB phosphorylation, by PKA and/or CaMKs, activates at nuclear and mitochondrial level a transcriptional regulatory cascade which promotes the concerted expression of nuclear and mitochondrial encoded subunits of complex I and other respiratory chain proteins. [Copyright &y& Elsevier]

This study evaluates the effects of bone morphogenetic protein 2 (BMP-2) and all trans retinoic acid (ATRA) on adipogenesis in primary mouse embryo fibroblasts (MEFs). In BMP-2-treated MEFs, lipid accumulation and substantial induction of the adipocyte specific marker 442-aP2 suggested the conversion of MEFs into adipocytes. Such adipogenesis was found to be mediated through sequential induction of C/EBPα, C/EBPβ, and PPARγ. Both the BMP/Smad and BMP/p38 pathways contributed to the adipocyte differentiation. Contrary to the effects of BMP-2, ATRA was demonstrated to inhibit adipocyte differentiation in MEFs. Semi-quantitative RT-PCR analysis revealed that ATRA caused a selective inhibition of both the basal and induction levels of C/EBPα and PPARγ, without altering the expression pattern of C/EBPβ. Taken together, these data suggest the roles of BMP-2 and ATRA in adipogenic differentiation of primary MEFs, and the possible molecular mechanism that involves the regulation of C/EBPα, C/EBPβ, and PPARγ. [ABSTRACT FROM AUTHOR]

Abstract: The role of AFP in the retinoic acid-RAR signaling pathway was investigated in human hepatoma Bel 7402 cells. The results showed that AFP and RAR-β were co-localized and interacted in cytoplasm. AFP may inhibit translocation of RAR-β into the nucleus via competitive binding to RAR-β with ATRA, which was reversed by AFP-siRNA transfection. Our data suggest that the ATRA resistance of Bel 7402 cells is at least in part attributable to their high level of cytoplasmic AFP. Thus, by counteracting the effect of AFP, it may be possible to increase the sensitivity of tumor cells to ATRA. [Copyright &y& Elsevier]

Abstract: Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863–78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45–67%. The possible implications of these changes in hepatic atRA levels on cell proliferation in the mouse tumorigenesis process are discussed. [Copyright &y& Elsevier]

Previous studies have demonstrated that all-trans retinoic acid (RA) increases collagen production and decreases matrix metalloproteinase (MMP) activity in organ-cultured human skin. Decreased MMP activity is associated with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1). These changes are accompanied by a hyperplastic response in the epidermis. Here we show that a synthetic picolinic ester-substituted retinoid (designated as MDI 301) has comparable effects to those of RA in regard to these activities. What makes these findings of interest is that RA also stimulates elaboration of several pro-inflammatory cytokines and up-regulates leukocyte adhesion molecules in organ-cultured skin. MDI 301 does not induce such changes or is much less active. In a past study we showed that while RA was irritating to the skin of topically treated hairless mice, MDI 301 was essentially non-irritating under the same conditions [Varani et al. (2003) Arch. Dermatol Res 295:255–262]. Taken in conjunction with the findings from the past study, the present data suggest that MDI 301 will be similar to RA in capacity to repair damaged skin, but will be effective under conditions that are not irritating. These findings, thus, suggest that retinoid efficacy and clinically relevant irritancy are not inextricably linked. Potential for efficacy under conditions in which irritation is not observed is a strong rationale for further development of MDI 301 as a skin-repair agent. [ABSTRACT FROM AUTHOR]

Beta-defensins and surfactant proteins are components of the pulmonary innate immune system. Their gene expression is regulated by development, hormones, growth and immunoregulatory factors. It was our hypothesis that growth and differentiation factors such as all-trans retinoic acid (RA) and vascular endothelial growth factor (VEGF) may affect expression of selected innate immune genes by respiratory epithelial cells. Ovine JS7 cells (alveolar type II pneumocytes) were incubated in serum-free Dulbecco's modified Eagle's medium (DMEM) complete media that contained: no treatment (negative control), RA (500 nM), or VEGF (100 ng/ml) for 6, 12 or 24 h incubation. Total RNA was isolated, cDNA synthesized, and relative mRNA levels of surfactant protein A (SP-A) and SP-D, and sheep beta-defensin-1 (SBD-1) were determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Cells had significantly increased expression of SP-D mRNA at 6 h and 24 h, decreased expression of SP-A mRNA at 12 h, and unchanged levels of SBD-1 mRNA after the treatment with RA compared with their respective negative controls. VEGF did not alter the expression of the three innate immune genes. These findings suggest that SP-A and SP-D have different transcription regulation pathways, and that expression of SBD-1 is not inducible by RA similar to its human homolog HBD-1. The lack of changes induced by VEGF treatment suggests that VEGF does not have a direct effect on epithelial cells, but may affect gene expression indirectly. [ABSTRACT FROM AUTHOR]

Summary A case is reported of a pregnant 16-year-old-woman diagnosed with Acute promyelocytic leukaemia (APL) at 25 weeks gestation and treated with all-trans retinoic acid (ATRA) (45 mg/m2 ) for 25 days in combination with chemotherapy. She achieved a complete cytogenetic and molecular remission. Clinical course was complicated, with an intracerebral bleed, respiratory failure requiring ventilation and prolonged pancytopenia following initial chemotherapy. A live female infant was born at 28 weeks gestation who survived to discharge with significant pulmonary complications. She remains oxygen dependent at 6 months of age. ATRA has been used from the 3rd week of gestation, but fetal malformations are common during the first trimester. In contrast it seems to be safe in the second and third trimesters with regard to teratogenesis but can cause other side-effects. Most successful outcomes in treatment of APL during pregnancy are seen after treatment with ATRA and delivery of the baby at as late a stage as possible. Pregnancies terminated before remission has been obtained or those treated in the first trimester have a poor maternal outcome. [ABSTRACT FROM AUTHOR]

Detailed knowledge about differentiation syndrome (DS) has remained limited. There are 2 large studies conducted by the Spanish workgroup PETHEMA (Programa Español de Tratamientos en Hematología; Spanish Program on Hematology Treatments) and the European group trial (LPA 96-99 and APL 93) in which the incidence, characteristics, prognostic factors and outcome of patients developing DS are evaluated. Both have described the median time of DS development between 10 and 12 days. The severity of the DS has been evaluated in the study conducted by PETHEMA, and severe DS usually occurs at the beginning of the treatment (median of 6 days), as compared with moderate DS (median of 15 days). We report here in two cases of late severe DS, with late diagnosis due to both time and form of presentation. We discuss the physiopathology, clinical presentation, prophylaxis and treatment of DS. [ABSTRACT FROM AUTHOR]

Network pharmacology is an emerging field which is currently capturing interest in drug discovery and development. Chronic kidney conditions have become a threat globally due to its associated lifelong therapies. Nephrotic syndrome (NS) is a common glomerular disease that is seen in paediatric and adult population with characteristic manifestation of proteinuria, oedema, hypoalbuminemia, and hyperlipidemia. It involves podocyte damage with tubulointerstitial fibrosis and glomerulosclerosis. Till date there has been no specific treatment available for this condition that provides complete remission. Repurposing of drugs can thus be a potential strategy for the treatment of NS. Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA). Epigenetic drugs act by binging about changes in gene expression without altering the DNA sequence. The changes include DNA methylation or histone modifications. The targets for the two drugs ATRA and VPA were collated from ChEMBL and Binding DB. All the genes associated with NS were collected from DisGeNET and KEGG database. Interacting proteins for the target genes were acquired from STRING database. The genes were then subjected to gene ontology and pathway enrichment analysis using a functional enrichment software tool. A drug-target and drug-potential target-protein interaction network was constructed using the Cytoscape software. Our results revealed that the two drugs VPA and ATRA had 65 common targets that contributed to kidney diseases. Out of which, 25 targets were specifically NS associated. Further, our work exhibited that ATRA and VPA were synergistically involved in pathways of inflammation, renal fibrosis, glomerulosclerosis and possibly mitochondrial biogenesis and endoplasmic reticulum stress. We thus propose a synergistic potential of the two drugs for treating chronic kidney diseases, specifically NS. The outcomes will undoubtedly invigorate further preclinical and clinical explorative studies. We identify network pharmacology as an initial inherent approach in identifying drug candidates for repurposing and synergism., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Arsenic trioxide (ATO) combined with all trans retinoic acid (ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia (APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients' compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel (PPSG) loaded with ATO and ATRA was developed. ATO+ATRA-PPSG (AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t 1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO+ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application., Competing Interests: The authors declare no conflict of interest., (© 2021 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Objectives: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer, mainly due to high early mortality mainly due bleeding. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, Mexico and Uruguay. Methods: The IC-APL treatment protocol is similar to the PETHEMA 2005, but changing idarubicin to daunorubicin. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. The immunofluorescence using an anti-PML antibody allowed a rapid confirmation of the diagnosis and, the importance of supportive measures was reinforced. Results: The interim analysis of 97 patients enrolled in the IC-APL protocol showed that complete remission (CR) rate was 83% and the 2-year overall survival and disease-free survival were 80% and 90%, respectively. Of note, the early mortality rate was reduced to 7.5%. Discussion: The results of IC-APL demonstrate the impact of educational programs and networking on the improvement of the leukemia treatment outcome in developing countries. [ABSTRACT FROM AUTHOR]

• ATRA therapy leads to alveolar regeneration. • Proliferation/differentiation/EMT leads to alveolar regeneration. • ATRA attenuates the deregulated pathways (Notch, Hedgehog, Wnt, TGFβ and BMP). • ATRA leads to alveolar regeneration via amelioration of deregulated pathways. Pulmonary emphysema is characterized by destruction of alveoli leading to inadequate oxygenation, disability and frequently death. This destruction was understood so far as irreversible. Published data has shown that ATRA (All Trans Retinoic Acid) reverses elastase-induced emphysema in rats. However, the molecular mechanisms governing regeneration process are so far unknown. To examine the therapeutic potential of ATRA on various molecular pathways and their coordination towards governance of alveolar epithelial regeneration in emphysematous rats. Emphysema was induced by elastase versus saline in Sprague-Dawley rats. On days 26–37, rats received daily intraperitoneal injections with ATRA (500 μg/kg b.w.) versus olive-oil. Lungs were removed at day 38 for histopathology and investigation of relative mRNA and protein expressions. Histopathological analysis has shown that losses of alveoli were recovered in therapy (EA) group. Moreover, expressions of markers genes for alveolar cell proliferation, differentiation and EMT events at mRNA and protein levels were significantly increased in EA group than emphysema group (ES). Upon validation at genomics level, expressions of components of Notch, Hedgehog, Wnt, BMP and TGFβ pathways were significantly attenuated in EA group when compared with ES and were well comparable with the healthy group. Therapeutic supplementation of ATRA rectifies the deregulated Notch, Hedgehog, Wnt, BMP and TGFβ pathways in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema. Nevertheless, elaborated studies are to be conducted. [ABSTRACT FROM AUTHOR]

Background: TreXTAM ® is a combination of the key regulatory cytokine transforming growth factor beta (TGFβ) and all trans retinoic acid (ATRA) microencapsulated for oral delivery to immune structures of the gut. It is in development as a novel treatment for inflammatory bowel disease (IBD)., Aim: To measure TGFβ levels in blood and tissue after oral administration of encapsulated TGFβ., Methods: Animals were orally administered encapsulated TGFβ by gavage. Levels of drug substance in blood and in gut tissues at various times after administration were measured by ELISA., Results: We made the surprising discovery that oral administration of TreXTAM dramatically (approximately 50%) and significantly ( P = 0.025) reduced TGFβ levels in colon, but not small intestine or mesenteric lymph nodes. Similarly, levels in rat serum after 25 d of thrice weekly dosing with either TreXTAM, or microencapsulated TGFβ alone (denoted as TPX6001) were significantly ( P < 0.01) reduced from baseline levels. When tested in the SCID mouse CD4+CD25- adoptive cell transfer (ACT) model of IBD, oral TPX6001 alone provided only a transient benefit in terms of reduced weight loss., Conclusion: These observations suggest a negative feedback mechanism in the gut whereby local delivery of TGFβ results in reduced local and systemic levels of the active form of TGFβ. Our findings suggest potential clinical implications for use of encapsulated TGFβ, perhaps in the context of IBD and/or other instances of fibrosis and/or pathological TGFβ signaling., Competing Interests: Conflict-of-interest statement: Dr. Auci reports grants from NIH, during the conduct of the study; In addition, Dr. Auci has a patent Micronized freeze-dried particles issued, and a patent Compositions for stabilizing and delivering proteins pending and Authors hold equity in Therapyx., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)