All-trans Retinoic Acid Research Articles

CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies

AbstractCD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38KO/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38+ hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38KO/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1KO/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38+ hematologic malignancies, further increased by combination treatment with ATRA.

Experimental design and characterization of dual-antibody-conjugated all-trans retinoic acid-loaded lipid nanoparticles as a potential cancer therapy

Antibody-targeted immunotherapy has emerged in cancer therapies regarding checkpoint inhibition with monoclonal antibodies, such as anti-programmed death-ligand 1 (anti-PD-L1) either given alone or in combination. However, when given alone, it may fail to activate tumor-specific T cells. The combinational therapy of anti-PD-L1 with anti-4-1BB and all-trans retinoic acid (ATRA) has come into prominence due to disease heterogeneity, resulting in the synergistic effects associated with greater T-cell responses. This study introduces anti-PD-L1 and anti-4-1BB-conjugated ATRA-loaded solid lipid nanoparticles (SLNs), where the Design-Expert Program was applied for the optimization. Accordingly, antibody–conjugated ATRA-loaded SLNs had uniform dispersions with mean diameters of 179.6 ± 12.6 nm. The formulations achieved the encapsulation efficiency (EE %) of ATRA at 21.2 ± 1.4 %, regarding the three-dimensional response surface graph. The binding efficiency of anti-4-1BB and anti-PD-L1 antibodies were determined as 85.59 ± 7.3 % and 90.02 ± 5.4 %, respectively. The release profile of formulations indicated the biphasic release of ATRA (ie., 76 ± 4.4 %) from SLNs within 24 h via the Higuchi model. Particle size distributions of SLNs displayed a 7 % increase (i.e., 190.5 ± 7.63 nm) at 4 °C over 2 months. The experimental design of anti-PD-L1- and anti-4-1BB-conjugated- ATRA-loaded SLNs highlighted the promising strategy for the development of alternative formulations and the potential approach for further cancer therapies.

Linalool and Geraniol Defend Neurons from Oxidative Stress, Inflammation, and Iron Accumulation in In Vitro Parkinson's Models.

Parkinson's disease is one of the most prevalent neurological disorders affecting millions of people worldwide. There is a growing demand for novel and natural substances as complementary therapies. Essential oils and their various compounds are highly investigated natural plant-based products as potential treatment options for common human diseases, such as microbial infections, chronic diseases, and neurodegenerative disorders. The present study focuses on the beneficial effects of linalool and geraniol, the major compounds of lavender (Lavandula angustifolia L.) and geranium (Pelargonium graveolens L'Hér. in Aiton) essential oils, on oxidative stress, inflammation, and iron metabolism of the rotenone and 6-hydroxydopamine-induced in vitro Parkinson's models. The experiments were carried out on all-trans retinoic acid differentiated SH-SY5Y cells. The effects of linalool and geraniol were compared to rasagiline, an MAO-B inhibitor. The results revealed that both essential oil compounds reduce the level of reactive oxygen species and alter the antioxidant capacity of the cells. They lower the secretion of IL-6, IL-8, and IL-1β pro-inflammatory cytokines. Moreover, linalool and geraniol change the expression of iron-related genes, such as the iron importer transferrin receptor 1, heme-oxygenase-1, and ferroportin iron exporter, and influence the intracellular iron contents. In addition, it has been unveiled that iron availability is concatenated with the actions of the essential oil compounds. Based on the results, linalool and geraniol are vigorous candidates as an alternative therapy for Parkinson's disease.

Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL

AbstractAtypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene–positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X– or X::RAR::Y–type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3′ splices was associated with their 5′ fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3′ splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5′ splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3′ fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion–positive aAPL, through a protein allosteric dysfunction mechanism.

All-trans retinoic acid induces lipophagy by reducing Rubicon in Hepa1c1c7 cells

All-trans retinoic acid (atRA), a metabolite of vitamin A, reduces hepatic lipid accumulation in liver steatosis model animals. Lipophagy, a new lipolysis pathway, degrades a lipid droplet (LD) via autophagy in adipose tissue and the liver. We recently found that atRA induces lipophagy in adipocytes. However, it remains unclear whether atRA induces lipophagy in hepatocytes. In this study, we investigated the effects of atRA on lipophagy in Hepa1c1c7 cells and the liver of mice fed a high-fat diet (HFD). First, we confirmed that atRA induced autophagy in Hepa1c1c7 cells by Western blotting and the GFP-LC3-mCherry probe. Next, we evaluated the lipolysis in fatty Hepa1c1c7 cells treated with the knockdown of Atg5, an essential gene in autophagy induction. Atg5-knockdown partly suppressed the atRA-induced lipolysis in fatty Hepa1c1c7 cells. We also found that atRA reduced the protein, but not mRNA, expression of Rubicon, a negative regulator of autophagy, in Hepa1c1c7 cells and the liver of HFD-fed mice. Rubicon-knockdown partly inhibited the atRA-induced lipolysis in fatty Hepa1c1c7 cells. In addition, atRA reduced hepatic Rubicon expression in young mice, but the effect of atRA on it diminished in aged mice. Finally, we investigated the mechanism underlying reduced Rubicon protein expression by atRA in hepatocytes. A protein synthesis inhibitor, but not proteasome or lysosomal inhibitors, significantly blocked the reduction of Rubicon protein expression by atRA in Hepa1c1c7 cells. These results suggest that atRA may promote lipophagy in fatty hepatocytes by reducing hepatic Rubicon expression via inhibiting protein synthesis.

In Vivo Chemical Screening in Zebrafish Embryos Identified FDA-Approved Drugs That Induce Differentiation of Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is characterized by the abnormal proliferation and differentiation arrest of myeloid progenitor cells. The clinical treatment of AML remains challenging. Promoting AML cell differentiation is a valid strategy, but effective differentiation drugs are lacking for most types of AML. In this study, we generated Tg(drl:hoxa9) zebrafish, in which hoxa9 overexpression was driven in hematopoietic cells and myeloid differentiation arrest was exhibited. Using Tg(drl:hoxa9) embryos, we performed chemical screening and identified four FDA-approved drugs, ethacrynic acid, khellin, oxcarbazepine, and alendronate, that efficiently restored myeloid differentiation. The four drugs also induced AML cell differentiation, with ethacrynic acid being the most effective. By an RNA-seq analysis, we found that during differentiation, ethacrynic acid activated the IL-17 and MAPK signaling pathways, which are known to promote granulopoiesis. Furthermore, we found that ethacrynic acid enhanced all-trans retinoic acid (ATRA)-induced differentiation, and both types of signaling converged on the IL-17/MAPK pathways. Inhibiting the IL-17/MAPK pathways impaired ethacrynic acid and ATRA-induced differentiation. In addition, we showed that ethacrynic acid is less toxic to embryogenesis and less disruptive to normal hematopoiesis than ATRA. Thus, the combination of ethacrynic acid and ATRA may have broader clinical applications. In conclusion, through zebrafish-aided screening, our study identified four drugs that can be repurposed to induce AML differentiation, thus providing new agents for AML therapy.

Differentiation activates mitochondrial OPA1 processing in myoblast cell lines

Mitochondrial optic atrophy-1 (OPA1) plays key roles in adapting mitochondrial structure to bioenergetic function. When transmembrane potential across the inner membrane (Δψm) is intact, long (L-OPA1) isoforms shape the inner membrane through membrane fusion and the formation of cristal junctions. When Δψm is lost, however, OPA1 is cleaved to short, inactive S-OPA1 isoforms by the OMA1 metalloprotease, disrupting mitochondrial structure and priming cellular stress responses such as apoptosis. Previously, we demonstrated that L-OPA1 of H9c2 cardiomyoblasts is insensitive to loss of Δψm via challenge with the protonophore carbonyl cyanide chlorophenyl hydrazone (CCCP), but that CCCP-induced OPA1 processing is activated upon differentiation in media with low serum supplemented with all-trans retinoic acid (ATRA). Here, we show that this developmental induction of OPA1 processing in H9c2 cells is independent of ATRA; moreover, pretreatment of undifferentiated H9c2s with chloramphenicol (CAP), an inhibitor of mitochondrial protein synthesis, recapitulates the Δψm-sensitive OPA1 processing observed in differentiated H9c2s. L6.C11 and C2C12 myoblast lines display the same developmental and CAP-sensitive induction of OPA1 processing, demonstrating a general mechanism of OPA1 regulation in mammalian myoblast cell settings. Restoration of CCCP-induced OPA1 processing correlates with increased apoptotic sensitivity. Moreover, OPA1 knockdown indicates that intact OPA1 is necessary for effective myoblast differentiation. Taken together, our results indicate that a novel developmental mechanism acts to regulate OMA1-mediated OPA1 processing in myoblast cell lines, in which differentiation engages mitochondrial stress sensing.

Conversion of Retinoids along the Marine Food Chain Contributes to Adverse Impacts on the Spine, Liver, and Intestinal Health of the Marine Medaka (Oryzias melastigma).

Marine microalgae serve as an aquaculture bait. To enhance algal cell growth and breeding profits, high-intensity light conditions are standard for cultivating bait microalgae, potentially altering microalgal metabolite production. This research revealed that Thalassiosira pseudonana, when subjected to high-intensity light conditions, accumulated significant quantities of retinal (RAL) that transferred through the food chain and transformed into all-trans retinoic acid (atRA) in marine medaka. The study further explored the toxic effects on individual fish and specific tissues, as well as the mechanisms behind this toxicity. The accumulation of atRA in the liver, intestine, and spinal column resulted in structural damage and tissue inflammation, as well as oxidative stress. It also down-regulated the gene transcription levels of key pathways involved in immune function and growth. Furthermore, it disrupted the homeostasis of the intestinal microbial communities. The implications for wildlife and human health, which are influenced by the regulation of microalgal metabolite accumulation and their transfer via the food chain, require further investigation and could hold broader significance.

O-133 Retinoic acid has an essential role in meiotic progression beyond the zygotene stage in mouse testis

Abstract Study question Is all-trans retinoic acid (ATRA) instrumental to male germ cell differentiation in the mouse beyond the A1 spermatogonia cell stage? Summary answer While ATRA is useless to meiosis initiation, it is crucial to allow germ cells progressing beyond the mid-pachytene stage of meiosis. What is known already In mammals, ATRA is instrumental to spermatogenesis. It is synthesized by retinaldehyde dehydrogenases (RALDH), and then it binds to and activates nuclear receptors (RAR) either within the ATRA-synthesizing cells or in the neighboring cells. We established previously that ATRA synthesized by Sertoli cells initiates differentiation of A aligned into A1 spermatogonia during the 1st spermatogenic cycle. A controversy exists as to the requirement of ATRA in meiosis and spermiogenesis initiations. Some authors propose that ATRA is indispensable to both, while others claim that ATRA is useless to meiotic initiation but essential to spermiogenesis. Study design, size, duration In order to determine the role of ATRA in meiosis and spermiogenesis, we have generated mutant mice lacking all retinaldehyde dehydrogenase (RALDH) activities either in Sertoli cells or in the whole seminiferous epithelium (i.e., in both Sertoli and germ cells). We then compared in these two types of mutants the fate of spermatocytes generated during the first wave of spermatogenesis, following A1 spermatogonia differentiation at post-natal day 4. Participants/materials, setting, methods To generate these mutants, transgenic mice in which the Cre recombinase expression is driven by Stra8 or Amh promoters (active in undifferentiated spermatogonia and Sertoli cells, respectively) were crossed with mice bearing loxP-flanked alleles of Raldh1, Raldh2 and Raldh3. The animals bearing the Amh-Cre transgene lack ATRA only in Sertoli cells, while those bearing both the Amh-Cre and Stra8-Cre transgenes lack ATRA in the whole seminiferous epithelium. Main results and the role of chance In mice lacking RALDH in the whole seminiferous epithelium, we show that differentiated spermatogonia initiate meiosis properly, despite the evident lack of ATRA. However, the generated spermatocytes die by apoptosis at the mid-pachytene stage. They display signs of altered meiotic recombination (i.e., increased methylation of histone H3 on lysine 4, increased phosphorylation of histone H2AX variant, increased number of RAD51 foci), without abnormal chromosomal pairing, as assessed by SYCP1 and SYCP3 distributions. In addition, they lose TEX14 expression and inter-cytoplasmic connections, thus forming syncytia. When ATRA is missing in seminiferous epithelium, the Sertoli cells also are affected. They display an altered architecture, a disrupted distribution of connexin 43, and fail to maintain a functional blood-testis barrier. These defects are possibly related to a cell-autonomous, abnormal, increase of SRC kinase phosphorylation. We finally demonstrate that ATRA given at the preleptotene/leptotene stage is able to rescue all of these defects and to allow normal meiotic progression and spermiogenesis. Altogether, these results indicate that ATRA is required during the early step of meiotic prophase I, not to initiate meiosis by inducing STRA8 expression, but to allow proper chromosome recombination, survival of spermatocytes beyond the mid-pachytene stage and maintenance of Sertoli cell functioning. Limitations, reasons for caution These results were obtained using a mouse model and therefore the relevance for human spermatogenesis remains to be demonstrated. Wider implications of the findings Pharmacological studies support a role for ATRA in spermatogenesis in humans. Whether testicular impairment of ATRA synthesis or functioning might be a cause of azoospermia or oligozoospermia remains to be explored in clinical research. According to our study, ATRA emerges as a potential candidate for developing treatments in infertile patients. Trial registration number N.A.

Retinoic acid reduces kidney injury by regulating oxidative stress, NRF-2, and apoptosis in hyperoxic mice.

Nuclear factor-erythroid-2-related factor-2 (NRF-2) is a cellular resistance protein to oxidants. We investigated the effect of exogenous all-trans retinoic acid (ATRA) on the antioxidant system and NRF-2 in mice kidneys under hyperoxia-induced oxidative stress. Mice were divided into four groups. Daily, two groups were given either peanut-oil/dimethyl sulfoxide (PoDMSO) mixture or 50 mg/kg ATRA. Oxidative stress was induced by hyperoxia in the remaining groups. They were treated with PoDMSO or ATRA as described above, following hyperoxia (100% oxygen) for 72 h. NRF-2 and active-caspase-3 levels, lipid peroxidation (LPO), activities of antioxidant enzymes, xanthine oxidase (XO), paraoxonase1 (PON1), lactate dehydrogenase (LDH), tissue factor (TF), and prolidase were assayed in kidneys. Hyperoxia causes kidney damage induced by oxidative stress and apoptosis. Increased LPO, LDH, TF, and XO activities and decreased PON1 and prolidase activities contributed to kidney damage in hyperoxic mice. After hyperoxia, increases in the activities of antioxidant enzymes and NRF-2 level could not prevent this damage. ATRA attenuated damage via its oxidative stress-lowering effect. The decreased LDH and TF activities increased PON1 and prolidase activities, and normalized antioxidant statuses are indicators of the positive effects of ATRA. We recommend that ATRA can be used as a renoprotective agent against oxidative stress induced-kidney damage.

Metabolomics reveals dysregulated all-trans retinoic acid and polyunsaturated fatty acid metabolism contribute to PXR-induced hepatic steatosis in mice

Activation of pregnane X receptor (PXR) by xenobiotics has been associated with metabolic diseases. This study aimed to reveal the impact of PXR activation on hepatic metabolome and explore novel mechanisms underlying PXR-mediated lipid metabolism disorder in the liver. Wild-type and PXR-deficient male C57BL/6 mice were used as in vivo models, and hepatic steatosis was induced by pregnenolone-16α-carbonitrile, a typical rodent PXR agonist. Metabolomic analysis of liver tissues showed that PXR activation led to significant changes in metabolites involved in multiple metabolic pathways previously reported, including lipid metabolism, energy homeostasis, and amino acid metabolism. Moreover, the level of hepatic all-trans retinoic acid (ATRA), the main active metabolite of vitamin A, was significantly increased by PXR activation, and genes involved in ATRA metabolism exhibited differential expression following PXR activation or deficiency. Consistent with previous research, the expression of downstream target genes of peroxisome proliferator-activated receptor α (PPARα) was decreased. Analysis of fatty acids by Gas Chromatography-Mass Spectrometer further revealed changes in polyunsaturated fatty acid metabolism upon PXR activation, suggesting inhibition of PPARα activity. Taken together, our findings reveal a novel metabolomic signature of hepatic steatosis induced by PXR activation in mice.

Retinoic Acid and Its Derivatives in Dermatological Disorders

Retinoids are a group of compounds consisting of vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids can regulate the physiological functions of various organs and tissues and play an important role in normalising immune function, cell growth and differentiation. Vitamin A Vitamin A derivatives have a role in the treatment of tumours and ATRA has a role in the differentiation therapy of acute promyelocytic leukaemia (APL). ATRA and other retinoids also have many applications in dermatological conditions (e.g. skin cancer, psoriasis). ATRA and other retinoids also have many applications in dermatological conditions (e.g. skin cancer, psoriasis, acne and ichthyosis). In addition, the physiological functions of skin cells can also be regulated by modulating retinoic acid receptors and retinoid X (or rexinoid) receptors. The results of numerous genetic modelling experiments have shown that the regulation of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) may have great potential for the treatment of serious skin diseases such as skin cancer. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.

Inhibitory effect of all-trans retinoic acid on ferroptosis in BeWo cells mediated by the upregulation of heme Oxygenase-1

IntroductionThis study aimed to explore the association between ferroptosis, a newly identified type of cell death, and the role of retinoic acid in developing pregnancy complications. Therefore, the effects of all-trans retinoic acid (ATRA) on ferroptosis susceptibility in BeWo cells were assessed to understand abnormal placental development. MethodsBeWo cells were used as surrogates for cytotrophoblasts. The effect of ATRA on ferroptosis sensitivity was assessed on BeWo cells pretreated with ATRA or dimethyl sulfoxide (DMSO; control), following which the LDH-releasing assay was performed. The effects of ATRA pretreatment on the antioxidant defense system (including glutathione [GSH], mitochondrial membrane potential, and heme oxygenase-1 [HMOX1]) in BeWo cells were assessed using assay kits, RT-qPCR, and HMOX1 immunostaining. To evaluate the effect of ATRA on BeWo cells, HMOX1 was silenced in BeWo cells using shRNA. ResultsATRA pretreatment increased ferroptosis resistance in BeWo cells. Although with pretreatment, qPCR indicated upregulation of HMOX1, no significant change was observed in the GSH levels or mitochondrial membrane potential. This was corroborated by intensified immunostaining for heme oxygenase-1 protein (HO-1). Notably, the protective effect of ATRA against ferroptosis was negated when HO-1 was inhibited. Although HMOX1-silenced BeWo cells exhibited heightened ferroptosis sensitivity compared with controls, ATRA pretreatment counteracted ferroptosis in these cells. DiscussionATRA pretreatment promotes BeWo cell viability by suppressing ferroptosis and upregulating HMOX1 and this can be used as a potential therapeutic strategy for addressing placental complications associated with ferroptosis.

FAP-activated liposomes achieved specific macropinocytosis uptake by pancreatic stellate cells for efficient desmoplasia reversal

The desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) severely compromises drug delivery and efficacy. To disrupt stromal barriers, we constructed an all-trans retinoic acid (ATRA)-loaded liposome, FrLip@R, that contained calcium phosphate (CaP) cores and arginine 12-mer peptide (r12) ligands shielded by fibroblast activation protein (FAP)-detachable polyglutamate. Shielding r12 protected FrLip@R from nonspecific uptake, e.g., eluding the mononuclear phagocyte system (MPS) uptake for extended blood retention. Then, FrLip@R could be specifically activated by FAP overexpressed on activated pancreatic stellate cells (PSCs) to expose r12, thereby promoting its PSC uptake via an efficient macropinocytosis pathway. Accordingly, FrLip@R exhibited 2.42- and 2.85-fold higher internalization by in vivo PSCs than r12-modified and unmodified liposomes, respectively. In particular, the FrLip amount in the FAP+ PSCs was 54.46-fold higher than that in the other intratumoral cells. In addition, CaP core dissolution in acidic endosomes promoted ATRA release in the cytoplasm. Through efficient and specific ATRA delivery, FrLip@R induced PSC quiescence and disrupted stromal barriers, enhancing intratumoral drug delivery. Finally, in a murine pancreatic cancer model, FrLip@R combined with gemcitabine exerted antitumor efficacy superior to a 1.5-fold dose of gemcitabine while avoiding its severe side effects. Furthermore, FrLip@R modulation created a microenvironment adverse to tumor growth. Therefore, FrLip@R represents a potent and safe stromal barrier-disrupting agent that can amplify chemotherapeutic efficacy in desmoplastic PDAC.

All-Trans Retinoic Acid-Induced Cell Surface Heat Shock Protein 90 Mediates Tau Protein Internalization and Degradation in Human Microglia.

This study investigates the role of all-trans retinoic acid (ATRA) in modulating the expression of heat shock protein 90 (Hsp90) and its influence on the uptake and degradation of tau proteins in immortalized human microglia cells. We demonstrate that ATRA significantly upregulates Hsp90 expression in a concentration-dependent manner, enhancing both extracellular and intracellular Hsp90 levels. Our results show that ATRA-treated cells exhibit increased tau protein uptake via caveolae/raft-dependent endocytosis pathways. This uptake is mediated by surface Hsp90, as evidenced by the inhibition of tau internalization using an extracellular Hsp90-selective inhibitor. Further, we establish that the exogenously added full-sized monomeric tau proteins bind to Hsp90. The study also reveals that ATRA-enhanced tau uptake is followed by effective degradation through both lysosomal and proteasomal pathways. We observed a significant reduction in intracellular tau levels in ATRA-treated cells, which was reversed by lysosome or proteasome inhibitors, suggesting the involvement of both degradation pathways. Our findings highlight the potential therapeutic role of ATRA in Alzheimer's disease and related tauopathies. By enhancing Hsp90 expression and facilitating tau degradation, ATRA could contribute to the clearance of pathological tau proteins, offering a promising strategy for mitigating neurodegeneration. This research underscores the need for further exploration into the molecular mechanisms of tau protein internalization and degradation, which could provide valuable insights into the treatment of neurodegenerative diseases.

Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ.

All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.

Negative expression of CD117 predicted inferior OS and PFS in acute promyelocytic leukemia.

In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117-) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. The median follow-up period was 63.0 months. CD117- was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117- subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117- APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively). To sum up, CD117- is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.

Acute promyelocytic leukemia in children cancer hospital Egypt

BackgroundPediatric acute promyelocytic leukemia (APL) accounts for 5 to 15% of all myelocytic leukemia. A retrospective analysis of pediatric patients diagnosed and treated with APL was conducted at CCHE from July 2012 to the end of December 2019, to report the prevalence, clinical characteristics, results, and risk factors associated with induction failure and early death.ResultSixty-two patients were reported, with an age greater than ten, an initial poor coagulation profile, and a total leukocyte count (TLC) greater than 30 103/mm3 influencing 5-year overall (OS) and event-free survival (EFS), as well as a high promyelocyte count affecting 5-year EFS. Patients received a regimen based on the COG AAML0631 protocol. High-risk patients with an initial TLC > 10 × 103/mm3 and an initial promyelocytic count of 30% or more with a substantial P-value are prognostic markers for early death during induction. In females, wild FLT3 increases the risk of differentiation syndrome (DS). Receiving steroids with all-trans retinoic acid (ATRA) induction may reduce the occurrence of DS. Relapse alters the outcome. In the current study, 45 patients are alive in complete remission, with a 5-year OS of 72.5% and a 5-year EFS of 69.4%, respectively.ConclusionPediatric APL outcomes are influenced by age above 10, an initial poor coagulation profile, and a promyelocyte count of more than 10%. An initial leukocyte count of more than 10 × 103/mm and an initial promyelocytic count of more than 30% increase the risk of early death. Receiving steroids with ATRA may reduce the occurrence of DS.

Functional multiomics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma

AbstractCD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. Pretreatment CD38 density on tumor cells is an important determinant of mAb efficacy. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a cotreatment strategy. Numerous other CD38-targeting therapeutics are currently in preclinical or clinical development. Here, we sought to extend our currently limited insight into CD38 surface expression by using a multiomics approach. Genome-wide CRISPR interference screens integrated with patient–centered epigenetic analysis confirmed known regulators of CD38, such as RARA, while revealing XBP1 and SPI1 as other key transcription factors governing surface CD38 levels. CD38 knockdown followed by cell surface proteomics demonstrated no significant remodeling of the myeloma “surfaceome” after genetically induced loss of this antigen. Integrated transcriptome and surface proteome data confirmed high specificity of all-trans retinoic acid in upregulating CD38, in contrast to the broader effects of azacytidine and panobinostat. Finally, unbiased phosphoproteomics identified inhibition of MAP kinase pathway signaling in tumor cells after daratumumab treatment. Our work provides a resource to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma.