Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia.

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

Successfully treatment of PLZF-RARα positive acute promyelocytic leukemia by Venetoclax combining with decitabine: a case report and literature review.

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

The red blood cell distribution width to albumin ratio was a potential prognostic biomarker for acute respiratory failure: a retrospective study.

BACKGROUND: The association between red blood cell distribution width (RDW) to albumin ratio (RAR) and prognosis in patients with acute respiratory failure (ARF) admitted to the Intensive Care Unit (ICU) remains unclear. This retrospective cohort study aims to investigate this association. METHODS: Clinical information of ARF patients was collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) version 2.0 database. The primary outcome was, in-hospital mortality and secondary outcomes included 28-day mortality, 60-day mortality, length of hospital stay, and length of ICU stay. Cox regression models and subgroup analyses were conducted to explore the relationship between RAR and mortality. RESULTS: A total of 4547 patients with acute respiratory failure were enrolled, with 2277 in the low ratio group (RAR < 4.83) and 2270 in the high ratio group (RAR > = 4.83). Kaplan-Meier survival analysis demonstrated a significant difference in survival probability between the two groups. After adjusting for confounding factors, the Cox regression analysis showed that the high RAR ratio had a higher hazard ratio (HR) for in-hospital mortality (HR 1.22, 95% CI 1.07-1.40; P = 0.003), as well as for 28-day mortality and 60-day mortality. Propensity score-matched (PSM) analysis further supported the finding that high RAR was an independent risk factor for ARF. CONCLUSION: This study reveals that RAR is an independent risk factor for poor clinical prognosis in patients with ARF admitted to the ICU. Higher RAR levels were associated with increased in-hospital, 28-day and 60-day mortality rates.

Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia.

In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.

Halogenated retinoid derivatives as dual RARα and RXRα modulators for treating acute promyelocytic leukemia cells.

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα's tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.

Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling.

T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-ß); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-ß-driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-ß-SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.

GATA2­miR­374a axis promotes vascular smooth muscle cells proliferation, migration via targeting circTADA2A/RORA axis.

Evidence has shown that microRNAs (miRNAs/miRs) play key roles in biological functions of vascular smooth muscle cells (VSMCs). However, the role of miR-374a in VSMCs remains to be elucidated. The present study aimed to explore the influence of miR-374a on VSMCs and its molecular mechanism. The expression level of miR-374a was measured by reverse transcription-quantitative (RT-q) PCR. MTT and Transwell assay were employed to assess the role of miR-374a in proliferation and migration of VSMCs. To order to determine miR-374a targets, a dual-luciferase reporter assay was conducted, which was further verified by rescue experiments. Chromatin Immunoprecipitation Assay and JASPAR databases were applied to explore the regulatory association between GATA binding protein 2 (GATA2) and miR-374a. Western blotting or RT-qPCR were employed to detect the protein expression levels of GATA2 or RAR-related orphan receptor A (RORA). The present study found that miR-374a was elevated in VSMCs following treatment with platelet-derived growth factor-BB (PDGF-BB) compared with that in control group. In addition, the results demonstrated that a higher expression of a miR-374a could promote proliferation and migration of VSMCs while miR-374a inhibitor suppressed the PDGF-BB-induced proliferation and migration of VSMCs in vitro. Furthermore, circTADA2A bound to miR-374a and then upregulated RORA expression, which resulted in inhibition in VSMCs proliferation and migration. On the other hand, the result indicated that GATA2 overexpression could augment the proliferation, migration of PDGF-bb-induced VSMCs, which could be rescued by miR-374a inhibitor. The findings suggested that the GATA2/circTADA2A-miR-374a axis promoted the proliferation and migration of VSMCs by targeting RORA, which were closely related to atherosclerosis (AS). Thus the results might offer a new therapeutic target for AS.

Targeting AFP-RARß complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARß interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARß complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARß complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.

Screening (ant)agonistic activities of xenobiotics on the retinoic acid receptor alpha (RARα) using in vitro and in silico analysis.

Retinoic acid receptors (RARs) are known as crucial endocrine receptors that could mediate a broad diversity of biological processes. However, the data on endocrine disrupting effects of emerging chemicals by targeting RAR (ant)agonism are far from sufficient. Herein, we investigated the RARα agonistic or antagonistic activities for 75 emerging chemicals of concern, and explored their interactions with this receptor. A recombinant two-hybrid yeast assay was used to examine the RARα activities of the test chemicals, wherein 7 showed effects of RARα agonism and 54 exerted potentials of RARα antagonism. The representative chemicals with RARα agonistic activities, i.e. 4-hydroxylphenol (4-HP) and bisphenol AF (BPAF), significantly increased the mRNA levels of CRABP2 and CYP26A1, while 4 select chemicals with RARα antagonistic potentials, including bisphenol A (BPA), tetrabromobisphenol A (TBBPA), 4-tert-octylphenol (4-t-OP), and 4-n-nonylphenol (4-n-NP), conversely decreased the transcriptional levels of the test genes. The in silico molecular docking analysis using 3 different approaches further confirmed the substantial binding between the chemicals with RARα activities and this nuclear receptor protein. This work highlights the promising strategy for screening endocrine-disrupting effects of emerging chemicals of concern by targeting RARα (ant)agonism.

Retinoic acid enhances HIV-1 reverse transcription and transcription in macrophages via mTOR-modulated mechanisms.

The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing vitamin A-derived retinoic acid (RA), which transcriptionally reprograms CD4+ T cells for increased HIV-1 replication/outgrowth. Consistently, colon-infiltrating CD4+ T cells carry replication-competent viral reservoirs in people with HIV-1 (PWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by monocytes, represents a rare event in ART-treated PWH, thus questioning the effect of RA on macrophages. Here, we demonstrate that RA enhances R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA sequencing, gene set variation analysis, and HIV interactor NCBI database interrogation reveal RA-mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations uncover post-entry mechanisms of RA action including SAMHD1-modulated reverse transcription and CDK9/RNA polymerase II (RNAPII)-dependent transcription under the control of mammalian target of rapamycin (mTOR). These results support a model in which macrophages residing in the intestine of ART-untreated PWH contribute to viral replication/dissemination in an mTOR-sensitive manner.

Spinal myeloid sarcoma presenting as initial symptom in acute promyelocytic leukemia with a rare cryptic PLZF::RARα fusion gene: a case report and literature review.

Background: Acute promyelocytic leukemia (APL) is rarely caused by the PLZF::RARα fusion gene. While APL patients with PLZF::RARα fusion commonly exhibit diverse hematologic symptoms, the presentation of myeloid sarcoma (MS) as an initial manifestation is infrequent. Case presentation: A 61-year-old patient was referred to our hospital with 6-month history of low back pain and difficulty walking. Before this admission, spine magnetic resonance imaging (MRI) conducted at another hospital revealed multiple abnormal signals in the left iliac bone and vertebral bodies spanning the thoracic (T11-T12), lumbar (L1-L4), and sacral (S1/S3) regions. This led to a provisional diagnosis of bone tumors with an unknown cause. On admission, complete blood count (CBC) test and peripheral blood smear revealed a slightly increased counts of monocytes. Immunohistochemical staining of both spinal and bone marrow (BM) biopsy revealed positive expression for CD117, myeloperoxidase (MPO), and lysozyme. BM aspirate showed a significant elevation in the percentage of promyelocytes (21%), which were morphologically characterized by round nuclei and hypergranular cytoplasm. Multiparameter flow cytometry of BM aspirate revealed that blasts were positive for CD13, CD33, CD117, and MPO. Through the integrated application of chromosome analysis, fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and Sanger sequencing, it was determined that the patient possessed a normal karyotype and a rare cryptic PLZF::RARα fusion gene, confirming the diagnosis of APL. Conclusion: In the present study, we report the clinical features and outcome of a rare APL patient characterized by a cryptic PLZF::RARα fusion and spinal myeloid sarcoma (MS) as the initial presenting symptom. Our study not only offers valuable insights into the heterogeneity of APL clinical manifestations but also emphasizes the crucial need to promptly consider the potential link between APL and MS for ensuring a timely diagnosis and personalized treatments.

Nuclear receptors for epidermal lipid barrier: Advances in mechanisms and applications.

The skin plays an essential role in preventing the entry of external environmental threats and the loss of internal substances, depending on the epidermal permeability barrier. Nuclear receptors (NRs), present in various tissues and organs including full-thickness skin, have been demonstrated to exert significant effects on the epidermal lipid barrier. Formation of the lipid lamellar membrane and the normal proliferation and differentiation of keratinocytes (KCs) are crucial for the development of the epidermal permeability barrier and is regulated by specific NRs such as PPAR, LXR, VDR, RAR/RXR, AHR, PXR and FXR. These receptors play a key role in regulating KC differentiation and the entire process of epidermal lipid synthesis, processing and secretion. Lipids derived from sebaceous glands are influenced by NRs as well and participate in regulation of the epidermal lipid barrier. Furthermore, intricate interplay exists between these receptors. Disturbance of barrier function leads to a range of diseases, including psoriasis, atopic dermatitis and acne. Targeting these NRs with agonists or antagonists modulate pathways involved in lipid synthesis and cell differentiation, suggesting potential therapeutic approaches for dermatosis associated with barrier damage. This review focuses on the regulatory role of NRs in the maintenance and processing of the epidermal lipid barrier through their effects on skin lipid synthesis and KC differentiation, providing novel insights for drug targets to facilitate precision medicine strategies.

ATRA regulates myoblast differentiation and fusion through the RARα/Pitx2 signaling pathway, causing abnormal development of PFMs in ARM fetal rats.

Anorectal malformation (ARM) is the most common congenital digestive tract anomaly in newborns, and children with ARM often have varying degrees of underdevelopment of the pelvic floor muscles (PFMs). To explore the effects of RARα and Pitx2 on the development of rat PFMs, we constructed a rat ARM animal model using all-trans retinoic acid (ATRA), and verified the expression of RARα and Pitx2 in the PFMs of fetal rats. Additionally, we used rat myoblasts (L6 cells) to investigate the regulatory roles of RARα and Pitx2 in skeletal muscle myoblast differentiation and their interactions. The results indicated a significant decrease in the expression of RARα and Pitx2 in the PFMs of fetal rats with ARM. ATRA can also decrease the expression of RARα and Pitx2 in the L6 cells, while affecting the differentiation and fusion of L6 cells. Knocking down RARα in L6 cells reduced the expression of Pitx2, MYOD1, MYMK, and decreased myogenic activity in L6 cells. When RARα is activated, the decreased expression of Pitx2, MYOD1, and MYMK and myogenic differentiation can be restored to different extents. At the same time, increasing or inhibiting the expression of Pitx2 can counteract the effects of knocking down RARα and activating RARα respectively. These results indicate that Pitx2 may be downstream of the transcription factor RARα, mediating the effects of ATRA on the development of fetal rat PFMs.

Development and validation of CYP26A1 inhibition assay for high-throughput screening.

All-trans retinoic acid (atRA) is an endogenous ligand of the retinoic acid receptors, which heterodimerize with retinoid X receptors. AtRA is generated in tissues from vitamin A (retinol) metabolism to form a paracrine signal and is locally degraded by cytochrome P450 family 26 (CYP26) enzymes. The CYP26 family consists of three subtypes: A1, B1, and C1, which are differentially expressed during development. This study aims to develop and validate a high throughput screening assay to identify CYP26A1 inhibitors in a cell-free system using a luminescent P450-Glo assay technology. The assay performed well with a signal to background ratio of 25.7, a coefficient of variation of 8.9%, and a Z-factor of 0.7. To validate the assay, we tested a subset of 39 compounds that included known CYP26 inhibitors and retinoids, as well as positive and negative control compounds selected from the literature and/or the ToxCast/Tox21 portfolio. Known CYP26A1 inhibitors were confirmed, and predicted CYP26A1 inhibitors, such as chlorothalonil, prochloraz, and SSR126768, were identified, demonstrating the reliability and robustness of the assay. Given the general importance of atRA as a morphogenetic signal and the localized expression of Cyp26a1 in embryonic tissues, a validated CYP26A1 assay has important implications for evaluating the potential developmental toxicity of chemicals.

Association of Rest-Activity Rhythm and Risk of Developing Dementia or Mild Cognitive Impairment in the Middle-Aged and Older Population: Prospective Cohort Study.

BACKGROUND: The relationship between 24-hour rest-activity rhythms (RARs) and risk for dementia or mild cognitive impairment (MCI) remains an area of growing interest. Previous studies were often limited by small sample sizes, short follow-ups, and older participants. More studies are required to fully explore the link between disrupted RARs and dementia or MCI in middle-aged and older adults. OBJECTIVE: We leveraged the UK Biobank data to examine how RAR disturbances correlate with the risk of developing dementia and MCI in middle-aged and older adults. METHODS: We analyzed the data of 91,517 UK Biobank participants aged between 43 and 79 years. Wrist actigraphy recordings were used to derive nonparametric RAR metrics, including the activity level of the most active 10-hour period (M10) and its midpoint, the activity level of the least active 5-hour period (L5) and its midpoint, relative amplitude (RA) of the 24-hour cycle [RA=(M10-L5)/(M10+L5)], interdaily stability, and intradaily variability, as well as the amplitude and acrophase of 24-hour rhythms (cosinor analysis). We used Cox proportional hazards models to examine the associations between baseline RAR and subsequent incidence of dementia or MCI, adjusting for demographic characteristics, comorbidities, lifestyle factors, shiftwork status, and genetic risk for Alzheimer's disease. RESULTS: During the follow-up of up to 7.5 years, 555 participants developed MCI or dementia. The dementia or MCI risk increased for those with lower M10 activity (hazard ratio [HR] 1.28, 95% CI 1.14-1.44, per 1-SD decrease), higher L5 activity (HR 1.15, 95% CI 1.10-1.21, per 1-SD increase), lower RA (HR 1.23, 95% CI 1.16-1.29, per 1-SD decrease), lower amplitude (HR 1.32, 95% CI 1.17-1.49, per 1-SD decrease), and higher intradaily variability (HR 1.14, 95% CI 1.05-1.24, per 1-SD increase) as well as advanced L5 midpoint (HR 0.92, 95% CI 0.85-0.99, per 1-SD advance). These associations were similar in people aged <70 and >70 years, and in non-shift workers, and they were independent of genetic and cardiovascular risk factors. No significant associations were observed for M10 midpoint, interdaily stability, or acrophase. CONCLUSIONS: Based on findings from a large sample of middle-to-older adults with objective RAR assessment and almost 8-years of follow-up, we suggest that suppressed and fragmented daily activity rhythms precede the onset of dementia or MCI and may serve as risk biomarkers for preclinical dementia in middle-aged and older adults.

Integrated Network Pharmacology and Experimental Validation Approach to Investigate the Mechanisms of Radix Rehmanniae Praeparata - Angelica Sinensis - Radix Achyranthis Bidentatae in Treating Knee Osteoarthritis.

Background: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA. Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK-8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments. Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1ß and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1ß-induced chondrocytes and DMM-induced rats. Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.

Decoding the neurotoxic effects of propofol: insights into the RARα-Snhg1-Bdnf regulatory cascade.

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.

Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G).

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene that causes autistic phenotypes when deleted or duplicated. Observations from clinical cases and animal models also suggest that changes of RAI1 expression levels contribute to autism. Previously, we used a bioinformatic approach to identify several single nucleotide polymorphisms (SNPs) located within the 5'-region of RAI1 that correlate with RAI1 mRNA expression in the human brain. In particular, the SNP rs4925102 was identified as a candidate cis-acting regulatory variant, the genotype of which may affect the binding of transcription factors that influence RAI1 mRNA expression. In this study, we provide experimental evidence based on reporter gene, chromatin immunoprecipitation (ChIP), and chromatin conformation capture (3C) assays that rs4925102 regulates RAI1 mRNA expression in an allele-specific manner in human cell lines, including the neuroblastoma-derived cell line SH-SY5Y. We also describe a statistically significant association between rs4925102 genotype and autism spectrum disorder (ASD) diagnosis in a case-control study and near-statistically significant association in an Autism Genome Project (AGP) transmission disequilibrium (TDT) study using Caucasian subjects.

ATPR induces acute promyelocytic leukemia cells differentiation and cycle arrest via the lncRNA CONCR/DDX11/PML-RARα signaling axis.

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells.

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.