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Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Acne vulgaris is a common dermatologic disorder that affects approximately 85% of teenagers, which significantly impacts the quality of life in adolescents. It is a chronic disease of the sebaceous follicles that is multifactorial in etiology. Topical treatment is the first choice for mild and moderate acne, while systemic therapy is reserved for severe and certain moderate cases. Topical treatments include retinoids (e.g., tretinoin and adapalene), antibiotics (e.g., clindamycine), and other agents (e.g., benzoyl peroxide and azelaic acid), often applied in combination. The mechanisms of action include antimicrobial, anti-inflammatory, and keratolytic activities, as well as sebum secretion reduction, and the normalization of follicular keratinization. However, these topical agents commonly induce side effects, such as dryness, burning, stinging, peeling, redness, erythema, and photosensitivity. Therefore, there is a need to reduce the side effects of anti-acne drugs, while maintaining or enhancing their therapeutic effectiveness. This article aims to comprehensively outline nanotechnology strategies, particularly the use of phospholipid-based nanocarriers like liposomes and related vesicles, to enhance therapeutic efficacy, skin tolerability, and patient compliance in the treatment of acne vulgaris. In addition, novel active ingredients encapsulated in vesicles beyond those recommended in official guidelines are discussed.

Acanthosis nigricans (AN) is a dermatological condition, marked by hyperpigmentation and skin thickening, frequently affecting body folds like the axillae. Treatment options for axillary hyperpigmentation remain underexplored. This study evaluated the efficacy of 0.025% tretinoin cream in treating axillary hyperpigmentation associated with AN. In a randomized, intra-individual, split-side design study, participants applied 0.025% tretinoin cream on one axilla and a cream-based on the other. The study spanned 12 weeks, with topical application for the first 8 weeks, followed by a 4-week cessation period. Efficacy was measured using the melanin (M) index via narrowband reflectance spectrophotometry. Overall success was evaluated through investigator- and participant-global evaluation (IGE and PGE) scales, with adverse effects monitored. Twenty participants completed the study. The 0.025% tretinoin cream significantly reduced hyperpigmentation compared to the control (p < 0.001). By week 8, the mean M index reduction with tretinoin was 28.05%±12.20%, versus 6.55%±12.66% with the control. Hyperpigmentation reappeared partially after treatment cessation. By week 8, 75% of participants in the tretinoin group achieved more than 75% improvement in IGE, compared to 35% in the cream-based group. Similarly, 75% of the tretinoin group reported more than 75% improvement in PGE, whereas only 15% of the cream-based group achieved more than 50% improvement. Adverse effects were mild and included slight erythema, peeling, and itching. The 0.025% tretinoin cream significantly improved AN patients' axillary hyperpigmentation, demonstrating a safe and effective treatment option with minimal side effects. [ABSTRACT FROM AUTHOR]

Management of plane warts is difficult; techniques like cryotherapy and cauterization are linked with a significant number of recurrences, risk of scarring, pain, and costs. To evaluate the effectiveness of TCA 30% solution in comparison with tretinoin 0.05% cream and5-flurouracil (5-FU) 5% cream in treatment of plane wart. A total of 100 patients were haphazardly divided into three groups according to the treatment: 34 patients treated with TCA 30%, 34 patients treated with tretinoin 0.05%, and 32 patients treated with 5-FU 5%. The number of lesions was calculated in all patients before treatment initiation. The efficiency of drugs was evaluated at 6 and 12 weeks after treatment during which the number of the warts in each patient and any side effects associated with the study concoction were recorded. According to the reduction in number of warts, response was categorized in to complete, partial and no response. After 6 weeks' treatment with TCA, Tretinoin and 5-FU, the lesion number reduced to 24%, 70.1% and 68.11% respectively with significant differences between TCA and other two groups. Similarly, after 12 weeks, the lesion number reduced to 14%, 51.67% and 26.86%, respectively with significant differences between TCA and other 2 groups. Additionally, hyper/hypopigmentation was more frequent in TCA treated group than tretinoin and 5-FU groups. Each of TCA, tretinoin and 5-FU are effective in treatment of plane wart, however; TCA seems to be more effective but associated with more pigmentary problems. [ABSTRACT FROM AUTHOR]

Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases. [ABSTRACT FROM AUTHOR]

The SH-SY5Y human neuroblastoma cell line is a standard in vitro experimental model of neuronal-like cells used in neuroscience and toxicological research. These cells can be differentiated into mature neurons, most commonly using retinoic acid (RA). Despite differences in characteristics, both undifferentiated and differentiated SH-SY5Y cells are used in research. However, due to uncertainties regarding the expression of specific markers of neural function in each culture, there is no definite conclusion on which culture is better suited for (neuro)toxicological and/or neuroscience investigations. To address this dilemma, we investigated the basal expression/activity of the key elements of acetylcholine, dopamine, serotonin, and GABA neurotransmitter pathways, along with the elements involved in exocytosis of neurotransmitters, and neuron electrophysiological activity in undifferentiated and in RA-differentiated SH-SY5Y cells using a six-day differentiation protocol. Our findings revealed that both SH-SY5Y cell types are functionally active. While undifferentiated SH-SY5Y cells exhibited greater multipotency in the expression of tested markers, most of those markers expressed in both cell types showed higher expression levels in RA-differentiated SH-SY5Y cells. Our results suggest that the six-day differentiation protocol with RA induces maturation, but not differentiation of the cells into specific neuron phenotype. The greater multipotency of undifferentiated cells in neural markers expression, together with their higher sensitivity to xenobiotic exposure and more simple cultivation protocols, make them a better candidate for high throughput toxicological screenings. Differentiated neurons are better suited for neuroscience researches that require higher expression of more specific neural markers and the specific types of neural cells. [ABSTRACT FROM AUTHOR]

Objective(s): Peripheral nerve injury (PNI) is a critical clinical issue primarily caused by trauma. Tissue engineering approaches using nanofiber scaffolds have been extensively explored to improve material quality and create an environment resembling the natural extracellular matrix (ECM). Materials and Methods: In this study, we employed electrospinning technique to fabricate a composite scaffold comprising poly(ɛ-caprolactone) (PCL) and collagen (Col) loaded with all-trans retinoic acid (RA), a neural patterning and signaling chemical known to promote nerve regeneration. Results: The synthesized nanofiber scaffold exhibited a diameter of 391±79 nm and a tensile strength of 250±13 MPa, providing sufficient support for native peripheral nerve regeneration. The inclusion of Col enhanced the scaffold's hydrophilic behavior (contact angle: 43±6°), ensuring stability in an aqueous solution. Moreover, the results demonstrated the proliferation and adhesion of nerve cells on the scaffold, aligning with the directions of the warp and weft of the nanofiber mat. Importantly, the scaffolds demonstrated non-toxicity, making them a promising substitute for the native ECM for enhanced cell attachment and proliferation. Finally, immune-histochemistry analyses further confirmed that the scaffolds supported the release and growth of neurites, promoting cell differentiation toward nerve repair. Conclusion: The RA-loaded scaffolds demonstrated the enhanced biocompatibility, supported neurite growth, and showed potential as a capable candidate for nerve regeneration. [ABSTRACT FROM AUTHOR]

Background/Aim: Treatment with retinoic acid (RA) often promotes neuroblastoma differentiation and growth inhibition, including the suppression of the expression of the MYCN oncogene. However, RA also targets protumoral chemokines, such as CCL2, which may contribute to the development of resistance. The present study aimed to investigate the regulation and function of CCL2 and N-Myc in RA-treated neuroblastoma cells. Materials and Methods: In Kelly or SH-SY5Y cells, viability was quantified by cell fitness assays. Expression was analyzed using quantitative PCR and the regulation of proteins using enzyme-linked immunoabsorbent assays (ELISA) or western blots. Results: In MYCN-amplified Kelly cells, endogenous CCL2 levels were significantly lower compared to MYCN non-amplified SH-SY5Y cells. Treatment with 5 µM RA increased CCL2 release in both cell lines, but reduced N-Myc levels and cell numbers in Kelly cells. Over-expression of MYCN enhanced viability in SH-SY5Y cells, but did not affect RA-induced CCL2 release, while supplementation of CCL2 in Kelly cells did not prevent RA-mediated growth reduction. Impaired NMyc or CCL2 signaling reduced the survival of all RA-treated cells and inhibition of N-Myc also decreased CCL2 levels. However, attenuated survival signaling was not generally associated with reduced levels of N-Myc or CCL2. Coapplication of RA and the growth factor receptor inhibitors cediranib or crizotinib decreased N-Myc levels only in Kelly cells, while CCL2 release was dependent on the cell type and stimulus. Conclusion: CCL2 and N-Myc promote the viability of RA-treated cells, although the levels of these mediators were not consistently correlated with cellular outcomes, especially during apoptotic signaling. [ABSTRACT FROM AUTHOR]

Spotted scat (Scatophagus argus) is an economically important marine species in China, with high ornamental and edible value. The effects of dietary supplementation of Lianjiang red orange peels, a natural carotenoid source, at 0, 3, 6, 9 and 12%, hereafter referred to as G0, G3, G6, G9 and G12, were measured on color values, carotenoid content, expression of genes such as cyp2j6 , cyp1a1 , hsp70 , slc2a11 , bco2 , cyp26c1 after 4 weeks. Subsequently, the different color values (L*, a*, and b*), total carotenoids content, and gene expression pattern were analyzed. In the groups fed diets containing more than 9% Lianjiang red orange peels (9% and 12%), the L* value (lightness) decreased, while the a* value (redness) increased in red skin, and b* value (yellowness) increased in caudal fin (P < 0.05). Additionally, the total carotenoids content in red skin of the G9 group and caudal fin of the G12 group was substantially higher than in the other groups (P < 0.05). By comparative transcriptome analysis of the red skin in G0 and G9 groups, 419 differentially expressed genes (DEGs) were identified, of which 237 were upregulated and 182 were downregulated. Genes involved in carotenoid deposition (cyp2j6 , cyp1a1) and pigment cell development (hsp70 , slc2a11) were significantly upregulated, whereas genes related to carotenoid decomposition (bco2) and retinoic acid metabolism (cyp26c1) were significantly downregulated in the G9 group. These findings suggest that Lianjiang red orange peels, as a natural carotenoid source, enhance body coloration by influencing the deposition of carotenoid, pteridine pigments, erythrophore development, and inhibiting the oxidative cleavage of carotenoid and retinoic acid metabolism. This study enhances body coloration by influencing carotenoid and pteridine pigment deposition, and provides theoretical guidance for aquaculture practices involving spotted scat. [ABSTRACT FROM AUTHOR]

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The article discusses the anti-inflammatory effects of kaempferol on dendritic cells by accelerating the development of regulatory T cells (Tregs) through the activation of the Aldh1a2/Raldh2 gene. Kaempferol treatment increased the expression of Aldh1a2 mRNA in dendritic cells, leading to enhanced Treg development and suppression of T-cell proliferation. The study also explored the molecular mechanisms behind kaempferol's effects, including its interaction with the aryl hydrocarbon receptor (AhR) and transcription factors PU.1 and IRF4. The findings suggest that kaempferol may have potential therapeutic applications in immune regulation and anti-inflammatory responses. [Extracted from the article]

As a reliable alternative to animal testing in cardiovascular research, it is crucial to improve differentiation of immortalized cell lines. In this study, we focused on optimizing the differentiation efficiency of the H9c2 cell line into cardiomyocytes using a high-throughput, automated image processing approach. While previous studies used protocols involving retinoic acid to enhance cardiac differentiation, we applied a simplified medium composition that results in higher differentiation rates. Along that line, we differentiated H9c2 cells into cardiomyocytes, which not only showed sarcomere-characteristic striation but also periodic intracellular calcium signaling for the first time. As a second step, we examined the potential application of polyacrylamide hydrogels (E = 12 kPa) with defined fibronectin coating densities. The optimum fibronectin density of 2.6 μg/cm2 found for single cells was investigated to further improve the differentiation efficiency. However, the differentiation and proliferation dynamics dominate the adhesion forces between the cells and the hydrogel, and thus, result in premature clustering and detachment. In conclusion, we identified an optimized differentiation protocol and provided a basis for the further investigation necessary to potentially use hydrogels as natural cell environment, aiming to raise the differentiation efficiency even more. [ABSTRACT FROM AUTHOR]

Retinoic acid receptor‐related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions in circadian clock regulation, inflammation, and immunity. Its cyclic temporal role in circadian rhythms, and cell‐specific activity in the immune system, make it an intriguing target for spatially and temporally localised pharmacology. To create tools that can study RORγ biology with appropriate spatiotemporal resolution, we designed light‐dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors combining a large degree of potency photocontrol, with remarkable on‐target potency, and excellent selectivity over related off‐target receptors. This still rare combination of performance features distinguishes them as high quality photopharmaceutical probes, which can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders. [ABSTRACT FROM AUTHOR]

Cadherin−catenin cell−cell adhesion complexes, composed of cadherin, β-catenin or plakoglobin, and α-catenin (α-cat) molecules, are crucial for maintaining cell−cell contact and are commonly referred to as "adherens junctions (AJs)." Inactivating this system leads to loss of cell−cell contact and developmental arrest in early embryos. However, it remains unclear whether the loss of cell−cell contact affects the differentiation of embryonic cells. In this study, we explored the use of a murine embryonal carcinoma cell line, P19, as an in vitro model for early embryogenesis. P19 cells easily form embryoid bodies (EBs) and are susceptible to cellular differentiation in response to retinoic acid (RA) and teratoma formation. Using CRISPR/Cas9 technology to disrupt the endogenous α-cat gene in P19 cells, we generated α-cat knockout (KO) cells that exhibited a loss of cell−cell contact. When cultivated on non-coated dishes, these α-cat KO cells formed EBs, but their structures were labile. In the RA-containing medium, the α-cat KO EBs failed to produce differentiated cells on their outer layer and continued to express SSEA-1, an antigen specific to pluripotent cells. Teratoma formation assays revealed an absence of overt differentiated cells in tumors derived from α-cat KO P19 cells. Aggregation assays revealed the inability of the KO cells to colonize into the zona pellucida-denuded 8-cell embryos. These findings suggest that the AJs are essential for promoting the early stages of cellular differentiation and for the colonization of early-developing embryos. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has greatly improved the treatment of acute promyelocytic leukemia (APL), leading to high remission and survival rates. However, real-world outcomes are worse than those seen in clinical trials, largely due to the exclusion of older patients and those with comorbidities from trials. Moreover, the results from clinical trials overlook patients who die of APL complications before registering for trials. Delays in diagnosis and treatment, along with the limited experience and resources of some community healthcare centers in managing APL and its complications contribute to higher early mortality rates. Ongoing education and collaboration between local healthcare providers and specialists are vital to improve APL outcomes. Regular monitoring for disease recurrence and management of treatment side effects are also important. Additionally, understanding the phenomenon of APL clusters—groups of cases over specific times or areas—can help improve resource allocation for better outcomes. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL), resulting in excellent rates of remission and long-term survival. However, real-world outcomes often fall short of those observed in clinical trials due to various factors related to patient demographics and clinical practices. This review examines APL treatment outcomes in real-world settings and highlights the phenomenon of APL clusters. Clinical trials frequently exclude older patients and individuals with significant comorbidities, yet these groups represent a substantial portion of patients in clinical practice. Early mortality remains high in real-world settings, compounded by delayed diagnosis and treatment initiation, as well as the inexperience of some community providers and limited resources of their centers in managing APL and its associated complications. High rates of disease and induction-related complications further exacerbate early mortality. Continuous education and collaboration between community healthcare centers and expert institutions are essential, and international partnerships between resource-limited settings and expert centers can improve global APL outcomes. Ongoing monitoring for measurable residual disease (MRD) recurrence and long-term treatment toxicity, coupled with comprehensive patient evaluations, and experienced management, can enhance long-term outcomes. The clustered incidence of APL, while frequently reported, remains poorly understood. Regular reporting of these clusters could provide valuable insights into disease pathology and aid in developing predictive models for APL incidence, which would guide future resource allocation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]