Acrylamide (ACR) is an environmental reproductive toxicant with unclear testicular toxicity mechanisms. Retinoids are a group of vitamin A-related compounds that function by activating retinoid receptors. We aimed in this study to further explore All-trans retinoic acid's (ATRA) protective response against an acrylamide-induced testicular insult model and the underlying possible mechanisms. Fifty male rats were allocated into control, DMSO, ACR (40 mg/kg bwt, i.p. daily for 14 days), ATRA (7.5 mg/kg bwt, i.p. daily), and ACR + ATRA groups. Body and testes weights, sperm parameters, testosterone level, and lactate dehydrogenase-X (LDH-X) activity were measured. In addition, testicular levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), caspase-3, Bax, and Bcl-2 were determined. Also, tissues were examined for histopathologic changes and immune expression of retinoic acid receptor-alpha (RAR-α). ACR exposure led to reduced body and testicular weights, impaired sperm parameters, and suppressed reproductive hormones (testosterone, FSH, LH). Testicular LDH-X activity decreased, along with reduced testicular RAR-α expression. Oxidative stress resulted in GSH depletion, reduced CAT and SOD activities, and increased MDA. ACR also triggered inflammation and apoptosis, with elevated TNF-α, IL-1β, IL-6, caspase-3, Bax. In contrast, ATRA improved sperm parameters and levels of hormones, restored RAR-α expression, mitigated oxidative stress, and decreased inflammation and apoptosis markers. Morphometric and histopathologic studies supported these biochemical observations. Overall, RAR-α agonist (ATRA) is linked to attenuation against ACR-induced testicular damage, along with a reduction in oxidative stress, inflammation, and cell death. These findings suggest that retinoid signaling might serve as a possible therapeutic target for reproductive toxicities induced by ACR, necessitating further mechanistic exploration.

Our previous clinical studies show that all-trans retinoic acid (ATRA) induces a sustained response in patients with immune thrombocytopenia (ITP). However, its mechanisms of action remain unclear. In this study, we observed disorganized cytoskeleton and impaired proplatelet formation (PPF) in megakaryocytes from patients with ITP. Metabolite profiling revealed reduced sphingosine 1-phosphate (S1P) levels in ITP. Decreased sphingosine kinase 2 (SPHK2) expression was responsible for the low S1P levels in ITP. In addition, S1P was essential for activating S1P receptor 1 and Rac1, which regulate cytoskeletal reorganization and PPF. Furthermore, hypoxia-inducible factor-1α (HIF-1α) was shown to mediate SPHK2 and S1P production. Decreased HIF-1α expression in megakaryocytes from patients with ITP contributed to impaired PPF. We subsequently found that ATRA up-regulated HIF-1α and corrected impaired PPF in vitro and in vivo. These findings reveal that ATRA targets the HIF-1α/SPHK2/S1P pathway to improve PPF dysfunction, offering mechanistic insights into its clinical efficacy in ITP.

Topical retinoids are the cornerstone of the treatment of multiple dermatological conditions. Long established in acne therapy, they exert effects on keratinization, inflammation, fibroblast activity, and collagen remodeling, suggesting a potential role in both the prevention and treatment of acne scars. This narrative review summarizes current evidence on the use of topical retinoids in acne vulgaris and acne scarring, focusing on different retinoid molecules, formulation technologies, and combination strategies. A review of published clinical and experimental studies evaluating tretinoin, adapalene, tazarotene, and trifarotene was performed, including their use as monotherapy and in combination with other topical agents or procedural interventions. The available data indicate that topical retinoids have a well-established position in acne treatment, can improve the appearance of atrophic acne scars, reduce the progression of scarring, and support skin remodeling. Advances in formulation technologies have improved tolerability, while combination approaches with agents such as benzoyl peroxide, antibiotics or procedural techniques have shown additive or synergistic effects, particularly in more severe cases. Nevertheless, much of the evidence regarding novel formulations is derived from small or heterogeneous study populations. In conclusion, topical retinoids represent a relevant therapeutic option in acne vulgaris and acne scarring, from monotherapy in mild cases to components of multimodal treatment protocols in more severe disease. Further large-scale, comparative studies are needed to better define the optimal clinical use of advanced drug delivery systems for topical retinoids.

The SH-SY5Y cell line is widely used as an in vitro model for pharmacological and molecular investigations of Parkinson's disease (PD). The use of SH-SY5Y cells in PD research critically relies on their ability to differentiate into a mature, post-mitotic, dopaminergic (DAergic) neuronal phenotype. However, SH-SY5Y cells are inherently heterogeneous since they are firstly catecholaminergic cells and may express diverse phenotypic markers besides the DAergic ones. These properties seem to be determined by the differentiation protocol that is employed, thus meaning it is crucial to obtain proper cell types. This systematic review aims to discuss the main differentiation protocols used in PD research over the last 30 years. They include inducers such as retinoic acid (RA), the phorbol ester TPA, and the BDNF. Among the 514 studies that were screened, 249 employed these inducers. Then, we quantitatively report the ability of these protocols to differentiate SH-SY5Y cells in mature DAergic neurons, evaluating morphology, differentiation markers, and DAergic markers among the studies that specifically compared differentiated to undifferentiated SH-SY5Y cells (61 studies over 249). As our research shows, despite the highest usage of the RA differentiation protocol, the combination of RA with the BDNF inducer seems to increase the expression and the acquisition of a DAergic phenotype. Nevertheless, during this analysis, some limitations emerged, highlighting the intrinsic phenotypic heterogeneity of these cells, thereby limiting their suitability according to the specific biological question under investigation. A deep investigation into the literature about the molecular phenotypic features of differentiated SH-SY5Y cells may eventually help us to understand the advantages and disadvantages of each protocol that was employed, and adequately set experiments around the PD research.

Peripheral nerve injuries are a major clinical challenge, interrupting neural connectivity between the central nervous system (CNS) and peripheral organs. Traumatic events, natural disasters, and accidents often cause these complex injuries. Recent studies highlight the neurogenic potential of dexamethasone, retinoic acid, and umbilical cord blood stem cells in promoting nerve regeneration. Therefore, the aim of this study was to design electrospun conduits based on PLCL, gelatin, and collagen, along with dexamethasone, retinoic acid, carboxymethyl chitosan, and umbilical cord blood cells to repair sciatic nerve injuries. The chemical and physical properties of the conduits, in addition to biocompatibility and cytotoxicity, were evaluated with different experiments. Finally, the conduits were implanted into a 10 mm defect in the mouse sciatic nerve, and tissue regeneration was assessed after 3 months by related tests. The results showed that the presence of dexamethasone in the conduit designed improved biocompatibility, wettability, degradation rate, tensile strength, and increased cell viability. After seeding the umbilical cord blood cells on the conduit, the results showed good efficacy of the conduit, improving sensory and motor function and increasing nerve regeneration. These results indicate the potential of the resulting conduits as a promising tool for repairing nerve injuries and clinical trials.

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) and the fibrotic stroma generate form a dense stromal barrier that restricts the intratumoural exposure and spatial distribution of oxaliplatin. To enable local stromal remodelling of this pathological stromal compartment, we selected fibroblast activation protein (FAP) as a stromal target and co-assembled two amphiphilic conjugates, oncoFAP and retinoic acid (RA), into an FAP-directed RA nanoformulation termed LRA[FAP]. LRA[FAP] exhibited a uniform size distribution (107.1 ± 5.8 nm), remained stable for at least 7 d at 37 °C in PBS or serum-containing PBS, and showed accelerated esterase-responsive release. In a TGF-β-induced CAF-like model, LRA[FAP] markedly suppressed the expression of CAF activation-associated markers, reducing Fap and Acta2 mRNA levels by approximately 70% and 60%, respectively. In vivo, LRA[FAP] showed enhanced accumulation in CAF-enriched tumours and an increase in intratumoural oxaliplatin levels of approximately 2.5-fold relative to oxaliplatin alone. LRA[FAP] also reduced collagen deposition and CAF activation markers, and enhanced the antitumour efficacy of oxaliplatin while maintaining good tolerability. Collectively, these findings indicate that LRA[FAP] promotes local stromal remodelling and improves intratumoural oxaliplatin exposure, thereby enhancing the efficacy of oxaliplatin-based chemotherapy in CRC.

Since the FDA approval of tretinoin in 1971, retinoids have been key in treating acne and different skin pathologies. Tazarotene (TZE), a third-generation retinoid and prodrug, is converted in the skin to its active form, tazarotenic acid (TZA). Its structure allows absorption of UVA/UVB light, prompting concerns about potential phototoxicity, but data on the excited state properties of TZE and TZA are still lacking. This work investigates these retinoids' behavior under UVA light exposure through a combined spectroscopic, analytical, and biological approximation. The results show that both compounds form long-lived triplet excited states, which interact with oxygen to produce reactive singlet oxygen. Additionally, TZA interacts with tryptophan (Trp), leading to the formation of a photoproduct with a mass corresponding to a Trp/TZA cyclobutene adduct. These results correlate with reduced cell viability in fibroblasts exposed to light after treatment with TZE or TZA, indicating potential phototoxic effects. Such light-induced reactivity may also be related to the enhanced therapeutic results observed when TZE is used alongside narrow-band UVB phototherapy.

Retinoic acid (RA), a biologically active metabolite of vitamin A, acts as a potent signaling molecule regulating cell proliferation, differentiation, and apoptosis through nuclear RA receptors. RA influences expression of multiple genes, which are essential for development, neuronal differentiation, and synaptic plasticity. Long noncoding RNAs (lncRNAs), a class of regulatory RNAs, influence gene expression through chromatin organization, RNA processing and stability, translation, miRNA dynamics, and can also encode micropeptides. This review emphasizes the RA-mediated modulation of lncRNA expression through transcriptional and post-transcriptional mechanisms that influence differentiation and cell fate. This intricate RA-lncRNA crosstalk shapes tissue development and underlies the molecular pathology of various diseases. Both RA-signaling and lncRNA networks are involved in aging and age-related diseases. Furthermore, emerging RNA-based therapeutics such as RNA aptamers, RNA interference, and CRISPR-guided RNAs highlight their promise for treating age-related diseases. Exploring the crosstalk between RA and lncRNAs may provide novel opportunities for RNA-based therapeutic interventions targeting various diseases.

Silk sericin protein, a textile industry by-product showing no toxicity on oral/topical administration, has recently been exploited as a drug delivery system. The high serine content in sericin makes its functionalization through covalent ester-type bonds feasible; however, only in a few cases have covalent conjugates of sericin with the drug to be delivered been developed. In this paper, we report the preparation of sericin conjugates with carboxy drugs of dermatological interest, i.e., naproxen, retinoic acid, and azelaic acid. Characterization of the purified products by spectroscopic methods, particularly ATR-FTIR, provided evidence for the formation of the ester bond, while SDS-PAGE indicated a substantial modification of the protein. Proteomic analysis allowed the identification of drug-peptide adducts in the samples. The extent of ester functionalization (1-3 w/w%) was estimated by alkaline hydrolysis. No cytotoxicity of NAP@SER on HaCaT was observed over a broad range of concentrations. Ex vivo tests on defatted pig skin demonstrated effective passage of the free drug through the skin (5% w/w of the applied dose) from a NAP@SER glycerol suspension and a significant retention of the drug (33% w/w) within the dermal or epidermal tissues. These results hint at the potential of sericin conjugates as prodrugs for dermal administration.