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Cancer Cell Apr 2024Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released...
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.
Topics: Male; Humans; Animals; Mice; Cellular Senescence; Prostatic Neoplasms; Receptors, Retinoic Acid; Killer Cells, Natural; Adapalene
PubMed: 38428412
DOI: 10.1016/j.ccell.2024.02.004 -
Thoracic Cancer Mar 2024Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage...
BACKGROUND
Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder.
METHODS
To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR.
RESULTS
Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene.
CONCLUSION
We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.
Topics: Humans; Animals; Mice; Afatinib; Erlotinib Hydrochloride; Adapalene; ErbB Receptors; Skin Diseases; Inflammation; Protein Kinase Inhibitors; Lung Neoplasms
PubMed: 38379420
DOI: 10.1111/1759-7714.15249 -
Scientific Reports Jan 2024In our pursuit of enhancing acne treatment while minimizing side effects, we developed tailored Adapalene microsponges (MS) optimized using a Box-Behnken design 3. The...
In our pursuit of enhancing acne treatment while minimizing side effects, we developed tailored Adapalene microsponges (MS) optimized using a Box-Behnken design 3. The independent variables, Eudragit RS100 percentage in the polymer mixture, organic phase volume, and drug to polymer percentage, were explored. The optimized formulation exhibited remarkable characteristics, with a 98.3% ± 1.6 production yield, 97.3% ± 1.64 entrapment efficiency, and a particle size of 31.8 ± 1.1 µm. Notably, it achieved a 24 h cumulative drug release of 75.1% ± 1.4. To delve deeper into its efficacy, we evaluated the optimized microspongeal-gel in vitro, in vivo, and clinically. It demonstrated impressive retention in the pilosebaceous unit, a target for acne treatment. Comparative studies between our optimized Adapalene microspongeal gel and marketed Adapalene revealed superior performance. In vivo studies on Propionibacterium acnes-infected mice ears showed a remarkable 97% reduction in ear thickness, accompanied by a significant decrease in inflammatory signs and NF-κB levels, as confirmed by histopathological and histochemical examination. Moreover, in preliminary clinical evaluation, it demonstrated outstanding effectiveness in reducing comedonal lesions while causing fewer irritations. This not only indicates its potential for clinical application but also underscores its ability to enhance patient satisfaction, paving the way for future commercialization.
Topics: Humans; Mice; Animals; Adapalene; Acne Vulgaris; Skin; Polymers; Dermatologic Agents; Treatment Outcome; Gels
PubMed: 38228631
DOI: 10.1038/s41598-024-51392-1 -
ACS Catalysis Jan 2024Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and...
Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C-H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the optimized dirhodium catalyst, Rh(-(4-Br)TPPTTL), ((aryl)(diazo)methyl)phosphonates undergo highly enantioselective (84-99% ee) and site-selective (>30:1 r.r.) benzylic C-H functionalization. The phosphonate group is much more sterically demanding than the previously studied carboxylate ester group, leading to much higher selectivity for a primary site versus more sterically crowded positions. The effectiveness of this methodology has been demonstrated by the late-stage primary C-H functionalization of estrone, adapalene, ()-naproxen, clofibrate, and gemfibrozil derivatives.
PubMed: 38205024
DOI: 10.1021/acscatal.3c04661 -
Drug Safety Mar 2024In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often...
INTRODUCTION
In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often overlooked. The US FDA Adverse Event Reporting System (FAERS) records drug names as free text, necessitating mapping to active ingredients. Although pre-mapped databases exist, the subjectivity and lack of transparency of the mapping process lead to a loss of control over the object of study.
OBJECTIVE
We implemented the DiAna dictionary, systematically mapping individual free-text instances to their corresponding active ingredients and linking them to the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification.
METHODS
We retrieved all drug names reported to the FAERS (2004-December 2022). Using existing vocabularies and string editing, we automatically mapped free text to ingredients. We manually revised the mapping and linked it to the ATC classification.
RESULTS
We retrieved 18,151,842 reports, with 74,143,411 drug entries. We manually checked the first 14,832 terms, up to terms occurring over 200 times (96.88% of total drug entries), to 6282 unique active ingredients. Automatic unchecked translations extend the standardization to 346,854 terms (98.94%). The DiAna dictionary showed a higher sensitivity compared with RxNorm alone, particularly for specific drugs (e.g., rimegepant, adapalene, drospirenone, umeclidinium). The most prominent drug classes in the FAERS were immunomodulating (37.40%) and neurologic drugs (29.19%).
CONCLUSION
The DiAna dictionary, as a dynamic open-source tool, provides transparency and flexibility, enabling researchers to actively shape drug definitions during the mapping phase. This empowerment enhances accuracy, reproducibility, and interpretability of results.
Topics: United States; Humans; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Reproducibility of Results; Software; United States Food and Drug Administration
PubMed: 38175395
DOI: 10.1007/s40264-023-01391-4 -
Theranostics 2024Spinal cord injury (SCI) results in neural tissue damage. However, the limited regenerative capacity of adult mammals' axons upon SCI leads to persistent neurological...
Exosomes derived from CD271CD56 bone marrow mesenchymal stem cell subpopoulation identified by single-cell RNA sequencing promote axon regeneration after spinal cord injury.
Spinal cord injury (SCI) results in neural tissue damage. However, the limited regenerative capacity of adult mammals' axons upon SCI leads to persistent neurological dysfunction. Thus, exploring the pathways that can enhance axon regeneration in injured spinal cord is of great significance. Through the utilization of single-cell RNA sequencing in this research, a distinct subpopulation of bone marrow mesenchymal stem cells (BMSCs) that exhibits the capacity to facilitate axon regeneration has been discovered. Subsequently, the CD271CD56 BMSCs subpopulation was isolated using flow cytometry, and the exosomes derived from this subpopulation (CD271CD56 BMSC-Exos) were extracted and incorporated into a hydrogel to create a sustained release system. The aim was to investigate the therapeutic effects of CD271CD56 BMSC-Exos and elucidate the underlying mechanisms involved in promoting axon regeneration and neural function recovery. The findings indicate that CD271CD56 BMSC-Exos share similar physical and chemical properties with conventional exosomes. Importantly, in an SCI model, in situ implantation of CD271CD56 BMSC-Exos hydrogel resulted in increased expression of NF and synaptophysin, markers associated with axon regeneration and synapse formation, respectively. This intervention also contributed to improved neural function recovery. In vitro experiments demonstrated that CD271CD56 BMSC-Exos treatment significantly enhanced axon extension distance and increased the number of branches in dorsal root ganglion axons. Moreover, further investigation into the molecular mechanisms underlying CD271CD56 BMSC-Exos-mediated axon regeneration revealed the crucial involvement of the miR-431-3p/RGMA axis. In summary, the implantation of CD271CD56 BMSC-Exos hydrogel presents a promising and effective therapeutic approach for SCI.
Topics: Adult; Animals; Humans; Axons; Exosomes; Adapalene; Nerve Regeneration; Mesenchymal Stem Cells; Spinal Cord Injuries; Hydrogels; Sequence Analysis, RNA; Mammals
PubMed: 38169566
DOI: 10.7150/thno.89008 -
Drug and Therapeutics Bulletin Dec 2023Acne vulgaris is very common and can have significant negative impact on people. While sometimes a transient problem, acne may persist for many years and often leads to... (Review)
Review
Acne vulgaris is very common and can have significant negative impact on people. While sometimes a transient problem, acne may persist for many years and often leads to permanent scars or pigment changes. Guidelines unanimously advise topical treatments as first-line, although differ in recommending either topical benzoyl peroxide or topical retinoid (mainly adapalene) alone or in combination. Guidance published by the National Institute for Health and Care Excellence advises counselling patients regarding avoidance of skin irritation when starting topical treatments and promoting adherence (treatments take 6-8 weeks to work). Oral antibiotics are currently overprescribed for acne but have a role when coprescribed with a non-antibiotic topical treatment. Hormonal treatments, such as the combined contraceptive pill, are also effective and there is growing evidence for the use of spironolactone for women with persistent acne. Recent guidance from the Medicines and Healthcare products Regulatory Agency regarding isotretinoin has implications for specialist prescribing and monitoring, and increasing public awareness of potential risks of mental health problems and sexual dysfunction. Although acne is associated with psychiatric disorder, the mental health effects of isotretinoin remain controversial.
Topics: Humans; Female; Isotretinoin; Acne Vulgaris; Benzoyl Peroxide; Anti-Bacterial Agents; Adapalene
PubMed: 38154809
DOI: 10.1136/dtb.2023.000051 -
Clinical, Cosmetic and Investigational... 2023We aim to evaluate the effectiveness and tolerability of a sunscreen formulation containing licochalcone A (LicA) and L-carnitine (LC) as an adjuvant to adapalene in the...
Efficacy and Tolerability of a Sunscreen Containing Licochalcone a and L-Carnitine as an Adjunct to Retinoids in the Management of Acne and Post-Acne Pigmentation Among Malaysian Patients.
PURPOSE
We aim to evaluate the effectiveness and tolerability of a sunscreen formulation containing licochalcone A (LicA) and L-carnitine (LC) as an adjuvant to adapalene in the management of acne and post-acne pigmentation (PAH).
PATIENTS AND METHODS
A randomized, double-blind, active comparator-controlled trial of 51 patients aged 18 years or older with a clinical diagnosis of mild-to-moderate acne vulgaris was conducted at the Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia. The efficacy and tolerability of once-daily adapalene 1.0% were assessed during the 2-week run-in period. Subsequently, patients were randomized to receive either an add-on investigational LicA-containing sunscreen or niacinamide-containing comparator sunscreen every 4 hourly during daytime for 4 weeks. Patients were followed up at Weeks 2 and 4 to assess for improvement in acne severity, PAH, calorimetric parameters and cutaneous tolerability.
RESULTS
Two weeks of adapalene usage significantly improved acne severity; however, up to 52% of patients experienced dryness, burning and stinging. Adding LicA-containing or comparator sunscreens was associated with further improvement in acne severity, PAH and calorimetric parameters at the study endpoint. No significant differences in the cutaneous tolerability profiles were observed between treatment groups. Notably, significantly fewer patients receiving LicA-containing sunscreen developed scaliness at Week 4 compared with those in the comparator group. In addition, more patients receiving LicA-containing sunscreen reported less dryness, burning and stinging reactions than the comparator group. Importantly, more patients receiving LicA-containing sunscreen agreed that their treatment led to excellent improvement than the comparator group; of note, one patient reported that their condition worsened with the receipt of the comparator product.
CONCLUSION
The concurrent use of LicA-containing sunscreen with adapalene may improve the cutaneous tolerance to adapalene among Malaysian patients.
PubMed: 38152154
DOI: 10.2147/CCID.S422898 -
Cell Reports. Medicine Dec 2023Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb...
Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb ischemia. Through single-cell transcriptomic analysis of human tissues, we identify CD271 progenitors specifically from subcutaneous adipose tissue (AT) as having the most prominent pro-angiogenic gene profile distinct from other stem cell populations. AT-CD271 progenitors demonstrate robust in vivo angiogenic capacity over conventional adipose stromal cell grafts, characterized by long-term engraftment, augmented tissue regeneration, and significant recovery of blood flow in a xenograft model of limb ischemia. Mechanistically, the angiogenic capacity of CD271 progenitors is dependent on functional CD271 and mTOR signaling. Notably, the number and angiogenic capacity of CD271 progenitors are strikingly reduced in insulin-resistant donors. Our study highlights the identification of AT-CD271 progenitors with in vivo superior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy.
Topics: Humans; Adapalene; Angiogenesis; Gene Expression Profiling; Adipose Tissue; Ischemia
PubMed: 38118404
DOI: 10.1016/j.xcrm.2023.101337 -
JPMA. the Journal of the Pakistan... Oct 2023
Topics: Humans; Adapalene; Acne Vulgaris; Anti-Inflammatory Agents, Non-Steroidal; Melanoma; Gels; Treatment Outcome; Dermatologic Agents
PubMed: 37876097
DOI: 10.47391/JPMA.8438