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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 -
Computational Biology and Chemistry Feb 2024Androgen Receptor (AR) is overexpressed in almost all the molecular subtypes of breast cancer. Besides aiding the tumorigenic environment of cancer by abnormal cell...
Androgen Receptor (AR) is overexpressed in almost all the molecular subtypes of breast cancer. Besides aiding the tumorigenic environment of cancer by abnormal cell proliferation, AR also takes part in promoting cancer signaling pathways, thereby promoting aggressiveness. In this study, AR was selected as the target protein in breast cancer cells. Following this, a library of 1293 FDA-approved drugs was screened via molecular docking, MD simulation, and MMPBSA binding energy. Amongst the library of compounds, Adapalene exhibited the least binding energy of (-10.2 kCal/mol) in comparison to that of the chosen reference compound, Nilutamide (-8.6 kCal/mol). Furthermore, the in vitro efficacy of Adapalene was also determined in two different breast cancer cell lines such as MCF7 (AR-positive/ER-positive) and MDA-MB-231 (AR negative/TNBC). Initially, the cell viability assay (MTT) was performed, which endowed us with a lesser IC value of Adapalene in comparison to Nilutamide in both cell lines. The IC of Adapalene was found to be 12 μM and 39.4 μM in MCF7 and MDA-MB-231 cells, respectively. Furthermore, Adapalene also induced cellular ROS and apoptosis by 3.5-fold and 26.58% in MCF7 cells. However, the overall effect of Adapalene was significantly lower in the case of MDA-MB-231 cell lines, which could be attributed to its inherent nature of the absence of hormone receptors. Conclusively, Adapalene possesses greater therapeutic efficacy in comparison to the control drug, thereby hinting towards the potential use of Adapalene in the treatment of AR-positive breast cancer.
Topics: Humans; Female; Breast Neoplasms; Molecular Docking Simulation; Drug Repositioning; Cell Line, Tumor; Cell Proliferation; Adapalene; Triple Negative Breast Neoplasms
PubMed: 38157661
DOI: 10.1016/j.compbiolchem.2023.108007 -
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 -
Journal of Cosmetic Dermatology Apr 2024Topical retinoids cause retinoid-induced skin discomfort (RISD) mainly during the first weeks of use leading to noncompliance and premature treatment discontinuation. A... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Topical retinoids cause retinoid-induced skin discomfort (RISD) mainly during the first weeks of use leading to noncompliance and premature treatment discontinuation. A dermocosmetic (DC) may help to reduce treatment-related signs and symptoms and improve adherence.
OBJECTIVES
To assess the benefit of a DC regimen compared to a routine skin care regimen (RC) by reducing RISD signs and symptoms induced by a retinoid/benzoyl peroxide fixed-drug combination in subjects with acne.
MATERIALS AND METHODS
Double-blind, randomized, comparative study in subjects ≥16 years with mild to moderate acne candidates to a topical adapalene/BPO fixed drug combination (A/BPO). Evaluations took place at Day 0, 7, 14, 28, and 84 and included erythema, desquamation, burning, itching and stinging and RISD (SD, a composite score of local treatment-related signs and symptoms and acne severity. Subjects used daily the DC or RC together with the fixed combination for 84 days.
RESULTS
Eighty-eight subjects were included, the mean age was 21 years; 84% were females. At Day 0 the SD score was 0.8 in both groups. A statistically significant difference in terms of skin sensitivity with DC compared to RC (1.6 points, vs. 2.4 points p < 0.05) was observed at Day 14. Clinical sign and symptom scores were more reduced with DC than with RC at all time points. Acne severity improved in both groups.
CONCLUSION
DC significantly reduces A/BPO-related RISD compared to RC, especially during the first 14 days of treatment, without interfering with the clinical efficacy of the treatment, thus helping to maintain treatment adherence.
Topics: Female; Humans; Young Adult; Adult; Male; Dermatologic Agents; Retinoids; Naphthalenes; Acne Vulgaris; Benzoyl Peroxide; Adapalene; Drug Combinations; Treatment Outcome; Gels
PubMed: 38102855
DOI: 10.1111/jocd.16120 -
Journal of Drugs in Dermatology : JDD Dec 2023A dermocosmetic (DC) containing salicylic acid, niacinamide, and thermal spring water has been developed for the management of mild to moderate acne. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A dermocosmetic (DC) containing salicylic acid, niacinamide, and thermal spring water has been developed for the management of mild to moderate acne.
AIM
To assess the efficacy of DC as an adjunct to benzoyl peroxide (BPO) every other day compared with BPO over 3 months, and its efficacy as maintenance post-BPO care compared with vehicle for another 3 months.
METHODS
Single-center, randomized, double-blind study in 100 patients with mild to moderate facial acne according to the Global Acne Severity (GEA) Scale. During phase 1, subjects received either BPO + vehicle (vehicle group) or BPO + DC (DC group) for 12 weeks. During phase 2, patients were re-randomized to receive either the vehicle or the DC for 12 weeks. Assessments included inflammatory and non-inflammatory lesion count, acne severity using the GEA Scale, local tolerance, quality of life, and quantity of product used.
RESULTS
During phase 1, both groups, DC and vehicle, reached the same level of efficacy at month 3, although the quantity of BPO used was significantly reduced in the DC group (P=0.0001). During phase 2, acne continued to significantly improve (all P<0.05) in the DC group, as did clinical signs and symptoms; while patients randomized to vehicle reported relapses of their acne and related symptoms.
CONCLUSION
The use of DC significantly reduces the need for BPO with no impact on the efficacy of mild to moderate acne. The use of DC as a maintenance post-BPO allowed a significant reduction of acne relapse compared with vehicle after 3 months of follow-up, with a good tolerance. J Drugs Dermatol. 2023;22(12):1172-1177. doi:10.36849/JDD.7449R1.
Topics: Humans; Acne Vulgaris; Adapalene; Benzoyl Peroxide; Dermatologic Agents; Drug Combinations; Quality of Life; Salicylic Acid; Treatment Outcome; Double-Blind Method
PubMed: 38051857
DOI: 10.36849/JDD.7449 -
Genes To Cells : Devoted To Molecular &... Jan 2024Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor,...
Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.
Topics: Humans; Adapalene; Receptors, Nerve Growth Factor; Cell Proliferation; Signal Transduction; Urinary Bladder Neoplasms; Cell Movement; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38016691
DOI: 10.1111/gtc.13087