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BioRxiv : the Preprint Server For... May 2024Methicillin-resistant (MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level...
Methicillin-resistant (MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level of resistance to β-lactam antibiotics in MRSA is attributed to the expression of penicillin-binding protein 2a (PBP2a), which catalyzes cell wall cross-linking. According to numerous research reports, the activity of the PBP2a protein is known to be regulated by an allosteric site distinct from the active site where cell wall cross-linking occurs. Here, we conducted a screening of 113 compounds containing a 1,3,4-oxadiazole core to design new covalent inhibitors targeting the allosteric site of PBP2a and establish their structural-activity relationship. The stereochemically selective synthesis of sulfonyl oxadiazole compounds identified in the initial screening resulted in a maximum eightfold enhancement in cell inhibition activity. The sulfonyl oxadiazole-based compounds formulated as PEG-based ointments, with low toxicity test results on human cells (CC : >78μM), demonstrated potent antimicrobial effects not only in a mouse skin wound infection model but also against oxacillin-resistant clinical isolate MRSA (IC ≈ 1μM), as evidenced by the results. Furthermore, additional studies utilizing LC-MS/MS and in-silico approaches clearly support the allosteric site covalent binding mechanism through the nucleophilic aromatic substitution (S Ar) reaction, as well as its association with the closure of the major active site of PBP2a.
PubMed: 38853829
DOI: 10.1101/2024.05.29.596450 -
Journal of Drug Targeting Jun 2024Conventional topical psoriasis treatments suffer from limited delivery to affected areas and skin irritation due to high local drug concentration.
BACKGROUND
Conventional topical psoriasis treatments suffer from limited delivery to affected areas and skin irritation due to high local drug concentration.
PURPOSE
This study aims to prepare hypericin (HYP) loaded nanostructured lipid carriers (NLCs) and their application in psoriasis treatment through intradermal administration using hollow microneedles assisted by photodynamic therapy.
METHODS
The colloidal characteristics of NLCs, entrapment efficiency and morphology were evaluated. skin distribution study was conducted along with testing the antipsoriatic activity in mice with the imiquimod-induced psoriasis model.
RESULTS
The particle size and zeta potential of HYP-NLCs were 167.70 nm and -18.1, respectively. The skin distribution study demonstrated the superior distribution of HYP-NLCs to a depth of 1480 µm within the skin layers relative to only 750 µm for free HYP. studies revealed that the levels of NF-KB, IL 6, MMP1, GSH, and catalase in the group treated with HYP-NLCs in the presence of light were comparable to the negative control.
CONCLUSIONS
The histopathological inspection of dissected skin samples reflected the superiority of HYP-NLCs over HYP ointment. This could be ascribed to the effect of nanoencapsulation on improving HYP properties besides the ability of hollow microneedles to ensure effective HYP delivery to the affected psoriatic area.
PubMed: 38853622
DOI: 10.1080/1061186X.2024.2365930 -
International Journal of Dermatology Jun 2024
PubMed: 38853388
DOI: 10.1111/ijd.17268 -
Photodiagnosis and Photodynamic Therapy Jun 2024Actinic keratosis (AK) is a common precancerous condition found on sun-damaged skin. Tirbanibulin 1 % ointment has been approved for the topical treatment of...
Actinic keratosis (AK) is a common precancerous condition found on sun-damaged skin. Tirbanibulin 1 % ointment has been approved for the topical treatment of non-hyperkeratotic facial and scalp Olsen grade I AKs over a contiguous area of 25 cm with a daily application for 5 consecutive days. Our aim was to investigate the use of in vivo RCM in the assessment of the response of AKs treated with tirbanibulin, as it has never been described in the published Literature. A total of 10 AKs in 10 consecutive outpatients were enrolled in the present study in May 2023. The follow-up visit was scheduled after 30 days from last application of tirbanibulin ointment. At follow-up visit, a complete response was described by clinical, dermoscopic and in vivo RCM examination in 10 out of 10 lesions, with a recovery of stratum corneum, decrease in atypical honeycomb pattern and changes in dermal collagen. All patients were followed up for at least 8 months and further recurrences were not registered. Based on our experience, we confirm the efficacy and safety of tirbanibulin in treating AKs and the usefulness of RCM in vivo examination for the therapeutic monitoring of such lesions, even in a very early stage.
PubMed: 38851311
DOI: 10.1016/j.pdpdt.2024.104235 -
Archives of Dermatological Research Jun 2024Loss and absence of melanocytes due to a number of factors is responsible for vitiligo; known to be the commonest disorder of pigmentation. The aim of the current work... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Loss and absence of melanocytes due to a number of factors is responsible for vitiligo; known to be the commonest disorder of pigmentation. The aim of the current work was to compare the efficacy and safety of excimer light with topical tacrolimus ointment 0.1% versus excimer light with topical bimatoprost gel 0.01% in treatment of facial vitiligo. The study was carried out on 48 patients presented with facial vitiligo. The patients were divided randomly using sealed envelope method into two groups (24 patients each). Group 1 were treated with excimer light plus topical tacrolimus ointment 0.1% and group 2 treated with excimer light plus topical bimatoprost gel 0.01%. Clinical improvement based on the quartile grading scale at the end of treatment did not show any statistically significant difference between groups. The majority of subjects in both groups experienced good to excellent improvement. Only 20.9% of patients in group 1 and 33.3% of subjects in group 2 achieved less than 50% repigmentation (p = 0.889). Our study demonstrated that 0.01% topical bimatoprost gel in combination with excimer light is considered safe and effective as treatment of nonsegmental facial vitiligo with comparable results to 0.1% tacrolimus.
Topics: Humans; Vitiligo; Tacrolimus; Bimatoprost; Female; Male; Adult; Treatment Outcome; Young Adult; Adolescent; Middle Aged; Lasers, Excimer; Administration, Topical; Skin Pigmentation; Face; Administration, Cutaneous; Child; Combined Modality Therapy; Immunosuppressive Agents
PubMed: 38850408
DOI: 10.1007/s00403-024-03054-5 -
Sleep Science (Sao Paulo, Brazil) Jun 2024Obstructive Sleep Apnea Syndrome (OSA) is a common sleep disorder characterized by recurrent episodes of partial or complete upper airway obstruction during sleep....
Obstructive Sleep Apnea Syndrome (OSA) is a common sleep disorder characterized by recurrent episodes of partial or complete upper airway obstruction during sleep. Floppy Eye Syndrome (FES) is a condition in which the upper eyelids easily evert with upward traction due to underlying tarsal plate laxity and is associated with chronic, reactive papillary conjunctivitis; this causes the eye to be vulnerable to discomfort and visual symptoms. A 49-year-old man with an 8-year history of snoring, sleep fragmentation, and daytime sleepiness was admitted as an outpatient in our sleep clinic. The patient had complied ocular symptoms such as burning eyes, redness, and irritative ocular symptoms in the past five years, arising upon waking up. The symptoms did not regress with the use of artificial tears and proper ointment. The patient was diagnosed with OSA and began using continuous positive airway pressure (CPAP). CPAP therapy significantly corrected the symptoms of FES associated with OSA . This would help to sensibilize ocular findings in patients with OSA and identify hidden sleeping diseases needing a more appropriate investigation and possible treatment. We must look beyond our approach to sleep clinic patients and avoid being kept to the common symptoms patients represent.
PubMed: 38846583
DOI: 10.1055/s-0043-1777784 -
Botanical Studies Jun 2024The clinical efficacy of Jinchuang Ointment, a traditional Chinese medicine (TCM), in treating chronic non-healing diabetic wounds has been demonstrated over the past...
BACKGROUND
The clinical efficacy of Jinchuang Ointment, a traditional Chinese medicine (TCM), in treating chronic non-healing diabetic wounds has been demonstrated over the past decades. Both in vitro and in vivo angiogenic activities have been reported for its herbal ingredients, including dragon blood from the palm tree Daemonorops draco and catechu from Uncaria gambir Roxb. Additionally, crude extracts of dragon blood have exhibited hypoglycemic effects not only in animal studies but also in cell-based in vitro assays.
RESULTS
Our findings indicate that crude dragon blood extract promotes the differentiation of myoblasts into myotubes. Partially purified fractions of dragon blood crude extract significantly enhance the expression of muscle cell differentiation-related genes such as myoG, myoD, and myoHC. Our results also demonstrate that crude extracts of dragon blood can inhibit platelet-derived growth factor-induced PAI-1 expression in primary rat vascular smooth muscle cells, thereby favoring changes in hemostasis towards fibrinolysis. Consistent with previous reports, reduced expression of plasminogen activator inhibitor 1 (PAI-1) accelerates wound healing. However, further separation resulted in a significant loss of both activities, indicating the involvement of more than one compound in these processes. Stem cells play a crucial role in muscle injury repair. Neither dragon blood nor catechu alone stimulated the proliferation of human telomerase reverse transcriptase (hTERT)-immortalized and umbilical cord mesenchymal stem cells. Interestingly, the proliferation of both types of stem cells was observed when crude extracts of dragon blood and catechu were present together in the stem cell growth medium.
CONCLUSIONS
Dragon blood from D. draco offers multifaceted therapeutic benefits for treating chronic nonhealing diabetic wounds from various perspectives. Most drugs in Western medicine consist of small molecules with defined ingredients. However, this is not the case in TCM, as the activities of dragon blood reported in this study. Surprisingly, the activities documented here align with descriptions in ancient Chinese medical texts dating back to A.D. 1625.
PubMed: 38842634
DOI: 10.1186/s40529-024-00422-2 -
The American Journal of Dermatopathology Jun 2024Enfortumab is a monoclonal antibody directed against nectin-4 and, when combined with vedotin, is an antibody-drug conjugate approved for the treatment of locally...
Enfortumab is a monoclonal antibody directed against nectin-4 and, when combined with vedotin, is an antibody-drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancers. A 75-year-old woman with stage IV papillary urothelial carcinoma of the bladder who completed cycle 2 of enfortumab vedotin (EV) infusions presented to our dermatology department for new-onset symmetric and painful dusky erythematous patches on the extremities and trunk without mucosal involvement. Two biopsies were obtained, which revealed an interface dermatitis with notable ring mitoses within the basal and suprabasal layers of the epidermis without epidermal necrosis. The patient was diagnosed with toxic erythema of chemotherapy and improved with application of triamcinolone 0.1% ointment twice daily without discontinuation of her EV infusions. Although a targeted therapy, EV commonly exhibits cutaneous side effects due to the expression of nectin-4 in the skin. Most cutaneous side effects are mild and can be managed symptomatically. However, severe drug-induced eruptions, such as toxic epidermal necrolysis, have been described. The histologic findings of EV associated skin eruptions can aid in correctly identifying the culprit drug and assist in management. This case provides insights for dermatologists by highlighting the common cutaneous side effects of EV and the associated histologic findings as this targeted therapy becomes increasingly utilized in the treatment of refractory neoplasms.
PubMed: 38842397
DOI: 10.1097/DAD.0000000000002750