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Biomaterials Advances Jul 2024Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral...
Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.
Topics: Diclofenac; Animals; Needles; Rats; Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Drug Delivery Systems; Nanoparticles; Male; Skin; Skin Absorption; Transdermal Patch; Rats, Sprague-Dawley
PubMed: 38781739
DOI: 10.1016/j.bioadv.2024.213889 -
Biological & Pharmaceutical Bulletin 2024Patch tests are often used in safety evaluations to identify the substance causing skin irritation, but the same substance can sometimes give positive or negative...
Patch tests are often used in safety evaluations to identify the substance causing skin irritation, but the same substance can sometimes give positive or negative results depending on the test conditions. Here, we investigated differences in the skin penetration of two test compounds under different application conditions. We studied the effects of the anionic surfactant sodium dodecyl sulfate (SDS) and the nonionic surfactant polysorbate 80 (PS) on skin penetration of the preservatives methylisothiazolinone (MT) and methylchloroisothiazolinone (MCT), which are used in cosmetics such as shampoos. The skin permeation of MT was enhanced by SDS but was unchanged by PS. Skin impedance decreased in the presence of SDS whereas PS had the same effect as the control aqueous solution, suggesting that SDS reduction of the barrier function of skin affects the permeation of MT, a hydrophilic drug. Application of a mixture of MCT and MT in the presence of SDS did not affect the skin permeation of MCT whereas the permeation of MT was enhanced by SDS, indicating that the skin permeation of MCT is less affected by SDS than is MT. Thus, attention should be paid to the possible effect of co-solutes, especially hydrophilic drugs.
Topics: Thiazoles; Surface-Active Agents; Skin Absorption; Polysorbates; Sodium Dodecyl Sulfate; Skin; Animals; Preservatives, Pharmaceutical; Swine; Cosmetics; Electric Impedance; Permeability
PubMed: 38777759
DOI: 10.1248/bpb.b24-00127 -
JAAD International Sep 2024Psoriasis and allergic contact dermatitis are 2 very common dermatoses. The relationship between them has not yet been fully understood. Contact dermatitis can be an...
BACKGROUND
Psoriasis and allergic contact dermatitis are 2 very common dermatoses. The relationship between them has not yet been fully understood. Contact dermatitis can be an additional cause of epidermal disruption in psoriasis patients, resulting in poor management of the disease.
OBJECTIVE
To analyze the tendencies of contact sensitization in a cohort of psoriasis patients with suspected allergic contact dermatitis.
METHODS
Psoriasis patients ( = 85) with suspected contact dermatitis underwent patch testing with European Baseline allergen series S-1000 in Vilnius University Hospital Santaros Klinikos Centre of Dermatovenereology from August 2020 to August 2021. Their results are presented in this study.
RESULTS
The patch test was positive in 43.5% ( = 37) of patients. Contact sensitization was more prevalent in patients with mild psoriasis, as characterized by Psoriasis Area Surface Index scores ≤10, compared to those with moderate-to-severe psoriasis ( < .05). Generalized psoriasis and nail involvement were more common among nonsensitized patients ( < .05). Most common contact allergens among sensitized patients were nickel (II) sulfate, formaldehyde, and potassium dichromate.
CONCLUSION
An inverse trend was observed between psoriasis severity and contact sensitization. Extended psoriatic involvement was uncommon in sensitized patients.
PubMed: 38774342
DOI: 10.1016/j.jdin.2024.02.015 -
Journal of Traditional Chinese Medicine... Jun 2024To evaluate the analgesic effects of total flavonoids of Longxuejie () (TFDB) and explore the possible analgesic mechanism associated with transient receptor potential...
OBJECTIVE
To evaluate the analgesic effects of total flavonoids of Longxuejie () (TFDB) and explore the possible analgesic mechanism associated with transient receptor potential vanilloid 1 (TRPV1).
METHODS
Whole-cell patch clamp technique was used to observe the effects of TFDB on capsaicin-induced TRPV1 currents. Rat experiments were used to observe the analgesic effects of TFDB. Western blot and immunofluorescence experiments were used to test the change of TRPV1 expression in DRG neurons induced by TFDB.
RESULTS
Results showed that TFDB inhibited capsaicin-induced TRPV1 receptor currents in acutely isolated dorsal root ganglion (DRG) neurons of rats and the half inhibitory concentration was (16.7 ± 1.6) mg/L. TFDB (2-20 mg/kg) showed analgesic activity in the phase Ⅱ of formalin test and (0.02-2 mg per paw) reduced capsaicin-induced licking times of rats. TFDB (20 mg/kg) was fully efficacious on complete Freund's adjuvant (CFA)-induced inflammatory thermal hyperalgesia and capsaicin could weaken the analgesic effects. The level of TRPV1 expressions of DRG neurons was also decreased in TFDB-treated CFA-inflammatory pain rats.
CONCLUSION
All these results indicated that the analgesic effect of TFDB may contribute to their modulations on both function and expression of TRPV1 channels in DRG neurons.
Topics: Animals; TRPV Cation Channels; Rats; Flavonoids; Analgesics; Male; Rats, Sprague-Dawley; Ganglia, Spinal; Humans; Drugs, Chinese Herbal; Neurons; Pain
PubMed: 38767627
DOI: 10.19852/j.cnki.jtcm.20240423.004 -
Cureus Apr 2024Mongolian spots are bluish-grey, irregular, hyperpigmented macules present at birth or that appear in the first few weeks of life. They are classified as atypical if...
Mongolian spots are bluish-grey, irregular, hyperpigmented macules present at birth or that appear in the first few weeks of life. They are classified as atypical if they occur in unusual locations without spontaneous disappearance after infancy; or if new lesions continue to appear beyond early infancy. Although they are generally considered benign, recent studies have shown that atypical Mongolian spots may be associated with inborn errors of metabolism, such as lysosomal storage disorders and neurocristopathies. An 11-month-old male presented with multiple aberrant Mongolian spots on the abdomen, back, buttocks, arms, and legs, with the largest patch measuring 10x10 cm. Additionally, the child exhibited coarse facial features, a high-arched palate, low-set ears, and a depressed nasal bridge. Systemic examination revealed hepatosplenomegaly, fundus examination showed a hazy cornea, and the urine glycosaminoglycan test was positive, prompting us to conduct further research prioritising lysosomal storage disorders. The mucopolysaccharidosis (MPS) spot test was positive, and electrophoresis for MPS revealed bands for chondroitin sulfate and dermatan sulfate, confirming the diagnosis of MPS. Enzyme assay revealed no alpha-iduronidase activity and normal beta-galactosidase activity, thus confirming Hurler's disease. This case report highlights the importance of considering atypical Mongolian spots as a potential indicator of underlying storage disorders, enabling early intervention.
PubMed: 38765368
DOI: 10.7759/cureus.58501 -
The Journal of Headache and Pain May 2024Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional...
BACKGROUND
Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood.
METHODS
The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats.
RESULTS
The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application.
CONCLUSIONS
Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
Topics: Animals; Migraine Disorders; Calcitonin Gene-Related Peptide; Rats, Sprague-Dawley; Cerebral Cortex; Anxiety; Rats; Male; Disease Models, Animal; Adenylyl Cyclases; Receptors, N-Methyl-D-Aspartate
PubMed: 38760739
DOI: 10.1186/s10194-024-01778-3 -
Allergologie Select 2024Allergic contact dermatitis is one of the most frequent occupational skin diseases. Targeted allergen avoidance can only be achieved by identification of the causative... (Review)
Review
Allergic contact dermatitis is one of the most frequent occupational skin diseases. Targeted allergen avoidance can only be achieved by identification of the causative allergen. Therefore, patch testing is of utmost importance in occupational dermatology, not only in terms of assessing causal relationships but also regarding the implementation of prevention measures and evaluation of the legal criteria for an occupational skin disease in Germany (statutory occupational disease BK 5101). The lack of commercial patch test preparations poses a great diagnostic challenge. Patch testing of patient's own materials from their workplace is therefore very important to reduce diagnostic gaps. The performance and documentation of the patch test should be in line with current guidelines and recommendations to ensure the necessary test quality and comprehensibility of the test results.
PubMed: 38756208
DOI: 10.5414/ALX2483E -
Frontiers in Oncology 2024Whole Slide Image (WSI) analysis, driven by deep learning algorithms, has the potential to revolutionize tumor detection, classification, and treatment response...
BACKGROUND
Whole Slide Image (WSI) analysis, driven by deep learning algorithms, has the potential to revolutionize tumor detection, classification, and treatment response prediction. However, challenges persist, such as limited model generalizability across various cancer types, the labor-intensive nature of patch-level annotation, and the necessity of integrating multi-magnification information to attain a comprehensive understanding of pathological patterns.
METHODS
In response to these challenges, we introduce MAMILNet, an innovative multi-scale attentional multi-instance learning framework for WSI analysis. The incorporation of attention mechanisms into MAMILNet contributes to its exceptional generalizability across diverse cancer types and prediction tasks. This model considers whole slides as "bags" and individual patches as "instances." By adopting this approach, MAMILNet effectively eliminates the requirement for intricate patch-level labeling, significantly reducing the manual workload for pathologists. To enhance prediction accuracy, the model employs a multi-scale "consultation" strategy, facilitating the aggregation of test outcomes from various magnifications.
RESULTS
Our assessment of MAMILNet encompasses 1171 cases encompassing a wide range of cancer types, showcasing its effectiveness in predicting complex tasks. Remarkably, MAMILNet achieved impressive results in distinct domains: for breast cancer tumor detection, the Area Under the Curve (AUC) was 0.8872, with an Accuracy of 0.8760. In the realm of lung cancer typing diagnosis, it achieved an AUC of 0.9551 and an Accuracy of 0.9095. Furthermore, in predicting drug therapy responses for ovarian cancer, MAMILNet achieved an AUC of 0.7358 and an Accuracy of 0.7341.
CONCLUSION
The outcomes of this study underscore the potential of MAMILNet in driving the advancement of precision medicine and individualized treatment planning within the field of oncology. By effectively addressing challenges related to model generalization, annotation workload, and multi-magnification integration, MAMILNet shows promise in enhancing healthcare outcomes for cancer patients. The framework's success in accurately detecting breast tumors, diagnosing lung cancer types, and predicting ovarian cancer therapy responses highlights its significant contribution to the field and paves the way for improved patient care.
PubMed: 38746682
DOI: 10.3389/fonc.2024.1275769 -
American Journal of Human Genetics Jun 2024Anoctamins are a family of Ca-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease...
Anoctamins are a family of Ca-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.
Topics: Humans; Anoctamins; Mutation, Missense; Male; Female; Epilepsy; Child; Phospholipid Transfer Proteins; Genetic Association Studies; Pedigree; Calcium; Genes, Dominant; Child, Preschool; HEK293 Cells; Adolescent
PubMed: 38744284
DOI: 10.1016/j.ajhg.2024.04.014 -
ACS Chemical Neuroscience Jun 2024In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the...
In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the and assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds and displayed the following pharmacological values: ED = 64.3 mg/kg (MES), ED = 15.6 mg/kg (6 Hz, 32 mA), ED = 29.9 mg/kg (6 Hz, 44 mA), and ED = 34.9 mg/kg (MES), ED = 12.1 mg/kg (6 Hz, 32 mA), ED = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, and were effective in the PTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and ADME-Tox data proved favorable drug-like properties of . The patch-clamp recordings in rat cortical neurons showed that at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.
Topics: Animals; Anticonvulsants; Analgesics; Seizures; Male; Rats; Mice; Disease Models, Animal; Rats, Wistar; Hippocampus; Electroshock; Neurons
PubMed: 38741575
DOI: 10.1021/acschemneuro.4c00013