Search Results (3,396)

Phosphodiesterase-4 (PDE4) is involved in the synthesis of inflammatory cytokines that mediate several chronic inflammatory disorders, including psoriasis and atopic dermatitis. In recent years, the therapeutic armamentarium in dermatology has expanded with the introduction of PDE4 inhibitors, both in oral and topical formulations. PDE4 inhibitors have gained increasing interest due to their remarkable safety record and ease of prescription, as evidenced by the recent influx of literature detailing its off-label uses. Apremilast was the first PDE4 inhibitor approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for psoriasis, psoriatic arthritis, and oral ulcers of Behcet’s disease. Off-label use has been reported in diverse dermatological conditions, including aphthous stomatitis, chronic actinic dermatitis, atopic dermatitis, cutaneous sarcoidosis, hidradenitis suppurativa, lichen planus, and discoid lupus erythematosus. Roflumilast is a PDE4 inhibitor that was approved by the FDA and the EMA as an oral treatment of chronic obstructive pulmonary disease. Since patent expiration, several generic formulations of oral roflumilast have become available, and various studies have documented its off-label use in psoriasis and other dermatological conditions such as hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet’s disease. Topical roflumilast has received FDA approval for treatment of plaque psoriasis and seborrheic dermatitis. The favorable safety profile encourages its long-term use as an alternative to corticosteroids, addressing the chronic nature of many dermatological conditions. New oral PDE4 inhibitors are being developed, such as orismilast (LEO-32731), mufemilast (Hemay005), difamilast (OPA-15406) or lotamilast (E6005/RVT-501), among others. This narrative review provides a comprehensive synthesis of the pharmacology, clinical efficacy, safety profile, and practical considerations regarding the oral and topical use of PDE4 inhibitors in dermatology. Full article

Lucky bamboo (Dracaena sanderiana hort. ex. Mast. = Dracaena braunii) is a popular decorative plant in China. In March 2022, a severe outbreak of anthracnose disease occurred on the stems of lucky bamboo plants in a nursery garden in Nanjing, Jiangsu Province, China. Thirty-two fungal isolates were obtained from the infected stem tissues and were morphologically identified as Colletotrichum species. A multilocus phylogenetic analysis based on the internal transcribed spacer (ITS) region, the actin (ACT) gene, and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene indicated the isolate FGZ-1 as Colletotrichum gloeosporioides (Penz.) Penz. and Sacc. The pathogenicity of isolate FGZ-1 was verified by inoculating mycelial plugs on stem segments and spraying spores on the whole one-year-old lucky bamboo plants. Koch’s postulates were fulfilled via the re-isolation of C. gloeosporioides from the diseased tissues. To the best of our knowledge, this is the first report of C. gloeosporioides causing anthracnose on lucky bamboo in China. The detection of C. gloeosporioides on lucky bamboo in China expands the range of Colletotrichum species that are associated with anthracnose in this popular ornamental plant. This study lays a solid foundation for future investigations into the pathogenic mechanisms of anthracnose on D. sanderiana and control strategies for this disease, such as biocontrol agents and the construction of resistant cultivars. Full article

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer’s disease (AD). It is generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, is regulated by several stimuli. Tau protein has also been identified as a significant factor in AD. In particular, Tau phosphorylation is crucial for neuronal impairment, as phosphorylated Tau detaches from microtubules, leading to the formation of neurofibrillary tangles and the destabilization of the microtubule structure. This instability in microtubules damages axons and dendrites, resulting in neuronal impairment. Notably, Aβ is linked to Tau phosphorylation. Another crucial factor in AD is neuroinflammation, primarily occurring in the microglia. Microglia possess several receptors that bind with Aβ, triggering the expression and release of an inflammatory factor, although their main physiological function is to phagocytose debris and pathogens in the brain. NF-κB activation plays a major role in neuroinflammation. Additionally, the production of reactive oxygen species (ROS) in the microglia contributes to this neuroinflammation. In microglia, superoxide is produced through NADPH oxidase, specifically NOX2. Rho GTPases play an essential role in regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, and transcription. The typical function of Rho GTPases involves regulating actin filament formation. Neurons, with their complex processes and synapse connections, rely on cytoskeletal dynamics for structural support. Other brain cells, such as astrocytes, microglia, and oligodendrocytes, also depend on specific cytoskeletal structures to maintain their unique cellular architectures. Thus, the aberrant regulation of Rho GTPases activity can disrupt actin filaments, leading to altered cell morphology, including changes in neuronal processes and synapses, and potentially contributing to brain diseases such as AD. Full article

Background: For investigating the host response in Acinetobacter baumannii associated pneumonia, we analyzed the host genetic sequences obtained from metagenomic next-generation sequencing (mNGS). Methods: The samples for mNGS were bronchoalveolar lavage fluid (BALF) collected from the lungs of patients infected with A. baumannii and from patients without bacterial infections. BALF samples from patients with pneumonia were collected from the lungs of patients infected with A. baumannii with New Delhi metallo-β-lactamase (NDM, before treatment), A. baumannii with NDM (post-treatment), A. baumannii without resistant genes, and those without bacterial infection. Partek was used for investigating enriched functions and pathways related to the pulmonary host response to pneumonia caused by A. baumannii with NDM infection and A. baumannii without antimicrobial-resistant genes. The STRING was employed for identifying protein interaction pathways related to the pulmonary host response to pneumonia caused by A. baumannii without antimicrobial-resistant genes. Results: In pulmonary host response to pneumonia caused by A. baumannii with NDM, five immune system-related pathways and five pathways related to signal transduction were identified. No significant differences were observed in the immune system and signal transduction pathways in the pulmonary host response to pneumonia caused by A. baumannii without antimicrobial-resistant genes. However, significant differences were noted in the phagosome, ferroptosis, and regulation of the actin cytoskeleton in cellular processes. Conclusions: mNGS provides information not only on pathogen gene expression but also on host gene expression. In this study, we found that pneumonia with A. baumannii carrying the NDM resistance gene triggers stronger immune responses in the lung, while pneumonia with A. baumannii lacking antimicrobial resistance genes is more linked to iron-related pathways. Full article

In maximally Ca²⁺-activated demembranated fibres from the mammalian skeletal muscle, the depression of the force by lowering the temperature below the physiological level (~35 °C) is explained by the reduction of force in the myosin motor. Instead, cooling is reported to not affect the force per motor in Ca²⁺-activated cardiac trabeculae from the rat ventricle. Here, the mechanism of the cardiac performance depression by cooling is reinvestigated with fast sarcomere-level mechanics. We determine the changes in the half-sarcomere compliance of maximally Ca²⁺-activated demembranated rat trabeculae in the range of temperatures of 10–30 °C and analyse the data in terms of a simplified mechanical model of the half-sarcomere to extract the contribution of myofilaments and myosin motors. We find that the changes in the ensemble force are due to changes in the force per motor, while the fraction of actin-attached motors remains constant independent of temperature. The results demonstrate that in the cardiac myosin, as in the skeletal muscle myosin, the force-generating transition is endothermic. The underlying large heat absorption indicates the interaction of extended hydrophobic surfaces within the myosin motor, like those suggested by the crystallographic model of the working stroke. Full article

Background: Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuropathy primarily involving motor and sensory neurons. Mutations in INF2, an actin assembly factor, cause two diseases: peripheral neuropathy CMT-DIE (MIM614455) and/or focal segmental glomerulosclerosis (FSGS). These two phenotypes arise from the progressive degeneration affecting podocytes and Schwann cells. In general, nerve enlargement has been reported in 25% of the demyelinating CMT subtype (CMT1), while little is known about the CMT-DIE caused by INF2 variants. Methods: To characterize the peripheral nerve phenotype of INF2-related CMT, we studied the clinical course, imaging, histology, and germline genetic variants in two unrelated CMT-DIE patients. Results: Patient 1 (INF2 p.Gly73Asp) and patient 2 (p.Val108Asp) first noticed walking difficulties at 10 to 12 years old. Both of them were electrophysiologically diagnosed with demyelinating neuropathy. In patient 2, the sural nerve biopsy revealed an onion bulb formation. Both patients developed nephrotic syndrome almost simultaneously with CMT and progressed into renal failure at the age of 16 to 17 years. Around the age of 30 years, both patients manifested multiple hypertrophy of the trunk, plexus, and root in the cervical, brachial, lumbosacral nerves, and cauda equina. The histology of the cervical mass in patient 2 revealed Schwannoma. Exome analysis showed that patient 2 harbors a germline LZTR1 p.Arg68Gly variant, while patient 1 has no schwannomatosis-related mutations. Conclusions: Peripheral neuropathy caused by INF2 variants may lead to the development of multifocal hypertrophy with age, likely due to the initial demyelination and subsequent Schwann cell proliferation. Schwannoma could co-occur when the tissues attain additional hits in schwannomatosis-related genes (e.g., LZTR1). Full article

Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of Stil resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7. Full article

Nuclear actin polymerization was reported to control different nuclear processes, but its regulation is poorly understood. Here, we show that N-WASP can trigger the formation of nuclear N-WASP/F-actin nodules. While a cancer hotspot mutant of N-WASP lacking the VCA domain (V418fs) had a dominant negative function on nuclear F-actin, an even shorter truncation mutant found in melanoma (R128*) strongly promoted nuclear actin polymerization. Nuclear localization of N-WASP was not regulated by the cell cycle and increasing nuclear F-actin formation by N-WASP had no obvious influence on replication. However, nuclear N-WASP/F-actin nodules colocalized partially with RNA Pol II clusters. N-WASP-dependent actin polymerization promoted the maturation of RNA Pol II clusters, with the short truncation mutant R128* unexpectedly showing the strongest effect. Nuclear N-WASP nodules including V418fs colocalized with WIP and cortactin. Importantly, cortactin binding was essential but not sufficient for F-actin formation, while WIP binding was required for actin polymerization by R128*. These data reveal a cortactin-dependent role for N-WASP in the regulation of nuclear F-actin and indicate contrasting nuclear effects for N-WASP mutants found in cancer. Full article

Background: Cholesterol gallstone disease (CGS) is often accompanied by gallbladder contraction dysfunction and chronic inflammation, but effective therapeutic options remain limited. This study investigates whether a low-intensity pulsed ultrasound (LIPUS) treatment can improve gallbladder motility and alleviate chronic inflammation while exploring the underlying mechanisms. Methods: Gallbladder motility was assessed through in vitro and in vivo contraction tests, while bile condition was evaluated by observing bile crystal clearance. Tissue analysis and Western blotting were performed to examine the expression of the cholecystokinin A receptor (CCKAR) and α-smooth muscle actin (α-SMA) as markers of gallbladder smooth muscle health and the inflammatory microenvironment. Blood cholesterol levels were measured via biochemical assays. Results: LIPUS treatment obviously enhanced gallbladder contractility in response to CCK-8 stimulation and accelerated bile crystal clearance. It also reduced inflammatory cell infiltration and tissue edema, and promoted new capillary formation in the gallbladder, mitigating the progression of CGS. Furthermore, LIPUS restored CCKAR expression and improved the thickness of the gallbladder smooth muscle layer, providing a structural basis for increased smooth muscle contractility. Conclusion: LIPUS improves gallbladder motility and reduces chronic inflammation in CGS by enhancing CCKAR expression and smooth muscle integrity. These findings highlight the potential of LIPUS as a non-invasive therapeutic approach for managing CGS. Full article

The primary mode of transmission for Chagas disease is vector-borne transmission, spread by hematophagous insects of the Triatominae subfamily. In Mexico, the triatomine Meccus pallidipennis is particularly significant in the transmission of Trypanosoma cruzi. This study focused on analyzing protein expression and modifications by glycosylation in different regions of the digestive tract of fifth-instar nymphs of M. pallidipennis. Two gut sections were dissected and extracted: the anterior midgut (AMG) and the proctodeum or rectum (RE). Proteins were extracted from each tissue sample and profiled by one- and two-dimensional electrophoresis; protein glycosylation was analyzed by lectin affinity. Our results showed significant differences in protein expression and glycosylation between both gut regions, with modifications being more frequent in the RE. The proteins HSP70, actin, and tubulin were analyzed, finding a differential expression of the latter two between AMG and RE. Understanding glycosylation patterns provides critical insights into vector–pathogen interactions that could eventually inform novel control approaches. Furthermore, the potential use of lectins as insecticidal agents highlights the broader implications of glycoprotein research in the future development of strategies on vector control to disrupt T. cruzi transmission. Full article

Background: Hypoxia triggers stress, leading to significant alterations in gene expression patterns, which in turn affect fish’s growth and development. Real-time quantitative PCR (RT-qPCR) is a pivotal technique for assessing changes in gene expression. However, its accuracy is highly contingent upon the stable expression of reference genes. Ribosomal RNA (18s), β-actin (actb), elongation factor 1-α (ef1a), α tubulin (tuba), and ribosomal protein L17 (rpl17) are the widely used reference genes, but their expression stability in the tissues of black rockfish under hypoxic conditions remains unclear. Methods: The expression of genes was detected by RT-qPCR and the stability was assessed by Delta Ct, geNorm, NormFinder, and BestKeeper algorithms. Results: Results showed that tuba exhibited stable expression in liver, heart, gill tissues under normoxic conditions, and in the liver and head kidney under hypoxic conditions. Ef1a was identified as the most stably expressed gene in gill tissue under hypoxia. For hypoxic heart studies, rpl17 and tuba were recommended as reference genes. 18s showed high stability in spleen tissue under hypoxic conditions. Actb was the most stably expressed gene in spleen and head kidney tissues under normoxic conditions. Conclusions: The identified reference genes exhibited tissue-specific stability, and it was necessary to select appropriate reference genes based on the specific tissue type for gene expression studies under hypoxic conditions. These findings help in enhancing the accuracy of gene expression analysis in the mechanism of hypoxia for black rockfish. Full article

Background: The literature reports that ezrin (EZR) is important as a linker between microfilaments and cellular environments. Moreover, it affects cancer cell migration, but the exact mechanism is not fully understood. In this study, we aimed to investigate the role of EZR in the migration of two different types of cervical cancer cells—from primary lesion (SiHa) and lymph node metastases (HT-3). In addition, we showed for the first time that a reduced EZR protein level affects the cellular response to the routinely used treatment with cisplatin. Methods: The most important stage of the study consisted of conducting a series of tests enabling the assessment of the migration potential of cervical cancer cells without altered EZR expression and with silenced protein expression. Results: Reducing the EZR level resulted in a decrease in the invasive and migration potential of SiHa and HT-3 cells’ inhibition of colony formation, a decrease in adhesive properties, and a strong reorganization of F-actin with a dominance of cells with a mitotic catastrophe phenotype. A lower level of protein significantly reduces the motor skills of SiHa and HT-3 cervical cancer cells. Conclusions: This significantly affects the assessment of EZR as a potential factor that can limit the development of metastases in targeted cancer therapy of cervical cancer. Full article

Background/Objectives: Skin cancer is becoming increasingly common due to increasing risk factors such as excessive ultraviolet (UV) radiation, genetic predisposition, fair skin, and a history of sunburn. Melanoma accounts for only 1% of cases but causes most skin cancer deaths. Dysplastic nevi (DN) are important precursors of melanoma. The aim of this study was to investigate the influence of these risk factors on the incidence and stage of skin cancer. Methods: The study included 591 patients aged 18 to 64 who visited the Department of Dermatology and Venereology in 2022–2023 for skin examinations. Each patient completed a questionnaire regarding the risk factors for melanoma and atypical melanocytic nevi and then underwent a dermatoscopic examination of the whole body using a digital videodermatoscope. Results: Dermatoscopic examination revealed a lesion suggestive of melanoma in 1.69% of the patients. Risk factors for developing melanoma included male gender, family history of melanoma, number of skin moles, sunburn in childhood, sun-dependent hobby, using a tanning bed, using low sun protection factor (SPF) cream, not avoiding sun exposure, and co-occurrence of actinic keratosis. Conclusions: Risk factors for melanoma and dysplastic nevi are still common among patients, but the situation has been improving over the years. Early intervention and education on sun safety can play pivotal roles in reducing the incidence of atypical moles and potentially preventing malignant transformations. Full article

Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease and inflammatory disorders. In these conditions, perturbed TCA cycle and subsequent succinate accumulation have been reported. The role of succinate as a regulator of immunological responses and inflammation is increasingly being recognized. Nevertheless, how endothelial cell function and phenotype are altered by elevated intracellular succinate has not been addressed yet. Thus, we employed numerous in vitro functional assays using primary HUVECs and diethyl succinate (DES), a cell membrane-permeable succinate analogue. An MTS assay 1 h post stimulation with DES suggested reduced metabolic activity in HUVECs. Concurrently, elevated production of ROS, including mitochondrial superoxide, and a reduction in mitochondrial membrane potential were observed. These findings were corroborated by Seahorse mito-stress testing, which revealed that DES acutely lowered the OCR, maximal respiration and ATP production. Given the link between mitochondrial stress and apoptosis, we examined important survival signalling pathways. DES transiently reduced ERK1/2 phosphorylation, a response that was followed by a skewed pro-apoptotic shift in the BAX to BCL2L1 gene expression ratio, which coincided with upregulating VEGF gene expression. This indicated an induction of mixed pro-apoptotic and pro-survival signals in the cell. However, the BAX/BCL-XL protein ratio was unchanged, suggesting that the cells did not commit themselves to apoptosis. An MTS assay, caspase 3/7 activity assay and annexin V/propidium iodide staining confirmed this finding. By contrast, stimulation with DES induced acute endothelial barrier permeability, forming intercellular gaps, altering cell size and associated actin filaments without affecting cell count. Notably, during overnight DES exposure gradual recovery of the endothelial barrier and cell sprouting was observed, alongside mitochondrial membrane potential restoration, albeit with sustained ROS production. COX-2 inhibition and EP4 receptor blockade hindered barrier restoration, implicating a role of COX-2/PGE₂/EP4 signalling in this process. Interestingly, ascorbic acid pre-treatment prevented DES-induced acute barrier disruption independently from ROS modulation. In conclusion, succinate acts as a significant regulator of endothelial mitochondrial function and barrier integrity, a response that is counterbalanced by upregulated VEGF and prostaglandin production by the endothelial cells. Full article

Cutaneous melanoma (CM) represents a severe skin cancer with a rising incidence at present and limited treatment options. 5-Fluorouracil (5-FU) is widely used, including for CM; however, the innate resistance of this cancer to conventional therapy remains problematic. Quercetin (QUE) is a flavonoid that can sensitize cancer cells to antitumor agents such as 5-FU. However, the potential sensitization capability of CM cells to 5-FU has scarcely been determined, and is investigated herein. Therefore, A375 CM cells were tested in terms of their cell viability, cell confluence, and morphological changes. Their nuclear and cytoskeletal aspects, clonogenic potential, and in ovo properties were also followed. The results showed that the 50% inhibitory concentrations (IC50s) of 5-FU and QUE determined by a cell proliferation assay were 11.56 and 11.08 µM, respectively. The addition of QUE (10 µM) to 5-FU (5–50 µM) increased the cytotoxic potential. A significant decline in cell viability (up to 43.51%), the loss of cell confluence, chromatin condensation and nuclear dysmorphology, tubulin and F-actin constriction, and a suppressed clonogenic ability were noted. The QUE + 5-FU association was non-irritating to the chorioallantoic membrane and showed an antiangiogenic effect in ovo. Thus, our results highlight that combining QUE with 5-FU can enhance the cytotoxic effect of 5-FU in A375 melanoma cells and present a safe profile in ovo. Full article