Electrochemically Driven Nickel-Catalyzed Enantioselective Hydro-Arylation/Alkenylation of Enones.

Herein, the study reports the first electrochemical nickel-catalyzed enantioselective hydro-arylation/alkenylation of enones in an undivided cell with low-cost electrodes in the absence of external reductants and supporting electrolytes. Aryl bromides/iodides/triflates or alkenyl bromides are employed as electrophiles for the efficient preparation of more than 56 valuable ß-arylated/alkenylated ketones in a simple manner (up to 97% yield, 97% ee). With the advantages of electrochemistry, excellent functional group tolerance and late-stage modification of complex natural products and pharmaceuticals made the established protocol greener and more economic. Mechanism investigation suggests that a NiI/NiIII cycle may be involved in this electro-reductive reaction rather than metal reductant driven Ni0/NiII cycle. Overall, the efficient electrochemical activation and turnover of the nickel catalyst avoid the drawbacks posed by the employment of stoichiometric amount of sensitive metal powder reductants.

The treatment of Tofacitinib for rosacea through the inhibition of the JAK/STAT signaling pathway.

Rosacea is a chronic inflammatory skin disease characterized by facial erythema and telangiectasia. Despite ongoing research, the pathogenesis of rosacea remains incompletely understood, and current therapies are not entirely satisfactory. The JAK/STAT signaling pathway plays an essential role in immunoregulation, inflammation, and neurovascular regulation. Inhibition of the JAK/STAT pathway appears to hold promise as a potential therapy for rosacea. This study aimed to investigate the effects of the JAK inhibitor tofacitinib on rosacea and to preliminarily explore its therapeutic mechanism. To this end, a rosacea-like mouse model was induced using LL37 and treated with a 2% tofacitinib emulsion. The results demonstrated that topical application of tofacitinib significantly ameliorated rosacea-like phenotype, reduced the infiltration of CD4+ T cells and mast cells, and suppressed dermal angiogenesis. RT-qPCR analysis revealed a reduction in mRNA expression levels of STAT1, STAT4, and STAT5a in skin lesions following topical tofacitinib treatment. Additionally, three patients diagnosed with erythematotelangiectatic rosacea (ETR) were included in the study and treated with oral tofacitinib, leading to a significant improvement in erythema and flushing symptoms. These findings collectively suggest that tofacitinib alleviates LL37-induced rosacea-like skin inflammation in mice and rosacea skin lesions by inhibiting the JAK/STAT signaling pathway.

Electrochemical Nickel-Catalyzed Cross-Electrophile Coupling of Alkenyl Triflates with α-Chloroamides.

Cross-electrophile coupling reactions of different electrophiles have been extensively studied but mainly limited to bromides and iodides. Here, we report an electrochemically induced nickel-catalyzed cross-electrophile coupling strategy between alkenyl triflates and α-chloroamides in an undivided cell under mild reaction conditions, affording the α-functionalized amide derivatives in good to excellent yields with broad substrate scopes and good functional group tolerance. The control experiments were conducted, and a plausible mechanism was proposed.

Electrochemical Reductive Cross-Coupling of Alkyl or Alkenyl Halides with gem-Difluoroalkenes.

Herein, we describe an electroreductive cross-electrophile coupling protocol for the construction of valuable monofluoroalkenes from easily accessible alkyl or alkenyl halides with gem-difluoroalkenes. The reaction can be conducted under sustainable and mild conditions delivering valuable and functionalized monofluoroalkenes with excellent Z-selectivity. The protocol's most notable advantage is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra hazardous metal catalyst and superstoichiometric reductant.

Acquired Digital Fibrokeratoma: A Report of Five Cases and Review of the Literature.

Acquired digital fibrokeratoma (ADF) is rare in clinical practice and is easily misdiagnosed. Herein, 5 cases of patients (3 males and 2 females) with ADF are reported. The mean age at onset was 42.6 years, and the mean disease duration was 3 years. Four patients had ADF on the hands, and 1 patient had ADF on the foot. The clinical manifestations were all solitary, skin-colored papules, with a firm texture and smooth surface, protruding from the skin surface. In 3 patients, ADF manifested as columnar protrusions, and in 2 patients, ADF manifested as dome-shaped protrusions. For all 5 patients, the diameters of the lesions were <1 cm. Clinically, all 5 patients were misdiagnosed (ie, eccrine poroma (EP), common warts, rudimentary polydactyly, pyogenic granuloma (PG), and acral fibroma). All cases of ADF were confirmed by histopathology. The histopathological manifestations of ADF were as follows: finger-like protrusions on the skin surface; collagen fiber bundles running vertically to the epidermis seen in the dermis; and thick red-stained collagen fibers connected with the normal dermal connective tissue below. All 5 patients underwent surgical resection; the distance between the incision margin and the edge of the tumor was 2-3 mm, and the surgical depth was the deep dermis. No recurrence was observed in more than half a year of follow-up after surgery.

Electrochemical Reductive Cross-Coupling of Vinyl Bromides for the Synthesis of 1,3-Dienes.

An electroreductive cross-electrophile coupling protocol was developed for the construction of valuable 1,3-dienes from vinyl bromides. Furthermore, this scalable method can also be used to forge complex [4 + 2] cycloadducts in a one-pot manner. One of the most important advantages of this green and sustainable protocol is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra harmful metal catalysts and reductant.

Multiple Bowen's disease due to long-term narrow-band ultraviolet B phototherapy: A case report and literature review.

OBJECTIVE: By presenting a case study on multiple instances of Bowen's disease and the consistent use of narrow-band ultraviolet B (NB-UVB) phototherapy over a three-year period, our aim is to enhance the comprehension of domestic clinicians regarding the disease. Additionally, we seek to review existing literature, encouraging dermatologists to consider clinical secondary primary lesion diagnoses. METHOD: Our approach involves analyzing a diagnosed case of multiple Bowen's disease, examining clinical manifestations, histopathology, imaging results, and treatment methods related to NB-UVB phototherapy. We aim to facilitate discussion and understanding through a comprehensive literature analysis. RESULTS: An elderly male with a 30-year history of psoriasis vulgaris initiated continuous NB-UVB therapy three years ago. A year later, he developed red patches and plaques with distinct borders and scaly surfaces on his face, trunk, lower extremities, and scrotum. Histopathological examination confirmed Bowen's disease. Treatment involved liquid nitrogen cryotherapy, with no recurrence observed during the one-year follow-up. CONCLUSION: This case highlights that Bowen's disease, typically solitary, can manifest as multiple instances, especially in individuals with a history of psoriasis vulgaris. While NB-UVB stands as the primary treatment for psoriasis vulgaris, caution is warranted due to the potential risk of skin tumor induction with prolonged high-dose usage. Clinicians should be vigilant in monitoring and assessing the long-term implications of such therapies.

Folic Acid-Modified Long-Circulating Liposomes Loaded with Sulfasalazine For Targeted Induction of Ferroptosis in Melanoma.

Melanoma is a malignant tumor that originates from melanocytes. The incidence of melanoma is increasing worldwide, partially because of its insensitivity to radiotherapy or chemotherapy. Therefore, effective treatments for melanoma are urgently required. In this study, we employed folic acid-modified sulfasalazine long-circulating liposomes (FA-SSZ-Lips) to precisely target drug delivery to melanoma cells, eliciting ferroptosis effectively. The synthesized FA-SSZ-Lips were characterized as small spheres of a double-layer membrane, a particle size of 110.1 nm, and a ζ-potential of -22.8 ± 0.66 mV. FA-SSZ-Lips are effective drug carriers with SSZ-loading ratio and SSZ release rate of 6.2 ± 0.10%, and 72.63 ± 1.40%, respectively. The liposomes enhanced SSZ solubility, and the folic acid modifications increased the liposome targeting to melanoma cells. Compared with SSZ alone, FA-SSZ-Lips more strongly inhibited B16F10 cell growth, significantly disrupted the intracellular redox balance, and induced ferroptosis. After treatment, considerable differences were observed in the tumor volumes between FA-SSZ-Lips and phosphate-buffered saline control groups. The tumor growth-inhibition value of the FA-SSZ-Lips group reached 70.09%. Thus, FA-SSZ-Lips exhibited favorable antitumor effects in vitro and in vivo and are a promising strategy for melanoma treatment.

Inhibition of Key Glycolytic Enzyme Hexokinase 2 Ameliorates Psoriasiform Inflammation in vitro and in vivo.

Purpose: Epidermal keratinocytes with an abnormal glucose metabolism have been identified in psoriasis. Hexokinase 2 (HK2) is a crucial enzyme involved in glycolytic metabolic pathways. However, the expression of HK2 and its potential therapeutic effects in psoriasis remains unclear. This study aimed to investigate the expression pattern of HK2 and evaluate its therapeutic effects in psoriasis. Patients and Methods: A gene expression dataset (GSE121212) downloaded from the Gene Expression Omnibus (GEO) database was used to examine the expression of HK2 in psoriasis. HK2 RNA and protein expression were investigated in psoriasis vulgaris (n=5) and healthy (n=5) samples. Immunohistochemistry for HK2 was performed on psoriasis vulgaris (n=22) and healthy skin (n=10) samples. Additionally, HaCaT cells were treated with M5 (interleukin [IL]-17A, tumor necrosis factor-α, IL-1α, IL-22, and Oncostatin-M) to induce a psoriatic inflammation cell model. A mouse model of psoriatic inflammation was established using topical 5% imiquimod cream. Psoriasis-like cells and mouse models were treated with the HK2 inhibitor 3-bromopyruvate (3-BrPA). Cell proliferation, glucose consumption, and lactate production were assessed. Furthermore, the activation of nuclear factor-kappa B (NF-Kb) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) was investigated using Western blot analysis. Results: According to the GEO dataset, HK2 expression was significantly elevated in psoriasis. Upregulation of HK2 in psoriatic tissues was confirmed by quantitative real-time polymerase chain reaction and Western blotting. The immunohistochemistry score for HK2 was higher in psoriatic lesions than in healthy skin. 3-BrPA inhibited the proliferation and glycolysis of M5-stimulated HaCaT cells. Topical 3-BrPA ameliorated imiquimod-induced psoriasis-like dermatitis. Activation of NF-kB and NLRP3 was downregulated by 3-BrPA treatment. Conclusion: Our study revealed that the glycolytic enzyme HK2 was upregulated in psoriasis and that the HK2 inhibitor 3-BrPA exhibited therapeutic effects in psoriasis cell and mouse models.

Exogenous Hydrogen Sulfide Induces A375 Melanoma Cell Apoptosis Through Overactivation of the Unfolded Protein Response.

Purpose: Melanomas are highly malignant and rapidly develop drug resistance due to dysregulated apoptosis. Therefore, pro-apoptotic agents could be effective for the management of melanoma. Hydrogen sulfide is ubiquitous in the body, and exogenous hydrogen sulfide has been reported to show inhibitory and pro-apoptotic effects on cancer cells. However, whether high concentrations of exogenous hydrogen sulfide have pro-apoptotic effects on melanoma and its mechanisms remain unknown. Hence, this study aimed to explore the pro-apoptotic effects and mechanisms of exogenous hydrogen sulfide on the A375 melanoma cell line treated with a hydrogen sulfide donor (NaHS). Methods: The cell proliferation test, flow cytometric analysis, Hoechst 33258 staining, and Western blotting of B-cell lymphoma 2 and cleaved caspase-3 were used to explore the pro-apoptotic effects of hydrogen sulfide on A375 cells. The transcriptional profile of NaHS-treated A375 cells was further explored via high-throughput sequencing. Western blotting of phosphorylated inositol-requiring enzyme 1α (p-IRE1α), phosphorylated protein kinase R-like ER kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), C/EBP homologous protein, glucose-regulating protein 78, IRE1α, PERK, and eIF2α was performed to verify the changes in the transcriptional profile. Results: NaHS inhibited A375 melanoma cell proliferation and induced apoptosis. The endoplasmic reticulum stress unfolded protein response and apoptosis-associated gene expression was upregulated in NaHS-treated A375 melanoma cells. The overactivation of the unfolded protein response and increase in endoplasmic reticulum stress was verified at the protein level. Conclusion: Treatment with NaHS increased endoplasmic reticulum stress, which triggered the overactivation of the unfolded protein response and ultimately lead to melanoma cell apoptosis. The pro-apoptotic effect of NaHS suggests that it can be explored as a potential therapeutic agent in melanoma.

CD207 Expression Level is a New Prognostic Marker for Condyloma Acuminatum.

Background: Condyloma cuminata (CA) is a sexually transmitted disease caused by human papillomavirus (HPV) infection, which is prone to recurrence and difficult to cure in the short term. CD207 is a C-type lectin receptor that is specifically expressed on the surface of Langerhans cells (LCs) and is considered as an LC-specific immunohistochemical marker. The main purpose of this study is to explore the correlation between the expression of CD207 in CA skin lesions and the duration of CA disease course and frequency of recurrence, in order to provide new prognostic markers for CA to clinicians. Materials and Methods: A total of 40 male patients with CA and their skin lesions were collected, as well as 40 healthy male penile tissue samples. The skin lesions of CA were clinically and histologically confirmed by acetic acid test. The expression of CD207 in epidermal tissues was detected using immunohistochemistry. The difference in the number of CD207 positive cells between CA skin lesions and healthy skin controls was compared, and the association between the number of CD207 positive cells in CA skin lesions and the duration of disease course and the frequency of recurrence was determined through Spearman correlation analysis. Conclusion: In CA skin lesions, CD207 positive cells were found to have morphological abnormalities and the number of cells was significantly reduced compared to healthy skin, suggesting that there may be antigen presentation dysfunction in CA skin lesions, which may be the reason for the prolonged and unresolved condition of the disease. The fewer CD207 positive cells in CA skin lesions, the longer the disease course and the more frequent the recurrence, therefore, the expression level of CD207 can be used as a new prognostic marker for predicting the outcome of CA.

Ruxolitinib Treatment During Myelofibrosis Leads to Cutaneous Mycobacterium marinum Infection: A Case Report.

Mycobacterium marinum is an atypical bacterium, and skin infections caused by it are relatively rare, usually occurring in workers engaged in seafood processing and housewives who clean and prepare fish for consumption. The infection often occurs after the skin is punctured by fish scales, spines, etc. The JAK/STAT signaling pathway is closely related to the human immune response to infections. Therefore, JAK inhibitors may induce and exacerbate various infections in clinical practice. This article reports a case of mycobacterium marinum skin infection in the left upper limb of a female patient with chronic idiopathic myelofibrosis during treatment with ruxolitinib. The patient denied being punctured or scratched by fish scales or spines. Clinical manifestations included multiple infiltrative erythemas and subcutaneous nodules in the thumb and forearm. Histopathological examination showed infiltration of mixed acute and chronic inflammatory cells in the subcutaneous tissue. The diagnosis was ultimately confirmed by NGS sequencing. The patient was cured after taking moxifloxacin and clarithromycin for 10 months. Infection is a common adverse reaction of JAK inhibitors, but no literature has reported on mycobacterium marinum skin infections occurring during JAK inhibitor treatment, which is relatively rare. As the clinical application of JAK inhibitors becomes more widespread, the skin infections they cause may present in various forms and require the attention of clinicians.

A hybrid technique for measurement of intra/extracellular proteins.

ELISA or Western blot is known as a basic technique to be used for measurement of intracellular proteins, but in some cases, they cannot overcome problems such as normalization between samples or extraneous costs for required commercial kits. In order to address this problem, we developed a rapid and effective method (a hybrid of Western blot and ELISA). We use this new hybrid method to detect and normalize trace protein changes in gene expression intracellularly at a lower cost.

Chronic Mucocutaneous Candidiasis: A Case Report.

Chronic mucocutaneous candidiasis (CMC) is a rare infectious skin disease. This study reported a case of CMC in a child with clinical manifestations of oral mucosal leukoplakia and erythema and crust-like thick scabs on the skin of the face and upper limbs. Microscopic fungal examination revealed a large amount of pseudohyphae, and the fungal culture indicated Candida albicans. A drug sensitivity test indicated that it was sensitive to itraconazole and nystatin. Laboratory tests did not show significant immunodeficiency or endocrine abnormalities, and gene sequencing did not identify DNA gene mutations in the coiled-coil domain (CCD) or the DNA-binding domain (DBD) of signal transducer and activator of transcription 1 (STAT1). The skin lesions subsided after oral administration of itraconazole but relapsed 6 months later, and hypoparathyroidism occurred 1 year later. Patients with repeated superficial fungal infection should be alert to the possibility of CMC. CMC has numerous complications and a poor prognosis that requires the attention of clinicians. In this case, STAT1 mutation was not found, and parathyroid dysfunction was rare, providing reference for clinical diagnosis and treatment of CMC.

The effect mitigation measures for COVID-19 by a fractional-order SEIHRDP model with individuals migration.

In this paper, the generalized SEIHRDP (susceptible-exposed-infective-hospitalized-recovered-death-insusceptible) fractional-order epidemic model is established with individual migration. Firstly, the global properties of the proposed system are studied. Particularly, the sensitivity of parameters to the basic reproduction number are analyzed both theoretically and numerically. Secondly, according to the real data in India and Brazil, it can all be concluded that the bilinear incidence rate has a better description of COVID-19 transmission. Meanwhile, multi-peak situation is considered in China, and it is shown that the proposed system can better predict the next peak. Finally, taking individual migration between Los Angeles and New York as an example, the spread of COVID-19 between cities can be effectively controlled by limiting individual movement, enhancing nucleic acid testing and reducing individual contact.

Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.

Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific.

Clinical Retrospective Analysis of 243 Patients with Rhinofacial Ulcers.

Purpose: The clinical and pathological data of patients with rhinofacial ulcers were retrospectively reviewed and analyzed to lay the foundation for standardized clinical treatment. Patients and Methods: We retrospectively analyzed the clinical data, etiology, pathological features, treatment methods, and prognosis of 243 patients with rhinofacial ulcers treated in the Departments of Otorhinolaryngology and Dermatology at six hospitals in Shandong Province, China from July 2014 to October 2021. The clinical characteristics and treatment methods of the rhinofacial ulcers were summarized to provide a basis for standardizing patients' diagnosis and treatment. Results: The male-to-female ratio of the 243 patients was 2.04:1, and their ages ranged from 25 to 91 years. The most common sites were the cheek, nasal dorsum, and upper lip. The common primary diseases were basal-cell carcinoma, squamous-cell carcinoma, and odontogenic fistula, but rare triggers played important roles in some cases, such as infection, autoimmune diseases, and adverse drug reactions. Surgical treatment was feasible for tumor ulcers; 71 patients with basal-cell carcinoma and 50 with squamous-cell carcinoma were treated with Mohs micrographic surgery. During the follow-up period of 1-84 months, most of the rhinofacial ulcers were cured, while natural killer/T-cell lymphoma, angiosarcoma, and melanoma were important causes of death. Conclusion: Various causes may lead to rhinofacial skin ulcers, and some cases lacking specificity of clinical manifestations are easily misdiagnosed in clinical practice. Histopathological biopsy is valuable for confirming the diagnosis, after which correct etiological treatment is very important.

Granular Parakeratosis: A Case Report.

Granular parakeratosis is an uncommon acquired keratinization disorder that occurs in the armpit, groin, and other parts of the body. It may be related to stimulation by detergents and antiperspirants. This article reports a case of granular parakeratosis in the groin. The patient was a young man with no predisposing factors. The clinical manifestations included symmetrical bilateral inguinal erythema, dryness, and a small amount of bran-like desquamation. After histopathological examination, the final diagnosis was granular parakeratosis, which was cured by topical application of glucocorticoid cream and silicone oil cream. Granular parakeratosis is a rare skin disease of unknown etiology. Clinicians need to pay attention to this disease and differentiate it from various diseases to avoid misdiagnosis.