Tofacitinib for the treatment of severe rare skin diseases: a narrative review.

PURPOSE: Autoimmune bullous diseases, connective tissue diseases, and vasculitis represent a group of severe rare skin diseases. While glucocorticoids and immunosuppressive agents serve as standard treatments for these diseases, their efficacy is limited due to adverse side effects, indicating the need for alternative approaches. Biologics have been used in the management of some rare skin diseases. However, the use of biologics is associated with concerns, such as infection risk and high costs, prompting the quest for efficacious and cost-effective alternatives. This study discusses the safety issues associated with tofacitinib and its potential in treating rare skin diseases. METHODS: This narrative review focuses on the pharmacodynamic properties of tofacitinib and its impact on the JAK/STAT pathway. In addition, we present a comprehensive discussion of the effects and mechanism of action of tofacitinib for each severe rare skin disease. RESULTS: This role of tofacitinib in treating severe rare skin diseases has been discussed, shedding light on its promising prospects as a treatment modality. Few reports of serious adverse events are available in patients treated with tofacitinib. CONCLUSION: We explored the mechanism of action, efficacy, and safety considerations of tofacitinib and found that it can be used as a treatment option for rare skin diseases. However, multicenter clinical studies are needed to confirm the efficacy and safety of JAK inhibitors.

Structures of Mammeasins P and Q, Coumarin-Related Polysubstituted Benzofurans, from the Thai Medicinal Plant Mammea siamensis (Miq.) T. Anders.: Anti-Proliferative Activity of Coumarin Constituents against Human Prostate Carcinoma Cell Line LNCaP.

A methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) showed anti-proliferative activity against human prostate carcinoma LNCaP cells (IC50 = 2.0 µg/mL). Two new coumarin-related polysubstituted benzofurans, mammeasins P (1) and Q (2), and a known polysubstituted coumarin mammea B/AC cyclo F (39) were isolated from the extract along with 44 previously reported polysubstituted coumarin constituents (3-38 and 40-47). The structures of two new compounds (1 and 2) were determined based on their spectroscopic properties derived from the physicochemical evidence including NMR and MS analyses and taking the plausible generative pathway into account. Among the coumarin constituents, mammeasins A (3, IC50 = 1.2 µM) and B (4, 0.63 µM), sugangin B (18, 1.5 µM), kayeassamins E (24, 3.0 µM) and G (26, 3.5 µM), and mammeas E/BA (40, 0.88 µM), E/BB (41, 0.52 µM), and E/BC (42, 0.12 µM) showed relatively potent anti-proliferative activity.

Aromatase inhibitors isolated from a flowering tea, snow Chrysanthemum (the capitula of Coreopsis tinctoria Nutt.).

Methanol extract from the capitula of Coreopsis tinctoria Nutt. (Asteraceae), which is also known as a flowering tea or blooming tea "Snow Chrysanthemum," was found to inhibit the enzymatic activity of aromatase. A total of 24 known isolates (1-24) were identified from the extract, including three chalcones (1-3), an aurone (4), five flavanones (5-9), four flavanols (10-13), a flavonol (14), and two biflavanones (15, 16). Among them, okanin (1, Ki = 1.6 µM), (2S)-naringenin (5, 0.90 µM), isookanin (6, 0.81 µM), (2S)-7,3',5'-trihydroxyflavaone (7, 0.13 µM), and (2S)-5,7,3',5'-tetrahydroxyflavanone (8, 0.32 µM) exhibited relatively potent competitive inhibition. Specifically, the isolates 7 and 8, having a common 3',5'-resorcinol moiety at the B ring in their flavanone skeleton, exhibited potent inhibitory activities compared to those of a clinically applied aminoglutethimide (0.84 µM) and naturally occurring flavone, chrysin (0.23 µM), which is a common non-steroidal aromatase inhibitor. Importantly, the active flavonoid constituents (1 and 5-8) did not inhibit the activity of 5α-reductase enzyme, which normally reacts with the same substrate "testosterone," thus, these compounds were suggested to be specific to aromatase.

Isoliquiritigenin Inhibits the Growth of Colorectal Cancer Cells through the ESR2/PI3K/AKT Signalling Pathway.

Colorectal cancer (CRC) is one of the most common malignancies. Isoliquiritigenin (ISL), a flavonoid phytoestrogen, has shown anti-tumour activities against various cancers. However, its anti-CRC mechanism has not been clarified. In this study, the potential molecular mechanism of ISL against CRC was investigated through network pharmacological prediction and experimental validation. The results of the network prediction indicate that ESR2, PIK3CG and GSK3ß might be the key targets of ISL against CRC, which was verified by molecular docking, and that its anti-tumour mechanisms might be related to the oestrogen and PI3K/AKT signalling pathway. The experimental results show that ISL reduced the viability of SW480 and HCT116 cells, induced apoptosis, blocked the cell cycle in the G2 phase in vitro, and suppressed xenograft tumour growth in vivo. In addition, ISL significantly down-regulated the protein expression of PIK3CG, AKT, p-AKT, p-GSK3ß, CDK1, NF-κB and Bcl-2; up-regulated ESR2 and Bax; decreased the ratio of p-AKT/AKT and p-GSK3ß/GSK3ß; and increased the Bax/Bcl-2 ratio. This study indicates that ISL can inhibit the growth of CRC cells and induce apoptosis, which may be related to the up-regulation of ESR2 and inhibition of the PI3K/Akt signalling pathway.

Phytochemicals with Chemopreventive Activity Obtained from the Thai Medicinal Plant Mammea siamensis (Miq.) T. Anders.: Isolation and Structure Determination of New Prenylcoumarins with Inhibitory Activity against Aromatase.

With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K (1), L (2), M (3), N (4), and O (5), were isolated from the methanolic extract of Mammea siamensis (Miq.) T. Anders. flowers (fam. Calophyllaceae), originating in Thailand. The stereostructures of 1-5 were elucidated based on their spectroscopic properties. Among the new compounds, 1 (IC50 = 7.6 µM) and 5 (9.1 µM) possessed relatively strong inhibitory activity against aromatase, which is a target of drugs already used in clinical practice for the treatment and prevention of estrogen-dependent breast cancer. The analysis through Lineweaver-Burk plots showed that they competitively inhibit aromatase (1, Ki = 3.4 µM and 5, 2.3 µM). Additionally, the most potent coumarin constituent, mammea B/AB cyclo D (31, Ki = 0.84 µM), had a competitive inhibitory activity equivalent to that of aminoglutethimide (0.84 µM), an aromatase inhibitor used in therapeutics.

Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis.

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 µmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

Application and Evaluation of the Flipped Classroom Based on Micro-Video Class in Pharmacology Teaching.

With the continuous development of information technology, new teaching resources "micro-video class" and teaching model "flipped classroom" have gradually attracted the attention of teachers. Whether and how they can be applied in pharmacology teaching has already become the focus of medical education research in recent years. This paper explores the application and evaluation of the flipped classroom based on micro-video class in pharmacology teaching in our college. Students in Class 1 and Class 2 majoring in clinical medicine of 2018 in Chengdu Medical College were randomly divided into experimental group and control group. The teaching model of flipped classroom based on micro-video class was used in the experimental group, while the traditional teaching model was used in the control group. Theory tests and questionnaires were carried out at the end of the course. The average scores of theoretical knowledge in experimental group were significantly higher than those in control group (P < 0.05). In addition, the results of the feedback questionnaire showed that the overall satisfaction of students participating in flipped classroom based on micro-video class was higher (P < 0.05), and students thought that their learning enthusiasm, learning efficiency, and abilities of autonomous learning and problem-solving were greatly improved compared with those of students taught applying the traditional teaching model. Flipped classroom based on micro-video class model successfully improved the outcome of pharmacology teaching. It is supposed to provide reference for the reform of pharmacology teaching in medical college.

Indole Glycosides from Calanthe discolor with Proliferative Activity on Human Hair Follicle Dermal Papilla Cells.

A methanol extract from the underground part of Calanthe discolor Lindl. (Orchidaceae) demonstrated significant proliferative activity on human hair follicle dermal papilla cells (HFDPC, % of control: 120.8 ± 0.2%) at 100 µg/mL against HFDPC. Through bioassay-guided separation of the extract, a new indole glycoside named 6'-O-ß-D-apiofuranosylindican (1) was isolated along with six known compounds (2-7) including three indole glycosides. The stereostructure of 1 was elucidated based on its spectroscopic properties and chemical characteristics. Among the isolates, 1 (110.0 ± 1.0%), glucoindican (3, 123.9 ± 6.8%), and calanthoside (4, 158.6 ± 7.1%) showed significant proliferative activity at 100 µM. Furthermore, the active indole glycosides (1, 3, and 4) upregulated the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-7 (FGF-7) mRNA and protein in HFDPC, which could be the mechanism of their proliferative activity.

Ent-kaurane-type diterpenoids from Isodonis Herba activate human hair follicle dermal papilla cells proliferation via the Akt/GSK-3ß/ß-catenin transduction pathway.

A methanol extract from Isodonis Herba demonstrated significant proliferative effect on human hair follicle dermal papilla cells (HFDPC, % of control: 150.0 ± 2.0% at 20 µg/mL, p < 0.01). From the extract, 14 ent-kaurane-type diterpenoids (1-14), two abietane-type diterpenoids (15 and 16) and four triterpenoids (17-20) were isolated. Among the isolates, enmein (1, 160.9 ± 3.0% at 20 µM, p < 0.01), isodocarpin (2, 169.3 ± 4.9% at 5 µM, p < 0.01), nodosin (4, 160.5 ± 12.4% at 20 µM, p < 0.01), and oridonin (8, 165.4 ± 10.6% at 10 µM, p < 0.01) showed the proliferative effects. The principal component enmein (1) activated the expression of vascular endothelial growth factor (VEGF) mRNA, upregulated the production of VEGF and increased levels of phospho-Akt, phospho-GSK-3ß, and ß-catenin accumulation in HFDPC, which could be the mechanism of these activate proliferation activity.

Anti-proliferative activities of coumarins from the Thai medicinal plant Mammea siamensis (Miq.) T. Anders. against human digestive tract carcinoma cell lines.

Geranylated coumarins named mammeasins G-J (1-4) were isolated from the methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) originating in Thailand. Their structures were established based on detailed spectroscopic analyses. The isolates, including previously reported coumarin constituents (5-28), exhibited anti-proliferative activities against human carcinoma cell lines HSC-2, HSC-4, MKN-45, and MCF-7. Mammeasin A (7, IC50 = 13.6 µM) and surangin B (15, 15.2 µM), both consisting of the geranyl group, were found to show relatively strong activities against HSC-4 cells and their mechanisms of action were found to involve apoptotic cell death.

Geranylated Coumarins From Thai Medicinal Plant Mammea siamensis With Testosterone 5α-Reductase Inhibitory Activity.

Geranylated coumarin constituents, kayeassamin I (1) and mammeasins E (2) and F (3) were newly isolated from the methanol extract of the flowers of Mammea siamensis (Calophyllaceae) originating in Thailand, along with five known isolates, such as mammea E/BC (23), deacetylmammea E/AA cyclo D (31), deacetylmammea E/BB cyclo D (32), mammea A/AA cyclo F (34), and mammea A/AC cyclo F (35). These compounds (1-3) were obtained as an inseparable mixture (ca. 1:1 ratio) of the 3″R and 3″S forms, respectively. Among the isolated coumarins from the extract, mammeasins E (2, 22.6 µM), A (4, 19.0 µM), and B (5, 24.0 µM), kayeassamins E (9, 33.8 µM), F (10, 15.9 µM), and G (11, 17.7 µM), surangin C (13, 5.9 µM), and mammeas A/AA (17, 19.5 µM), E/BB (22, 16.8 µM), and A/AA cyclo F (34, 23.6 µM), were found to inhibit testosterone 5α-reductase.

DeepPhos: prediction of protein phosphorylation sites with deep learning.

MOTIVATION: Phosphorylation is the most studied post-translational modification, which is crucial for multiple biological processes. Recently, many efforts have been taken to develop computational predictors for phosphorylation site prediction, but most of them are based on feature selection and discriminative classification. Thus, it is useful to develop a novel and highly accurate predictor that can unveil intricate patterns automatically for protein phosphorylation sites. RESULTS: In this study we present DeepPhos, a novel deep learning architecture for prediction of protein phosphorylation. Unlike multi-layer convolutional neural networks, DeepPhos consists of densely connected convolutional neuron network blocks which can capture multiple representations of sequences to make final phosphorylation prediction by intra block concatenation layers and inter block concatenation layers. DeepPhos can also be used for kinase-specific prediction varying from group, family, subfamily and individual kinase level. The experimental results demonstrated that DeepPhos outperforms competitive predictors in general and kinase-specific phosphorylation site prediction. AVAILABILITY AND IMPLEMENTATION: The source code of DeepPhos is publicly deposited at https://github.com/USTCHIlab/DeepPhos. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PTM-ssMP: A Web Server for Predicting Different Types of Post-translational Modification Sites Using Novel Site-specific Modification Profile.

Protein post-translational modifications (PTMs) are chemical modifications of a protein after its translation. Owing to its play an important role in deep understanding of various biological processes and the development of effective drugs, PTM site prediction have become a hot topic in bioinformatics. Recently, many online tools are developed to prediction various types of PTM sites, most of which are based on local sequence and some biological information. However, few of existing tools consider the relations between different PTMs for their prediction task. Here, we develop a web server called PTM-ssMP to predict PTM site, which adopts site-specific modification profile (ssMP) to efficiently extract and encode the information of both proximal PTMs and local sequence simultaneously. In PTM-ssMP we provide efficient prediction of multiple types of PTM site including phosphorylation, lysine acetylation, ubiquitination, sumoylation, methylation, O-GalNAc, O-GlcNAc, sulfation and proteolytic cleavage. To assess the performance of PTM-ssMP, a large number of experimentally verified PTM sites are collected from several sources and used to train and test the prediction models. Our results suggest that ssMP consistently contributes to remarkable improvement of prediction performance. In addition, results of independent tests demonstrate that PTM-ssMP compares favorably with other existing tools for different PTM types. PTM-ssMP is implemented as an online web server with user-friendly interface, which is freely available at http://bioinformatics.ustc.edu.cn/PTM-ssMP/index/.

Specifically binding of L-ficolin to N-glycans of HCV envelope glycoproteins E1 and E2 leads to complement activation.

L-ficolin, one of lectin families, is a recently identified complement factor that initiates lectin pathway of complement. Little is known about its role in viral hepatitis. In the present study, we found that L-ficolin in serum from 103 patients with hepatitis C virus (HCV), were significantly higher than that in 150 healthy controls. We further found that L-ficolin expressions were significantly increased in vitro study by HCV JFH-1 infected human hepatocyte cell line Huh7.5.1. Investigation of the mechanisms of the L-ficolin action on HCV demonstrated that L-ficolin protein could recognize and bind to envelope glycoproteins E1 and E2 of HCV, activating the lectin complement pathway-mediated cytolytic activity in HCV-infected hepatocyte. This interaction between L-ficolin and HCV E1 and E2 glycoproteins was attributed to the N-glycans of E1 and E2. These findings provide new insights into the biological functions of L-ficolin in clinically important hepatic viral diseases.

A novel recombinant bacterial vaccine strain expressing dual viral antigens induces multiple immune responses to the Gag and gp120 proteins of HIV-1 in immunized mice.

Recombinant Salmonella enterica serovar Typhi can function as a live vector to deliver foreign antigens to the mammalian immune system and induce both mucosal and systemic immunity. In this study, we generated a recombinant Salmonella Typhi strain pilS-pilT-Gag+ (pVAX1-gp120) harboring the human immunodeficiency virus (HIV) gag gene integrated into the bacterial chromosome and gp120 gene carried by a plasmid. Mice inoculated with this recombinant bacterium through intranasal route produced high titers of IgG to gp120 in sera and IgA to gp120 in fecal washes. In addition, Gag-specific and gp120-specific cytotoxic T lymphocyte (CTL) responses were observed in sorted spleen lymphocytes of immunized mice. These results demonstrated that this recombinant Salmonella Typhi strain elicits multiple immune responses against both Gag and gp120 antigens of HIV, and thus would be a potential vaccine candidate to the prevention of HIV/AIDS.