Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway.

BACKGROUND: Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. OBJECTIVES: This study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. METHODS: We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. RESULTS: Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. CONCLUSION: The findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.

Alkaloids isolated from the endophytic fungus Fusarium concentricum.

Endophytic fungi are an important resource for bioactive natural products. In this study, a new tryptophan derivative fusaconate A (1) and three pyridone alkaloids, including one new pyridone derivative 1'-methoxy-6'-epi-oxysporidinone (2) and two known ones (3-4), were identified from the endophytic fungus Fusarium concentricum which was isolated from the medicinal plant Anoectochilus roxburghii. Their structures were elucidated through extensive spectroscopic analysis, including HR-ESI-MS, 1 D and 2 D NMR. Compound 4 exhibited moderate cytotoxicities against HT29 and PC3 cells with IC50 values of 7.60 and 4.99 µM, respectively.

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia.

BACKGROUND: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. METHODS: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. RESULTS: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). CONCLUSIONS: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Novel Targeted Biological Agents for the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a common inflammatory dermatologic disease clinically characterized by intense itch, recurrent eczematous lesions, and a chronic or relapsing disease course. Mild-to-moderate AD can be controlled by using moisturizers and topical immunomodulators such as topical corticosteroids and calcineurin inhibitors. If topical therapies fail, phototherapy and systemic immunosuppressant therapies, such as ciclosporin, methotrexate, and azathioprine, can be considered. However, relapse and side effects could still occur. The pathogenesis of AD involves epidermal barrier dysfunction, skin microbiome abnormalities, and cutaneous inflammation. Inflammatory mediators, such as interleukin (IL)-4, IL-13, IL-31, IL-33, IL-17, IL-23, and thymic stromal lymphopoietin, are involved in AD development. Therefore, a series of biological agents targeting these cytokines are promising approaches for treating AD. Dupilumab is the first biological agent approved for the treatment of AD in patients aged 6 years and older in the United States. Tralokinumab, lebrikizumab, and nemolizumab have also been confirmed to have significant efficacy against AD in phase III or IIb clinical trials. Also, fezakinumab was effective in severe AD patients in a phase IIa trial. However, phase II trials of ustekinumab, tezepelumab, etokimab, secukinumab, and omalizumab have failed to meet their primary endpoints. Phase II trials of GBR 830 and KHK 4083 are ongoing. In general, further studies are needed to explore new therapeutic targets and improve the efficacy of biological agents.

Xiao-Yin-Fang Therapy Alleviates Psoriasis-like Skin Inflammation Through Suppressing γδT17 Cell Polarization.

Psoriasis is an immune-mediated chronic inflammatory skin disease primarily mediated by the activation of interleukin (IL)-17-producing T cells. Traditional Chinese Medicine (TCM) represents one of the most effective complementary and alternative medicine (CAM) agents for psoriasis, which provides treasured sources for the development of anti-psoriasis medications. Xiao-Yin-Fang (XYF) is an empirically developed TCM formula that has been used to treat psoriasis patients in Shanghai Changhai Hospital for over three decades. Imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was utilized to investigate the therapeutic effects of XYF by the assessment of disease severity and skin thickness. Flow cytometric assay was performed to explore the influence of XYF on skin-related immunocytes, primarily T cells. And, RNA sequencing analysis was employed to determine the alternation in gene expression upon XYF therapy. We discovered that XYF alleviated psoriasis-like skin inflammation mainly through suppressing dermal and draining lymph-node IL-17-producing γδT (γδT17) cell polarization. Moreover, XYF therapy ameliorated the relapse of psoriasis-like dermatitis and prohibited dermal γδT cell reactivation. Transcriptional analysis suggested that XYF might regulate various inflammatory signaling pathways and metabolic processes. In conclusion, our results clarified the therapeutic efficacy and inner mechanism of XYF therapy in psoriasis, which might promote its clinical application in psoriasis patients and facilitate the development of novel anti-psoriasis drugs based on the bioactive components of XYF.

Quantifying the Urban Food-Energy-Water Nexus: The Case of the Detroit Metropolitan Area.

The efficient provision of food, energy, and water (FEW) resources to cities is challenging around the world. Because of the complex interdependence of urban FEW systems, changing components of one system may lead to ripple effects on other systems. However, the inputs, intersectoral flows, stocks, and outputs of these FEW resources from the perspective of an integrated urban FEW system have not been synthetically characterized. Therefore, a standardized and specific accounting method to describe this system is needed to sustainably manage these FEW resources. Using the Detroit Metropolitan Area (DMA) as a case, this study developed such an accounting method by using material and energy flow analysis to quantify this urban FEW nexus. Our results help identify key processes for improving FEW resource efficiencies of the DMA. These include (1) optimizing the dietary habits of households to improve phosphorus use efficiency, (2) improving effluent-disposal standards for nitrogen removal to reduce nitrogen emission levels, (3) promoting adequate fertilization, and (4) enhancing the maintenance of wastewater collection pipelines. With respect to water use, better efficiency of thermoelectric power plants can help reduce water withdrawals. The method used in this study lays the ground for future urban FEW analyses and modeling.

Screening a novel FGF3 antagonist peptide with anti-tumor effects on breast cancer from a phage display library.

Accumulating evidence has suggested that fibroblast growth factor 3 (FGF3) is expressed in breast cancer and correlates with the stage and grade of the disease. In the present study, a specific FGF3­binding peptide (VLWLKNR, termed FP16) was isolated from a phage display heptapeptide library with FGF3. The peptide FP16 contained four identical (WLKN) amino acids and demonstrated high homology to the peptides of the 188­194 (TMRWLKN) site of the high­affinity FGF3 receptor fibroblast growth factor receptor 2. Functional analyses indicated that FP16 mediated significant inhibition of FGF3­induced cell proliferation, arrested the cell cycle at the G0/G1 phase by increasing proliferation­associated protein 2G4, suppressing cyclin D1 and proliferating cell nuclear antigen, and inhibited the FGF3­induced activation of extracellular signal­regulated kinase 1/2 and Akt kinase. Taken together, these results demonstrated that the peptide FP16, acting as an FGF3 antagonist, is a promising therapeutic agent for the treatment of breast cancer.

[Comparative study between montmorillonite and Smecta on anti-dysentery effect].

OBJECTIVE: To compare the efficiency of montmorillonite (Mengtuoshi) and Smecta. METHODS: The effects on the dysentery mice induced by MgSO4, rhubarb powder and castor oil, were observed by given respectively 15.6%, 31.2% Mengtuoshi and 31.2% Smecta. And the effects on the over-contracted rabbit intestines were also observed. RESULTS: Both Mengtuoshi and Smecta could relieve the over pushing speeding of stomach and intestine, and reduce the times of dysentery. CONCLUSION: The anti-dysentery effect of Mengtuoshi was similar to Smecta from France and may be used as good anti-dysentery drug.