CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes.

Psoriasis is a chronic inflammatory skin disease featuring rapid proliferation of epidermal cells. Although elevated glycolysis flux has been reported in psoriasis, the molecular mechanisms underlying its pathogenesis remain unclear. We investigated the role of the integral membrane protein CD147 in psoriasis pathogenesis, observing its high expression in psoriatic skin lesions of humans and imiquimod (IMQ)-induced mouse models. In mouse models, genomic deletion of epidermal CD147 markedly attenuated IMQ-induced psoriatic inflammation. We found that CD147 interacted with glucose transporter 1 (Glut1). Depletion of CD147 in the epidermis blocked glucose uptake and glycolysis in vitro and in vivo. In CD147-knockout mice and keratinocytes, oxidative phosphorylation was increased in the epidermis, indicating CD147's pivotal role in glycolysis reprogramming during pathogenesis of psoriasis. Using non-targeted and targeted metabolic techniques, we found that epidermal deletion of CD147 significantly increased the production of carnitine and α-ketoglutaric acid (α-KG). Depletion of CD147 also increased transcriptional expression and activity of γ-butyrobetaine hydroxylase (γ-BBD/BBOX1), a crucial molecule for carnitine metabolism, by inhibiting histone trimethylations of H3K9. Our findings demonstrate that CD147 is critical in metabolic reprogramming through the α-KG-H3K9me3-BBOX1 axis in the pathogenesis of psoriasis, indicating that epidermal CD147 is a promising target for psoriasis treatment.

The traditional chinese medicine monomer Ailanthone improves the therapeutic efficacy of anti-PD-L1 in melanoma cells by targeting c-Jun.

BACKGROUND: C-Jun, a critical component of AP-1, exerts essential functions in various tumors, including melanoma, and is believed to be a druggable target for cancer therapy. Unfortunately, no effective c-Jun inhibitors are currently approved for clinical use. The advent of immune checkpoint inhibitor (ICI) has brought a paradigm shift in melanoma therapy, but more than half of patients fail to exhibit clinical responses. The exploration of new combination therapies has become the current pursuit of melanoma treatment strategy. This study aims to screen out Chinese herbal monomers that can target c-Jun, explore the combined effect of c-Jun inhibitor and ICI, and further clarify the related molecular mechanism.  METHODS: We adopted a combinatorial screening strategy, including molecular docking, ligand-based online approaches and consensus quantitative structure-activity relationship (QSAR) model, to filter out c-Jun inhibitors from a traditional Chinese medicine (TCM) library. A mouse melanoma model was used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Multicolor flow cytometry was employed to assess the tumor microenvironment (TME). Multiple in vitro assays were performed to verify down-streaming signaling pathway. CD4 + T-cell differentiation assay was applied to investigate Treg differentiation in vitro. RESULTS: Ailanthone (AIL) was screened out as a c-Jun inhibitor, and inhibited melanoma cell growth by directly targeting c-Jun and promoting its degradation. Surprisingly, AIL also facilitated the therapeutic efficacy of anti-programmed death ligand-1 (PD-L1) in melanoma cells by reducing the infiltration of Tregs in TME. Additionally, AIL treatment inhibited c-Jun-induced PD-L1 expression and secretion. As a consequence, Treg differentiation was attenuated after treatment with AIL through the c-Jun/PD-L1 axis. CONCLUSION: Our findings identified AIL as a novel c-Jun inhibitor, and revealed its previously unrecognized anti-melanoma effects and the vital role in regulating TME by Treg suppression, which provides a novel combination therapeutic strategy of c-Jun inhibition by AIL with ICI. AIL down-regulates c-Jun by reducing its stability, and inhibits the function of Tregs via AIL-c-Jun-PD-L1 pathway, ultimately suppressing melanoma progression and enhancing the efficacy of anti-PD-L1.

[Pathological study of testicular injury induced by high power microwave radiation in rats].

OBJECTIVE: To explore the pathological characteristics and the dynamic change regularity of the testis induced by high power microwave (HPM) radiation. METHODS: One hundred and sixty-five male Wistar rats were exposed to 0, 3, 10, 30 and 100 mW/cm2 HPM radiation for five minutes, and changes of testicular morphology and teratogenic ratio of epididymal spermatozoa were observed through light microscope and electron microscope at 6 h, 1, 3, 7, 14, 28 and 90 d after radiation. RESULTS: Injury of testicular spermatogenic cells in rats might be induced by 3 to approximately 100 mW/cm2 HPM radiation, and the main pathological changes were degeneration, necrosis, shedding of spermatogenic cells, formation of multinuclear giant cells, decrease or loss of sperm and interstitial edema. Injury of spermatogenic cells underwent such phases as death and shedding, cavitation, regeneration and repair, characterized by being focalized, inhomogenous and phased. And the severity of pathological changes of the testis increased with power density. There was only scattered degeneration, necrosis, shedding of spermatogenic cells in the seminiferous tubule one day after 3 mW/cm2 radiation, and the pathological changes six hours after 10 mW/cm2 radiation was similar to those one day after 3 mW/cm2 radiation, but with the formation of multinuclear giant cells, and the above-mentioned pathological changes aggravated from one day to seven days after radiation. There was a significant increase in degeneration, necrosis, shedding of spermatogenic cells, as well as a significant decrease in spermatozoa and focal necrosis in simple seminiferous tubules six hours after 30 and 100 mW/cm2 radiation, and the subsequent changes were similar to those of 10 mW/cm2 radiation. There was a significant increase in teratogenic ratio of epididymal spermatozoa at 3 d, 1 to approximately 7 d, 6 h to approximately 7 d after 3, 10, 30 and 100 mW/cm2 microwave radiation respectively (P < 0.01 or P < 0.05). CONCLUSION: HPM radiation may cause injury of testicular spermatogenic cells in rats, which has a positive correlation to radiation dosage and time.

Ultrastructrural observation of the membrane surface of kainic acid-treated hippocampal neurons by atomic force microscopy.

OBJECTIVE: To observe the three-dimensional morphological changes on the membrane surface of primary cultured rat hippocampal neurons in response to kainic acid (KA) exposure. METHODS: After isolation and primary culture, Wistar rat hippocampal neurons were treated with KA at the concentrations of 0, 25, and 250 micromol/L for different durations (10 and 100 min) to observe the subsequent changes in the membrane surface structure of the neurons by nano-scale scanning with an atomic force microscope (AFM). RESULTS: Normal neurons displayed smooth membrane surface with even and regular undulation, while the neurons treated with KA, in contrast, presented degenerative changes characterized by cell swelling and coarse membrane surface with processes and holes. As the treatment was prolonged and KA concentration increased, the changes became more evident. CONCLUSION: As a result of the toxic effect of KA, the membrane surface ultrastructure of rat hippocampal neurons undergo obvious changes, which can be clearly observed and quantitatively analyzed by means of AFM.