Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer / 药物分析学报

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macro-phages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative acti-vation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice

Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism. Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation. Here, we report celastrol, a traditional Chinese medicine, can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation. Mechanistically, celastrol binds to adenylyl cyclase associated protein 1 (CAP1) and inhibits the interaction between CAP1 and resistin, which restrains the cyclic adenylate monophosphate (cAMP)-protein kinase A (PKA)-nuclear factor kappa-B (NF-

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

Species analysis of fungi isolated in a laboratory from patients with mycoses during 1960-2006 / 中华皮肤科杂志

Objective To analyze fungal isolates from patients with superficial fungal infections during 1960-2006.Methods Fungal strains isolated from patients with superficial (mucocutaneous and cutaneous)fungal infections and identified in the Medical Mycology Clinical Laboratory,Department of Dermatology and Venereology,Union Hospital,from 1960 to 2006 (data from September 1991 to July 1992 were unavailable),were subjected to a classification and statistical analysis.Clinical samples for mycological examination were taken from outpatients or inpatients of different departments in hospitals of Hubei province and surrounding areas.Morphological,physiological and biochemical methods were applied for species identification.Results A total of 11 989 Candida strains were isolated,which belonged to 23 species and 16 genera.They fell into 3 groups,i.e.,dermatophytes,Candida and yeasts (including Malassezia),and non-dermatophyte moulds.Since 287 strains of moulds were suspected to be contaminating fungi,11 702 residual isolates were analyzed.Of the analyzed isolates,Candida species (5642/11 702,48.2％ )and dermatophytes (5279/11 702,45.1％ )predominated,followed by yeasts (449/11 702,3.8％) and Malassezia species (332/11 702,2.8％).The most frequently isolated species was Trichophyton rubrum (3865/11 702,33.0％),Candida albicans (3110/11 702,26.6％ ) and non-albicans Candida species (2532/11 702,21.6％ ).Dermatophyte strains were mostly isolated from lesions of smooth skin with an exception of palmoplantar and interdigit regions (1787/5279,37.7％).The most common dermatophyte species was Trichophyton rubrum,followed by Trichophyton violanceum.Candida was mainly isolated from mucous membrane lesions (4099/5642,72.7％),with Candida albicans being the predominant species.Conclusions Candida species and dermatophytes predominate in patients with superficial fungal infections during 1960-2006,with Trichophyton rubrum being the most common species.