Erratum: Author correction to '3-O-Acetyl-11-keto-ß-boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma' [Acta Pharm Sin B 10 (2020) 301-312].

[This corrects the article DOI: 10.1016/j.apsb.2019.12.012.].

Interferon Gamma Inducible Protein 30: from biological functions to potential therapeutic target in cancers.

Interferon Gamma Inducible Protein 30 (IFI30), also known as Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT), is predominantly found in lysosomes and the cytoplasm. As the sole enzyme identified to catalyze disulfide bond reduction in the endocytic pathway, IFI30 contributes to both major histocompatibility complex (MHC) class I-restricted antigen cross-presentation and MHC class II-restricted antigen processing by decreasing the disulfide bonds of endocytosed proteins. Remarkably, emerging research has revealed that IFI30 is involved in tumorigenesis, tumor development, and the tumor immune response. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of patients. This review provided a comprehensive overview of the research progress on IFI30 in tumor progression, cellular redox status, autophagy, tumor immune response, and drug sensitivity, with a view to providing the theoretical basis for pharmacological intervention of IFI30 in tumor therapy, particularly in immunotherapy.

S670, an amide derivative of 3-O-acetyl-11-keto-ß-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

Design, synthesis and characterization of a novel multicomponent salt of bexarotene with metformin and application in ameliorating psoriasis with T2DM.

Psoriasis is a common systemic inflammatory skin disorder affecting over 60 million people globally. Some patients with psoriasis are associated with a higher risk of type 2 diabetes mellitus (T2DM). Psoriasis and T2DM occur concurrently in some patients; however, there is no effective drug for the treatment of psoriasis with T2DM. Bexarotene (BEX) is a specific RXR agonist and an antineoplastic agent indicated by the FDA for cutaneous T-cell lymphoma (CTLA). Metformin (MET) is the first-line treatment for T2DM. To develop novel effective drugs for the treatment of psoriasis with T2DM, multicomponent salts containing MET and BEX were designed and synthesized based on the drug-drug combination strategy. MET-BEX (1:1) and MET-BEX-H2O (1:1:1) were obtained and structurally characterized. The in vitro evaluation results showed that the hygroscopicity of MET was significantly optimized by the salt formation strategy, while the solubility of BEX was improved, which laid the foundation for improving the bioavailability of BEX in vivo. In a mouse model of imiquimod-induced psoriasis with T2DM, MET-BEX ameliorated imiquimod-induced psoriasis morphological features and systematic inflammation and improved glucolipid metabolism. These results showed that the multicomponent drug combination strategy in this study optimized the physicochemical properties of MET and BEX simultaneously, providing a promising candidate therapy for psoriasis with T2DM.

Progress on diagnostic and prognostic markers of pancreatic cancer.

Pancreatic cancer is a malignant disease characterized by low survival and high recurrence rate, whose patients are mostly at the stage of locally advanced or metastatic disease when first diagnosed. Early diagnosis is particularly important because prognostic/predictive markers help guide optimal individualized treatment regimens. So far, CA19-9 is the only biomarker for pancreatic cancer approved by the FDA, but its effectiveness is limited by low sensitivity and specificity. With recent advances in genomics, proteomics, metabolomics, and other analytical and sequencing technologies, the rapid acquisition and screening of biomarkers is now possible. Liquid biopsy also occupies a significant place due to its unique advantages. In this review, we systematically describe and evaluate the available biomarkers that have the greatest potential as vital tools in diagnosing and treating pancreatic cancer.

Increased impact of heat domes on 2021-like heat extremes in North America under global warming.

During summer 2021, Western North America (WNA) experienced an unprecedented heatwave with record-breaking high temperatures associated with a strong anomalous high-pressure system, i.e., a heat dome. Here, we use a flow analog method and find that the heat dome over the WNA can explain half of the magnitude of the anomalous temperature. The intensities of hot extremes associated with similar heat dome-like atmospheric circulations increase faster than background global warming in both historical change and future projection. Such relationship between hot extremes and mean temperature can be partly explained by soil moisture-atmosphere feedback. The probability of 2021-like heat extremes is projected to increase due to the background warming, the enhanced soil moisture-atmosphere feedback and the weak but still significantly increased probability of the heat dome-like circulation. The population exposure to such heat extremes will also increase. Limiting global warming to 1.5 °C instead of 2 °C (3 °C) would lead to an avoided impact of 53% (89%) of the increase in population exposure to 2021-like heat extremes under the RCP8.5-SSP5 scenario.

GABAergic signaling as a potential therapeutic target in cancers.

GABA is the most common inhibitory neurotransmitter in the vertebrate central nervous system. Synthesized by glutamic acid decarboxylase, GABA could specifically bind with two GABA receptors to transmit inhibition signal stimuli into cells: GABAA receptor and GABAB receptor. In recent years, emerging studies revealed that GABAergic signaling not only participated in traditional neurotransmission but was involved in tumorigenesis as well as regulating tumor immunity. In this review, we summarize the existing knowledge of the GABAergic signaling pathway in tumor proliferation, metastasis, progression, stemness, and tumor microenvironment as well as the underlying molecular mechanism. We also discussed the therapeutical advances in targeting GABA receptors to provide the theoretical basis for pharmacological intervention of GABAergic signaling in cancer treatment especially immunotherapy.

Sphingosine kinase 1 promotes growth of glioblastoma by increasing inflammation mediated by the NF-κB /IL-6/STAT3 and JNK/PTX3 pathways.

Glioblastoma (GBM) is the most challenging malignant tumor of the central nervous system because of its high morbidity, mortality, and recurrence rate. Currently, mechanisms of GBM are still unclear and there is no effective drug for GBM in the clinic. Therefore, it is urgent to identify new drug targets and corresponding drugs for GBM. In this study, in silico analyses and experimental data show that sphingosine kinase 1 (SPHK1) is up-regulated in GBM patients, and is strongly correlated with poor prognosis and reduced overall survival. Overexpression of SPHK1 promoted the proliferation, invasion, metastasis, and clonogenicity of GBM cells, while silencing SPHK1 had the opposite effect. SPHK1 promoted inflammation through the NF-κB/IL-6/STAT3 signaling pathway and led to the phosphorylation of JNK, activating the JNK-JUN and JNK-ATF3 pathways and promoting inflammation and proliferation of GBM cells by transcriptional activation of PTX3. SPHK1 interacted with PTX3 and formed a positive feedback loop to reciprocally increase expression, promote inflammation and GBM growth. Inhibition of SPHK1 by the inhibitor, PF543, also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models. In summary, we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM, which may provide opportunities for SPHK1-targeted therapy.

CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial-mesenchymal transition, G2/M phase transition, and PANoptosis.

BACKGROUND: Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. METHODS: By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. RESULTS: Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. CONCLUSIONS: CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.

Systematic pan-cancer analysis identifies APOC1 as an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Apolipoprotein C1 (APOC1) has been found to play an essential part in proliferation and metastasis of numerous cancers, but related mechanism has not been elucidated, especially its function and role in tumor immunity. Through systematic pan-cancer analysis, we identified that APOC1 was closely associated with the infiltration of various immune cells in multiple cancers. Besides, APOC1 was significantly co-expressed with the immune checkpoints, major histocompatibility complex (MHC) molecules, chemokines and other immune-related genes. Furthermore, single-cell sequencing analysis suggested that the vast majority of APOC1 was expressed in macrophages or tumor-associated macrophages (TAMs). Additionally, the expression of APOC1 was significantly related to the prognosis of different cancers. Since APOC1 was most significantly abnormally expressed in renal cell cancer (RCC), subsequent experiments were carried out in RCC to explore the role of APOC1 in tumor immunity. The expression of APOC1 was significantly elevated in the tumor and serum of RCC patients. Besides, APOC1 was mainly expressed in the macrophage and it was closely related to the immune cell infiltration of RCC. Co-culture with RCC cells could induce the generation of TAMs with M2 phenotype which be blocked by silencing APOC1. The expression of APOC1 was elevated in the M2 or TAMs and APOC1 promoted M2 polarization of macrophages through interacting with CD163 and CD206. Furthermore, macrophages overexpressing APOC1 promoted the metastasis of RCC cells via secreting CCL5. Together, these data indicate that APOC1 is an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Effect of Carboxymethyl Chitin on Capsule Formation around Silicone Implants: An In Vivo and In Vitro Study.

BACKGROUND: Capsular contracture is a serious complication that occurs after augmentation mammaplasty. The authors previously identified that carboxymethyl chitin had an inhibitory effect on capsule formation. This study was performed to elucidate the possible molecular mechanisms through which carboxymethyl chitin inhibits the formation of a capsule around silicone implants. METHODS: In this study, the authors cultured human dermal fibroblasts and treated them with carboxymethyl chitin in vitro. The difference in proliferation between treated and untreated cells was analyzed through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Protein levels of transforming growth factor beta-1 and alpha smooth muscle actin (α-SMA) were examined by Western blot analysis. Expression levels of type I and type III collagen were checked by enzyme-linked immunosorbent assay. In vivo, silicone implants were placed under the pectoralis muscle in 12 female rabbits. The thickness of the capsule was measured by histologic analysis, and the effect of carboxymethyl chitin on α-SMA, collagen type I and III expression levels was evaluated by real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence analysis. RESULTS: In the in vitro study, we confirmed that carboxymethyl chitin inhibited the proliferation of fibroblasts. The protein expression levels of collagen type I, transforming growth factor beta-1, and α-SMA were inhibited by carboxymethyl chitin treatment. In vivo, carboxymethyl chitin treatment reduced capsular thickness and the expression of α-SMA and collagen types I and III in capsules around silicone implants. CONCLUSION: The authors' results showed that carboxymethyl chitin could influence capsule formation around silicone implants by inhibiting the fibroblast activity, interrupting fibroblast-to-myofibroblast differentiation, and decreasing collagen synthesis. CLINICAL RELEVANCE STATEMENT: Carboxymethyl chitin influence capsule formation around silicone implants. Although more clinical studies are needed to verify the effect of carboxymethyl chitin on capsular contracture, the authors believe that it will play an effective role in the clinical application of reducing the occurrence of capsular contracture.