The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated with the earth's daily rotation and light/dark cycle. Such rhythms reflect the existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt the internal environment with the external cues. At the molecular level, the circadian clock consists of multiple sets of transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, in addition to their primary role as generator of circadian rhythm, the biological clock plays a key role in controlling physiological functions of almost all tissues and organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair and response, angiogenesis, metabolic and redox homeostasis, to inflammatory and immune response. In this review, we summarize findings showing the crosstalk between the circadian molecular clock and some key intracellular pathways, describing a scenario wherein their reciprocal regulation impinges upon several aspects of mammalian physiology. Moreover, based on evidence indicating that circadian rhythms can be challenged by environmental factors, social behaviors, as well as pre-existing pathological conditions, we discuss implications of circadian misalignment in human pathologies, such as cancer and inflammatory diseases. Accordingly, disruption of circadian rhythm has been reported to affect several physiological processes that are relevant to human diseases. Expanding our understanding of this field represents an intriguing and transversal medicine challenge in order to establish a circadian precision medicine. 

/pdf/molecular-regulations-of-circadian-rhythm-and-implications-246ceh4g.pdf

Molecular regulations of circadian rhythm and implications for physiology and diseases

Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting "undruggable" proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein-protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others. 

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Circadian regulation of cancer cell and tumor microenvironment crosstalk

Abstract Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs. 

Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer

Abstract Circadian rhythms are present in almost all cells and play a crucial role in regulating various biological processes. Maintaining a stable circadian rhythm is essential for overall health. Disruption of this rhythm can alter the expression of clock genes and cancer-related genes, and affect many metabolic pathways and factors, thereby affecting the function of the immune system and contributing to the occurrence and progression of tumors. This paper aims to elucidate the regulatory effects of BMAL1, clock and other clock genes on immune cells, and reveal the molecular mechanism of circadian rhythm’s involvement in tumor and its microenvironment regulation. A deeper understanding of circadian rhythms has the potential to provide new strategies for the treatment of cancer and other immune-related diseases. 

Circadian rhythm regulates the function of immune cells and participates in the development of tumors.

LINC00624/TEX10/NF-κB axis promotes proliferation and migration of human prostate cancer cells.

AURKA, a cell cycle-regulated kinase, is associated with malignant transformation and progression in many cancer types. We analyzed the expression change of AURKA in pan-cancer and its effect on the prognosis of cancer patients using the TCGA dataset. We revealed that AURKA was extensively elevated and predicted a poor prognosis in most of the detected cancer types, with an exception in colon cancer. AURKA was elevated in colon cancer, but the upregulation of AURKA indicated better outcomes of colon cancer patients. Then we revealed that undermethylation of the AURKA gene and several transcription factors contributed to the upregulation of AURKA in colon cancer. Moreover, we demonstrated that AURKA overexpression promoted the death of colon cancer cells induced by Oxaliplatin, whereas knockdown of AURKA significantly weakened the chemosensitivity of colon cancer cells to Oxaliplatin. Mechanistically, AURKA inhibited DNA damage response by suppressing the expression of various DNA damage repair genes in a TP53-dependent manner, which can partly explain that ARUKA is associated with a beneficial outcome of colon cancer. This study provided a possibility to use AURKA as a biomarker to predict the chemosensitivity of colon cancer to platinum in the clinic.

/pdf/aurka-increase-the-chemosensitivity-of-colon-cancer-cells-to-3mapepctpp.pdf

AURKA Increase the Chemosensitivity of Colon Cancer Cells to Oxaliplatin by Inhibiting the TP53-Mediated DNA Damage Response Genes.

Transcription factor c-Myc plays a critical role in various physiological and pathological events. c-Myc gene rearrangement is closely associated with multiple myeloma (MM) progression and drug resistance. Thereby, targeting c-Myc is expected to be a useful therapeutic strategy for hematological disease, especially in MM.Molecular docking-based virtual screening and dual-luciferase reporter gene assay were used to identify novel c-Myc inhibitors. Cell viability and flow cytometry were performed for evaluating myeloma cytotoxicity. Western blot, immunofluorescence, immunoprecipitation, GST pull down and Electrophoretic Mobility Shift Assay were performed for protein expression and interaction between c-Myc and Max. c-Myc downstream targets were measured by Q-PCR and Chromatin immunoprecipitation methods. Animal experiments were used to detect myeloma xenograft and infiltration in vivo.We successfully identified a novel c-Myc inhibitor D347-2761, which hindered the formation of c-Myc/Max heterodimer and disturbed c-Myc protein stability simultaneously. Compound D347-2761 dose-and time-dependently inhibited myeloma cell proliferation and induced apoptosis. Dual knockout Bak/Bax partially restored D347-2761-mediated cell death. Additionally, compound D347-2761 could, in combination with bortezomib (BTZ), enhance MM cell DNA damage and overcome BTZ drug resistance. Our in vivo studies also showed that compound D347-2761 repressed myeloma growth and distal infiltration by downregulating c-Myc expression. Mechanistically, novel dual-targeting c-Myc inhibitor D347-2761 promoted c-Myc protein degradation via stimulating c-Myc Thr58 phosphorylation levels, which ultimately led to transcriptional repression of CDK4 promoter activity.We identified a novel dual-targeting c-Myc small molecular inhibitor D347-2761. And this study may provide a solid foundation for developing a novel therapeutic agent targeting c-Myc. Video Abstract. 

/pdf/novel-dual-targeting-c-myc-inhibitor-d347-2761-represses-1o2byh0e.pdf

Novel dual-targeting c-Myc inhibitor D347-2761 represses myeloma growth via blocking c-Myc/Max heterodimerization and disturbing its stability

Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.

/pdf/identifying-potential-prognosis-markers-in-hepatocellular-27c635po.pdf

Identifying potential prognosis markers in hepatocellular carcinoma via integrated bioinformatics analysis and biological experiments

Despite apparently having completed surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying the drivers of relapse, who benefits from adjuvant therapy, and novel targets in this setting. Although emerging evidence has suggested a strong link between the pentose phosphate pathway (PPP) and cancer, the role of transketolase (TKT), an enzyme in the nonoxidative branch of the PPP that connects PPP and glycolysis, remains obscure in Lung adenocarcinoma (LUAD). In this study, TKT expression was first identified in The Cancer Genome Atlas (TCGA) and then validated with our database. TKT was upregulated at protein levels in cancer compared with normal tissues (P <0.05), and high TKT expression was associated with advanced tumor stage in our cohorts. Besides, TKT inhibitor promotes tumor cell apoptosis and cell cycle blockade. Clearly, TKT plays a critical role in LUAD progression and prognosis and could be a potential biomarker for prediction of recurrence after lung cancer resection.

/pdf/transketolase-serves-as-a-biomarker-for-poor-prognosis-in-cltniqqa.pdf

Transketolase Serves as a Biomarker for Poor Prognosis in Human Lung Adenocarcinoma

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