Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/β-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-β (TGF-β)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells.

Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response.

Cucurbitacin B (CuB, C32H46O8), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely distributed in a variety of plants and mainly isolated from plants in the Cucurbitaceae family. CuB is mostly obtained from the pedicel of Cucumis melo L. Modern pharmacological studies have confirmed that CuB has a broad range of pharmacological activities, with significant therapeutic effects on a variety of diseases including inflammatory diseases, neurodegenerative diseases, diabetes mellitus, and cancers. In this study the PubMed, Web of Science, Science Direct, and China National Knowledge Infrastructure (CNKI) databases were searched from 1986 to 2022. After inclusion and exclusion criteria were applied, 98 out of 2484 articles were selected for a systematic review to comprehensively summarize the pharmacological activity, toxicity, and pharmacokinetic properties of CuB. The results showed that CuB exhibits potent anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer activities mainly via regulating various signaling pathways, such as the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), nuclear factor (NF)-κB, AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt, focal adhesion kinase (FAK), Notch, and Hippo-Yes-associated protein (YAP) pathways. Studies of its toxicity and pharmacokinetic properties showed that CuB has non-specific toxicity and low bioavailability. In addition, derivatives and clinical applications of CuB are discussed in this paper. 

Cucurbitacin B: A Review of its Pharmacology, Toxicity, and Pharmacokinetics.

Natural products as chemo-radiation therapy sensitizers in cancers.

Cucurbitacin B (CuB), extracted from muskmelon pedicel, is a widely available triterpenoid molecule that exerts influence on various biological activities. Modern pharmacological studies have found that cucurbitacin B has many kinds of pharmacological anti-tumor and anti-metastasis functions.To explore the mechanism of anti-tumor and anti-metastasis effect of cucurbitacin B.The effect of cucurbitacin B on the growth of HCT116 and CT-26 was detected by CCK8; apoptosis was determined by flow cytometry and colony formation; the expression of apoptosis-related protein Bax, Bcl-2 and Cleaved-caspase-3 were examined by western Blot. To explore the underlying mechanism of cucurbitacin B against tumor, the Western blot, Immunofluorescence staining, Microscale Thermophoresis assays were used. Multiple molecular biology experiments were applied to validate the effect of polarization of cucurbitacin B-induced macrophages. The supernatant of Cucurbitacin B-induced macrophages and colon cells were co-cultured in vitro, and then transwell and wound healing assay were employed to the related phenotypes. C57BL/6 and BALB/c murine colon cancer model were also used to study the drug effects in vivo.Cucurbitacin B distinctly induced the apoptosis of CRC cells. It was observed that cucurbitacin B not only inhibited the phosphorylation of JAK2 and STAT3, but also the translocation from the cytosol to the nucleus. Meanwhile, we observed that cucurbitacin B is bound to STAT3. Further experimentation demonstrated that cucurbitacin B reduced the polarization of M2 macrophage by down-regulating JAK2/STAT3 signaling pathway. Cucurbitacin B-induced M2-like macrophages were found to diminish the migration of CRC cells. In vitro study suggested that cucurbitacin inhibited the CRC cells proliferation via JAK2/STAT3 and suppressed the cell migration by suppressing M2-like macrophages polarization. Consistent with in vitro results, the cucurbitacin B therapy significantly inhibited tumor growth and metastasis in mice. Moreover, in vivo the treatment with cucurbitacin B enhanced anti-tumor immunity by regulating M2-like macrophages and promoted the expression of CD4 and CD8 in tumor microenvironment.Our results proved that cucurbitacin B might be a potential candidate agent for adjuvant therapy in the process of CRC growth and metastasis. 

Cucurbitacin B controls M2 macrophage polarization to suppresses metastasis via targeting JAK-2/STAT3 signalling pathway in colorectal cancer

How to promote sustainable land use in Hangzhou Bay, China? A decision framework based on fuzzy multiobjective optimization and spatial simulation

Cancer stem cells (CSCs), a crucial cancer cell subpopulation, possess stemness phenotypic characteristics. Cucurbitacin B (CuB), a tetracyclic triterpenoid isolated from Cucurbitaceae, exerts widely pharmacological activities in many diseases. The aim of this study was to enrich, identify liver CSCs and investigate antitumor effects of CuB as well as explore the underlying molecular mechanisms in these liver CSCs. HepG2 cell lines were used for the enrichment of liver CSCs by serum-free medium culture and magnetic-activated cell sorting. The CSC characteristics were analyzed by immunofluorescent staining, sphere-forming, western blot and xenograft tumorigenicity assay. CuB' antitumor effects and underlying molecular mechanism were measured by cell counting kit-8, colony formation, sphere-forming, cell cycle, xenograft and western blot assay. Our results showed that we could enrich 97.29% CD133+ HepG2 cells, which possessed CSC characteristics including re-renewal capacity, proliferative ability, sorafenib resistance, overexpressed stemness-related molecules and enhanced tumorigenic potential. Furthermore, we also found that CuB inhibited cell viability, sphere formation, colony formation and arrested cell cycle at G2/M phase as well as sensitized CD133+ HepG2 cells to sorafenib in vitro and in vivo. Western blot assay indicated that CuB inhibited expression levels of cyclin B1, CDK1, CD133, p-JAK2 and p-STAT3. In conclusion, our findings indicated that CuB could exhibit antitumor effects on CD133+ HepG2 CSCs by inhibiting the Janus kinase 2/signal transducers and activators of transcription-3 signaling pathway, expanding basic and preclinical investigations on liver CSCs.

Cucurbitacin B exhibits antitumor effects on CD133+ HepG2 liver cancer stem cells by inhibiting JAK2/STAT3 signaling pathway.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/2211-5463.13035

Sorafenib and CuB exert synergistic antitumor effects against hepatocellular carcinoma cells via inhibition of STAT3 phosphorylation.

Schizophrenia, a common mental disorder, has a tremendous impact on the health and economy of people worldwide. Evidence suggests that the microbial-gut-brain axis is an important pathway for the interaction between the gut microbiome and the development of schizophrenia. What is not clear is how changes in the gut microbiota composition and structure during antipsychotic treatment improve the symptoms of schizophrenia. In this study, 25 patients with schizophrenia were recruited. Their fecal samples were collected before and after hospital treatment for 14–19 days. The composition and structure of the intestinal microbiota were evaluated by 16S rRNA sequencing analysis, and the results showed significant differences in fecal microbiota before and after treatment. Firmicutes (relative abundances of 82.60 and 86.64%) and Gemminger (relative abundances of 14.17 and 13.57%) were the first dominant species at the phylum and genus levels, respectively. The random forest algorithm and co-occurrence network analysis demonstrated that intestinal flora (especially the core species ASV57) could be used as biomarkers to distinguish different clinical states and match treatment regimens accordingly. In addition, after fecal microbiota transplantation, antibiotic-treated recipient mice showed multiple behavioral improvements. These included decreased psychomotor hyperactivity, increased social interaction, and memory. In conclusion, this study suggests that differences in the composition and structure of gut microbiota after treatment are associated with the development and severity of schizophrenia. Results may provide a potential target for the treatment of this disorder.

/pdf/intestinal-microbes-in-patients-with-schizophrenia-fxh15lc7.pdf

Intestinal Microbes in Patients With Schizophrenia Undergoing Short-Term Treatment: Core Species Identification Based on Co-Occurrence Networks and Regression Analysis

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How to promote sustainable land use in Hangzhou Bay, China? A decision framework based on fuzzy multiobjective optimization and spatial simulation

Cucurbitacin B exhibits antitumor effects on CD133+ HepG2 liver cancer stem cells by inhibiting JAK2/STAT3 signaling pathway.

Sorafenib and CuB exert synergistic antitumor effects against hepatocellular carcinoma cells via inhibition of STAT3 phosphorylation.

Intestinal Microbes in Patients With Schizophrenia Undergoing Short-Term Treatment: Core Species Identification Based on Co-Occurrence Networks and Regression Analysis