Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency.

BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNase H2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results provide a mechanistic basis for how BRCA2 shields against genomic instability by preventing HO-TRCs through both direct and indirect means occurring at predetermined genomic sites based on the pre-cancer transcriptome.

Hypoxia promotes metastasis by relieving miR-598-3p-restricted glycolysis in gastric cancer.

The activation of glycolysis, particularly in the context of reprogrammed energy metabolism, is increasingly recognized as a significant characteristic of cancer. However, the precise mechanisms by which glycolysis is promoted in metastatic gastric cancer cells under normal oxygen conditions remain poorly understood. MicroRNAs (miRNAs) play a crucial role in the development of malignant phenotypes in gastric cancer. Nevertheless, our understanding of the specific involvement of miRNAs in hypoxia-induced metabolic shifting and the subsequent metastatic processes is limited. Hypoxia-induced downregulation of miR-598-3p mechanistically leads to the upregulation of RMP and IGF1r, thereby promoting glycolysis. Either overexpression of miR-598-3p or R406 treatment effectively suppresses the metastasis of gastric cancer cells both in vitro and in vivo. Collectively, the depletion of miR-598-3p alters glucose metabolism from oxidative phosphorylation to glycolysis, thereby exacerbating the malignancy of gastric cancer cells. The present findings indicate a potential target for the development of therapeutics against gastric cancers with increased miR-598-3p expression.

Research progress on ethnobotany, phytochemistry, pharmacological action, and applications of Engelhardia roxburghiana Wall: a review.

OBJECTIVES: Engelhardia roxburghiana Wall is a plant of the Juglandaceae family, and its leaves is the main part used as a medicine. It is used to relieve heat and pain, gasification, and dampness. The purpose of this review is to provide a systematic review about the botany, traditional uses, phytochemistry, pharmacology, and toxicology of this plant. KEY FINDINGS: Many compounds have been isolated and identified from the plant, including flavonoids, triterpenoids, steroids, quinones, essential oils, and other types of chemical constituents. Extensive pharmacological activities of the extracts or compounds of E. roxburghiana Wall in vivo and in vitro were mainly confirmed, including anti-cancer, anti-diabetic, anti-inflammatory, and anti-allergic effects. SUMMARY: In this paper, the botany, traditional uses, phytochemistry, and pharmacology of E. roxburghiana Wall were reviewed. In the future, E. roxburghiana Wall needs further study, such as paying more attention to quality control and the utilization on agriculture. In addition, discussing the medicinal components of decoction as well as the toxicity will also contribute to the progress of clinical trial studies.

Ubiquitin E3 ligase SPOP is a host negative regulator of enterovirus 71-encoded 2A protease.

IMPORTANCE: EV71 poses a significant health threat to children aged 5 and below. The process of EV71 infection and replication is predominantly influenced by ubiquitination modifications. Our previous findings indicate that EV71 prompts the activation of host deubiquitinating enzymes, thereby impeding the host interferon signaling pathway as a means of evading the immune response. Nevertheless, the precise mechanisms by which the host employs ubiquitination modifications to hinder EV71 infection remain unclear. The present study demonstrated that the nonstructural protein 2Apro, which is encoded by EV71, exhibits ubiquitination and degradation mediated by the host E3 ubiquitin ligase SPOP. In addition, it is the first report, to our knowledge, that SPOP is involved in the host antiviral response.

mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death.

Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, regresses established polyps, and prolongs lifespan of APCMin/+ mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated ß-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control.

Investigation of the Effects of Glabridin on the Proliferation, Apoptosis, and Migration of the Human Colon Cancer Cell Lines SW480 and SW620 and Its Mechanism Based on Reverse Virtual Screening and Proteomics.

Colon cancer is a relatively common malignant tumor of the digestive tract. Currently, most colon cancers originate from adenoma carcinogenesis. By screening various licorice flavonoids with anticancer effects, we found that glabridin (GBN) has a prominent anticolon cancer effect. First, we initially explored whether GBN can inhibit proliferation, migration, and invasion and induce apoptosis in SW480 and SW620 cells. Next, we exploited reverse virtual and proteomics technologies to screen out closely related target pathways on the basis of a drug and target database. At the same time, we constructed the structure of the GBN target pathway in colon cancer. We predicted that GBN can regulate the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of the rapamycin pathway (mTOR) pathway to fight colon cancer. Finally, through Western blot analysis and qRT-PCR, we verified that the expression levels of the PI3K, AKT, and mTOR proteins and genes in this pathway were significantly reduced after GBN administration. In short, the promising discovery of the anticolon cancer mechanism of GBN provides a reliable experimental basis for subsequent new drug development.

Oncopreventive and Oncotherapeutic Potential of Licorice Chalcone Compounds: Molecular Insights.

BACKGROUND: Licorice is an important traditional Chinese medicine commonly used in clinical practice and contains more than 300 flavonoids. Chalcone is one of the main types of flavonoids with a wide range of biological functions and pharmacological activities. In the anticancer research, chalcone compounds have shown excellent performance. OBJECTIVE: This review aims to summarize the biosynthetic pathway and pharmacokinetics of chalcone from licorice and provide evidence for the anticancer effects of chalcone and the underlying mechanisms involved. METHODS: For this review, the following databases were consulted: the PubMed Database (https://pubmed.ncbi.nlm.nih.gov), Chinese National Knowledge Infrastructure (http:// www.cnki.net), National Science and Technology Library (http://www.nstl.gov.cn/), Wanfang Data (http://www.wanfangdata.com.cn/), and the Web of Science Database (http:// apps.webofknowledge.com/). RESULTS: To date, about 56 chalcones have been isolated and identified from licorice, 14 of which have antitumor effects. These chalcones have a wide range of biological activities and can inhibit the viability, proliferation, and migration of cancer cells by blocking the cancer cell cycle, thus inducing apoptosis and autophagy. However, the molecular mechanism of the anticancer effects of chalcone is not fully understood. CONCLUSION: In this paper, the molecular mechanism of chalcone regulating different types of cancer is reviewed in detail from the biosynthetic pathway. This comprehensive review article summarizes the biosynthetic pathway and pharmacokinetics of chalcone from the traditional Chinese medicine licorice and provides evidence for the potential anticancer effects of chalcone and the respective mechanisms of action. This paper also provides a basis for structural modification, biosynthesis, and new drug development of chalcone compounds in Glycyrrhiza uralensis.

Pulsatilla chinensis (Bge.) Regel: A Systematic Review on Anticancer of Its Pharmacological Properties, Clinical Researches and Pharmacokinetic Studies.

Pulsatilla chinensis (Bge.) Regel (PC) is one of the most commonly used Chinese medicines and has a history of thousands of years. This article reviews the research results of anti-cancer activity and its mechanism of action obtained from experimental, clinical, pharmacokinetic and bioinformatic studies in recent years. A large number of studies have shown that PC exerts had anti-cancer effects on different types of tumor cells by inhibiting cell proliferation, inducing apoptosis, inhibiting cell cycle and energy metabolism, inducing autophagy, and inhibiting angiogenesis. The literature has shown that PC can trigger the expression of autophagy-related molecules, activate the mitochondrial apoptotic pathway, inhibit the phosphorylation of PI3K downstream factors, down-regulate the expression of glycolysis-related proteins, and regulate a series of cancer-related signal pathways and proteins. The molecular mechanisms involved in PC include signal pathways such as Notch, PI3K/AKT/m TOR, AKT/mTOR, and MEK/ERK. The article also discusses the derivatives of the active ingredients in PC, which greatly improved the anti-cancer effect. In conclusion, this review provides a comprehensive overview of the biological effects and mechanisms of PC against cancer. The analysis of the literature shows that PC can be used as a potential drug candidate for the treatment of cancer.

Saikosaponin B4 Suppression Cancer Progression by Inhibiting SW480 and SW620 Cells Proliferation via the PI3K/AKT/mTOR Pathway in Colon Cancer.

BACKGROUND: Colon cancer is a gastrointestinal malignancy with high incidence and poor prognosis. OBJECTIVE: Saikosaponin B4 (SSB4) is a monomeric component of the Traditional Chinese medicine (TCM), Bupleurum. The current study investigates the therapeutic effect and mechanisms of SSB4 in colon cancer. METHODS: The proliferation of two colon cancer cell lines, SW480 and SW620, were assessed using CCK8 and expression of regulatory molecules, including Bax, Caspase3, Caspase9, Cleaved Caspase3, Cleaved Caspase9 and Bcl2 by flow cytometry and Western blotting. RESULTS: Survival rates, assessed by CCK8, of SW480 and SW620 cells decreased significantly when the SSB4 concentration was in the range 12.5-50 µg/ml. Flow cytometry measurements indicated apoptosis rates of 55.07% ± 1.63% for SW480 cells and 33.07% ± 1.28% for SW620 cells treated with 25 µg/ml SSB4. Western blotting revealed upregulation of the proapoptotic proteins, Bax, Caspase3, Caspase9, Cleaved Caspase3 and Cleaved Caspase9, and downregulation of the anti-apoptotic protein, Bcl2, in the presence of SSB4. Network pharmacology and molecular docking predicted that the PI3K/Akt/mTOR pathway might be the main regulatory target for the antitumor effect of SSB4. Further Western blotting experiments showed that SSB4 downregulated (p < 0.01) expression of PI3K, Akt, mTOR and the phosphorylated proteins, P-PI3K, P-Akt and P-MTOR. Expression of PI3K, Akt and mTOR mRNA was found to be downregulated by SSB4 (P < 0.01) as the result of RT-PCR measurements. CONCLUSION: SSB4 is a potent anti-colon cancer agent. Its effects are likely to be mediated by suppression of the PI3K/AKT/mTOR pathway.

Hyperoside: A Review of Its Structure, Synthesis, Pharmacology, Pharmacokinetics and Toxicity.

Hyperoside is an active ingredient in plants, such as Hypericum monogynum in Hypericaceae, Crataegus pinnatifida in Rosaceae and Polygonum aviculare in Polygonaceae. Its pharmacologic effects include preventing cancer and protecting the brain, neurons, heart, kidneys, lung, blood vessels, bones, joints and liver, among others. Pharmacokinetic analysis of hyperoside has revealed that it mainly accumulates in the kidney. However, long-term application of high-dose hyperoside should be avoided in clinical practice because of its renal toxicity. This review summarises the structure, synthesis, pharmacology, pharmacokinetics and toxicity of hyperoside.

The traditional uses, phytochemistry, pharmacology and toxicology of Dictamnus dasycarpus: a review.

OBJECTIVES: Dictamnus dasycarpus is a plant of the Rutaceae family, and its root bark is the main part used as a medicine, named 'Bai-Xian-Pi'. It is used to clear away heat, remove dampness, and dispel wind and also used for detoxification. The purpose of this review is to provide a systematic review about the botany, traditional uses, phytochemistry, pharmacology and toxicology of this plant. KEY FINDINGS: More than 200 compounds have been isolated and identified from the plant, including alkaloids and their glycosides, terpenoids and their derivatives and phenylpropanoids. Extensive pharmacological activities of the extracts or compounds of D. dasycarpus in vivo and in vitro were mainly confirmed, including anti-inflammatory activity, protecting cardiovascular activity, improving liver injury and anti-cancer activity. SUMMARY: In this paper, the botany, traditional uses, phytochemistry and pharmacology of D. dasycarpus were reviewed. In the future, D. dasycarpus needs further study, such as paying more attention to quality control and the utilization on agriculture. In addition, discussing the medicinal components of decoction as well as the toxicity will also contribute to the progress of clinical trial studies.

A Review on a Medicinal and Edible Plant: Aralia elata (Miq.) Seem.

Aralia elata (Miq.) Seem. (Araliaceae), which is the key point of this review, is a precious wild vegetable that has served in the treatment of diabetes and rheumatoid arthritis in traditional folk medicine in East Asia (China, Japan, Korea, Russia). This review aims to overview the results of the current research related to Aralia elata (Miq.) Seem., with particular emphasis on chemical composition and biological activity. The existing research has been searched and summarized through the database, and it has been found that it has a certain therapeutic effecta on a variety of chronic diseases such as: malignant tumors, cardio-cerebrovascular disease, diabetes, and its complications, etc. Additionally, it is loved by people in East Asia due to its rich taste as a wild vegetable. In conclusion, it offers the possibility of developing innovative pharmacological drugs as well as healthy food. Thus, it is critical to prove its validity and clarify the exact action mechanisms that promote it as a pharmacological drug. This review is expected to provide direction for future research.

Cynanchum paniculatum (Bunge) Kitag. ex H. Hara: A review of its ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum paniculatum (Bunge) Kitag. ex H. Hara (C. paniculatum), is a broadly used traditional medicinal plant by East Asians. The roots and rhizomes of this herb were named 'Xu-Chang-Qing' since the Qin or Han Dynasty (B.C.221-220) in China. It is pungent and warm in nature and associated with the liver and stomach meridians. Moreover, the efficacy of this herb are dispelling wind, resolving dampness, relieving pain and itching. It is used for treating the onset of rheumatic arthralgia, stomachache, toothache, lumbago, soft tissue injury, rubella and eczema. AIM OF THE STUDY: The purpose of this paper is to provide a systematic review about the botany, traditional uses, phytochemistry and pharmacology of C. paniculatum on the strength of the studies in the past two decades. MATERIALS AND METHODS: A comprehensive search on previous literature was conducted on databases such as Web of Science, Pubmed, Sciencedirect, American Chemical Society (ACS), Google scholar and China national knowledge internet (CNKI). The search was based on the botany, traditional uses, phytochemistry and pharmacology of C. paniculatum. The key search words were 'Cynanchum paniculatum' and 'Radix Cynanchi Paniculati'. In addition, some published books were searched for more information on the herb. RESULTS: Over 150 compounds have been isolated and identified from C. paniculatum, including C21 steroids, volatile oils, carbohydrates and phenanthroindolizidine alkaloids. Extensive pharmacological activities of the extracts or compounds of C. paniculatum in vivo and in vitro were confirmed including anti-inflammatory, anti-nociceptive, sedative antiviral, antitumor, neuroprotective, treating snake bites, immunomodulatory, anti-radiation, vasodilatory, acaricidal potentials and anti-adipogenic activities. CONCLUSIONS: In this paper, the botany, traditional uses, phytochemistry and pharmacology of C. paniculatum were reviewed. This herb has long been used as traditional medicine. It was reported with numerous chemical ingredients and various pharmacological activities with anti-inflammatory, antitumor, neuroprotection, etc. In the future, C. paniculatum still needs further study, such as identifying the active compounds, clarifying the pharmacological mechanisms, discussing quality and safety.