Herein, a novel photocatalytic 6-exo-trig difluoromethylation cyclization and subsquent domino O2 trap version is described. This protocol allows efficient access to structurally diverse 4-(hydroxymethyl)-gem-difluoro-quinolines under mild conditions. Broad substrate scope, good functional group compatibility, biologically active molecule modification, scale-up operation, and further derivatization demonstrate the utility of this protocol. A radical cyclization route was proposed based on radical inhibition experiments, deuterium-labeled experiments, visible-light irradiation on-off test, apparent quantum efficiency (AQE) calculation, and Stern-Volmer fluorescence quenching experiments.

Loss of breast cancer susceptibility gene 2 (BRCA2) function was found to exacerbate doxorubicin-mediated cardiomyocyte apoptosis and promote heart failure progression. We hypothesized that upregulation of BRCA2 may alleviate hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy was established in mice via chronic angiotensin II (Ang II) administration (1.44 mg/kg/day) using osmotic minipumps. Cardiac BRCA2 expression was significantly downregulated in Ang II-treated mice. Cardiac hypertrophy triggered by Ang II in mice was significantly attenuated upon BRCA2 overexpression. Similarly, in cultured primary cardiomyocytes, Ang II-induced hypertrophic responses were suppressed by BRCA2 upregulation. The cardiac fibrosis was significantly attenuated after upregulation of BRCA2 in Ang II-induced hypertrophic cardiomyopathy. The myocardial inflammatory response to Ang II, characterized by elevated interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels, was markedly reduced with BRCA2 overexpression. The apoptotic biomarkers including Bax and cleaved caspase 3 (CC3) increased in the heart of hypertrophic cardiomyopathy, and attenuated after upregulation of BRCA2. These results indicated that upregulation of BRCA2 could improve hypertrophic cardiomyopathy. BRCA2 alleviated cardiac hypertrophy via attenuation of inflammation and apoptosis.

Herein, a novel visible-light-induced sulfonylation cyclization for the facile construction of challenging carbazole-fused eight-membered N-heterocycles has been described for the first time under additive-, base-, and external photosensitizer-free conditions. Mild reaction conditions, good functional group compatibility, and scalability reaction demonstrate the potential for further industrial application. A radical route is proposed based on radical inhibition experiments, visible-light irradiation on-off test, apparent quantum efficiency calculation, and fluorescence quenching studies.

IRE1α and its downstream XBP1 signal is the most conserved unfolded protein response pathway that cells utilize to combat endoplasmic reticulum stress, also known to be utilized by tumor cells to adapt to harsh environment, leading to tumor progression. Several inhibitors against IRE1α have been developed, some of which show promising effect in clinical trial for cancer therapy, but none of them have been used in practice. Considering that hyper-activation of IRE1α induces cell death, we hypothesize that activation of IRE1α could be an alternative way for tumor suppression. Here, we identified divalent manganese ion as a potent activator to IRE1α, which interacts with the cytosolic part of IRE1α directly, augmenting the downstream pro-apoptotic pathway but not the pro-survival outcome. Mn2+ limits tumor growth in xenograft model in an IRE1α-dependent way. Our finding suggests pharmacological activation of IRE1α as an underestimated but promising way in cancer therapy.

A novel visible-light-induced sulfonylation cyclization to indole-fused medium-sized N-heterocycles was established under room temperature with biomass-derived 2-Me-THF as the solvent. This reaction proceeds in the absence of external photocatalyst, additive, metal salts, and base. Broad substrate scope, good functional group compatibility, and large-scale synthesis and derivatization via iodination, nitration, chlorination, cyanation, and selenylation demonstrate the utility of this protocol. A radical cyclization route was proposed based on radical inhibition experiments, visible-light irradiation on-off test, apparent quantum efficiency calculation, and UV-vis absorption spectroscopic studies.

Molecules containing ether skeletons are widely present in drugs, natural products, functional materials, and life science. Direct C(sp(3))-H bond ether functionalization is considered a powerful strategy for the construction of novel ether derivatives. Photo-/electro-chemical technology is a relatively green and sustainable synthesis method, which opens up a broad application prospect in the field of direct functionalization of C(sp(3))-H bonds. In recent years, photo-/electro-mediated C(sp(3))-H bond alkylation, arylation, alkynylation, esterification, mercaptoylation, sulfidation, and amination of ethers have been extensively studied. In this review, the research progress of photo-/electro-mediated C(sp(3))-H bond functionalization of ether compounds from 2014 to 2023 is systematically reviewed, and the scope, limitations, and mechanisms for some reactions are discussed.

Myeloid-derived suppressor cells(MDSCs)constitute a crucial component of the immunosuppressive tumor micro-environment.1 Prostaglandin E2 receptor 4(EP4)is involved in regulating immunosuppressive MDSC differentiation and is emerging as a promising target for cancer immunotherapy.2 No EP4 antagonists have been approved for anti-tumor therapy,underscoring the urgent requirement for the dis-covery of novel EP4 antagonists.G protein and β-arrestin represent two classical downstream pathways for EP4.The inactivity of G protein and β-arrestin serves as a readout to indicate EP4 antagonism,providing a rationale for estab-lishing EP4 drug screening platforms.From a broad perspective on the history of G protein-coupled receptor(GPCR)drug discovery,using a β-arrestin-based drug screening strategy may offer greater advantages over G protein strategies,especially for the GPCRs that have not been proven on which G proteins they bind.Several cellular assays for the detection of GPCR/β-arrestin interaction have been established,including the PRESTO-Tango assay and fluorescent β-arrestin labeling assay.However,these assays are not suitable for the real-time dynamic detection of GPCR-β-arrestin signaling.In this study,we aimed to develop a novel real-time β-arrestin recruitment assay for EP4 re-ceptor and to identify a potent EP4 antagonist that could attenuate the immunosuppressive effects of MDSCs.

AbstractBackgroundChronic infections by pathogenic microorganisms play a significant role in cancer development, disrupting the body's immune system and microenvironment. This interference impairs the body's ability to eliminate these microorganisms promptly, allowing them to persist by evading immune defenses.AimsThis study aimed to explore how chronic pathogenic infections influence the immune microenvironment, impacting tumorigenesis, cancer progression, and treatment strategies. Additionally, it seeks to investigate the effects of these infections on specific immune checkpoints and identify potential targets for immunotherapy.MethodsWe conducted searches, readings, and detailed analyses of key terms in databases like PubMed and Web of Science to evaluate the impact of chronic infections by pathogenic microorganisms on the immune microenvironment.ResultsOur analysis demonstrates a significant association between persistent chronic infections by pathogenic microorganisms and tumorigenesis. Notable impacts on the immune microenvironment include changes in immune cell function and the regulation of immune checkpoints, offering insights into potential targets for cancer immunotherapy.DiscussionThis study highlights the complex relationship between chronic infections and cancer development, presenting new opportunities for cancer immunotherapy by understanding their effects on the immune microenvironment. The influence of these infections on immune checkpoints emphasizes the crucial role of the immune system in cancer treatment.ConclusionChronic infections by pathogenic microorganisms greatly affect the immune microenvironment, tumorigenesis, and cancer treatment. Unraveling the underlying mechanisms can unveil potential targets for immunotherapy, improving our comprehension of the immune response to cancer and potentially leading to more effective cancer treatments in the future.

An efficient Au(I)-catalyzed intramolecular cascade reaction of tertiary enamides tethered an alkynyl group has been developed. The process is composed of a propargyl-claisen rearrangement and 5-exo-dig cyclization. This protocol provided a powerful method for the preparation of a variety of pentasubstituted pyrroles derivatives with excellent functional group tolerance in excellent yields. Scale-up experiment and chemical transformations of products exhibited the versatility of tertiary enamides in organic synthesis again.

Recent studies reveal that tumor microenvironment contributes to breast cancer (BRCA) development, progression, and therapeutic response. However, the contribution of the tumor microenvironment-related genes in routine diagnostic testing or therapeutic decision making for BRCA remains elusive. Immune/stromal/ESTIMATE scores calculated by the ESTIMATE algorithm quantify immune and stromal components in a tumor, and thus can reflect tumor microenvironment. To investigate the association of the tumor microenvironment-related genes with invasive BRCA prognosis, here we analyzed the immune/stromal/ESTIMATE scores in combination with The Cancer Genome Atlas (TCGA) database in invasive BRCA. We found that immune/stromal/ESTIMATE scores were significantly correlated with the invasive BRCA clinicopathological factors. Based on the immune/stromal/ESTIMATE scores, we extracted a series of differential expression genes (DEGs) related to the tumor microenvironment. Survival analysis was further performed to identify a list of high-frequency DEGs (HF-DEGs), which exhibited prognostic value in invasive BRCA. Importantly, consistent with the results of bioinformatics analysis, immunohistochemistry results showed that high SASH3 expression was associated with a good prognosis in invasive BRCA patients. Our findings suggest that the tumor microenvironment-related HF-DEGs identified in this study have prognostic values and may serve as potential biomarkers and therapeutic targets for invasive BRCA.

Breast cancer is the most common cancer in women worldwide. Although tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is widely used to treat ER-positive breast cancers, resistance to TAM remains a major clinical problem. NADPH-dependent cytochrome P450 reductase (POR) is known to participate in drug metabolism and steroid metabolism. Recent studies showed that high POR expression was correlated with poor outcomes in triple-negative breast cancer (TNBC), and POR might be a prognostic biomarker in TNBC. However, the role of POR in TAM resistance is still elusive. In this study, we found that high POR expression was associated with poor prognosis of ER-positive and TAM-treated breast cancer patients. In addition, COX analysis showed that POR expression was an independent prognostic biomarker for ER-positive as well as TAM-treated breast cancer patients. Furthermore, our results suggested that POR overexpression promoted TAM resistance by activating the STAT1/c-Myc pathway in ER-positive breast cancer cells. Immunohistochemical analysis showed that high POR/STAT1 expression was correlated with poor prognosis in TAM-treated breast cancer patients. Notably, combined treatment with TAM and a specific STAT1 inhibitor Fludarabine was more effective for inhibiting TAM-resistant breast cancer cells. Altogether, our findings suggested that POR overexpression induced TAM resistance through STAT1/c-Myc pathway and might serve as an independent prognostic biomarker in TAM-treated breast cancer patients. Combining TAM and STAT1 inhibitors might be an effective strategy for treating POR-induced TAM-resistant breast cancer.

Background: Breast cancer is the leading cancer-related deaths among women. Although great progress has been made in clinical surgical treatment, it is still urgently needed to look for a treatment model with smaller wounds, lower damage, and a better prognosis. Sentinel lymph node biopsy (SLNB) is a minimally invasive technique for breast cancer treatment, which can correctly assess the patients' condition, prognosis, and treatment response. Methods: We performed a PubMed-based bibliometric analysis to investigate publication trends of SLNB in breast cancer and determined the annual distribution of annual publication numbers, countries, authors, languages, journals, and high-frequency major Medical Subject Headings (MeSH) terms. Results: The results showed that the literature on SLNB in breast cancer has shown an upward trend, and stabilized with the most English literature in the past decade at least. The United States was the country with the most publications from 2010 to 2019. M Ahemd was the first-author who had published the most documents related to SLNB in breast cancer since 2010. The most high-frequency main MeSH words were breast neoplasms/pathology, breast neoplasms/surgery and SLNB. Conclusions: Through bicluster analysis, we divided the related articles of SLNB in breast cancer field from 2010 to 2019 into 4 clusters. Among them, indications for SLNB in breast cancer and detection of lymph node metastases and tracking methods for SLNB were considered to be current research hotspots, while assessment of axillary lymph nodes in neoadjuvant chemotherapy and application of SLNB was a potential hotspot.

A practical and efficient catalyst-free cascade cyclization reaction of 2-acylbenzoic acids with various amino alcohols or diamines was developed. This protocol provides a powerful and straightforward method for the one-pot synthesis of diverse isoindolobenzoxazinones, isoindoloquinazolinones and their derivatives. The synthetic strategy evades the use of catalyst, shows a broad substrate scope and could be performed in gram-scale.

NRP1 is a transmembrane glycoprotein that is highly expressed in a variety of tumors. There is evidence that NRP1 can enhance the stem cell properties of tumor cells, which are thought to be resistant to radiotherapy. This study aims to elucidate the potential mechanism of NRP1 in radiation resistance. We transfected NRP1 siRNA and plasmid in breast cancer cells to detect the expression of cancer stem cell markers by western blot and qRT-PCR. The effect of NRP1 on radiotherapy resistance was assesses by immunofluorescence and flow cytometry. In vivo, we established xenograft tumor model treating with shRNA-NRP1 to assess radiotherapy sensitivity. We found that NRP1 could enhance the stem cell properties and confer radioresistance of breast cancer cells. Mechanistically, we proved that NRP1 reduced IR-induced apoptosis by downregulation of Bcl-2 via methyltransferase WTAP in m6A-depentent way. It is suggested that these molecules may be the therapeutic targets for improving the efficacy of radiotherapy for breast cancer.

An exquisite metal-free cascade cyclization reaction of 2-acylbenzoic acids with amines was developed, which provided a powerful method for the one-pot synthesis of diverse isoindoloisoquinoline and benzoindolizinoindole derivatives. This protocol avoided the use of metal catalysts, proceeded with high efficiency and had broad substrate scope. These resulting products could be transformed into tertiary amines under the reduction of LiAlH4/AlCl3, followed by the Hofmann elimination offering lots of nitrogen-containing nine-membered ring compounds in excellent yields. All synthesized products containing fused N-polycyclic skeletons were difficult to be constructed using traditional methods and they have a wide range of applications in the pharmaceutical area.

Abstract Background Although the rapid development of diagnosis and treatment has improved prognosis in early breast cancer, challenges from different therapeutic response remain due to breast cancer heterogeneity. DEAD-box helicase 27 (DDX27) had been proved to influence ribosome biogenesis and identified as a promoter in gastric and colorectal cancer associated with stem cell-like properties, while the impact of DDX27 on breast cancer prognosis and biological functions is unclear. We aimed to explore the influence of DDX27 on stem cell-like properties and prognosis in breast cancer. Methods The expression of DDX27 was evaluated in 24 pairs of fresh breast cancer and normal tissue by western blot. We conducted Immunohistochemical (IHC) staining in paraffin sections of 165 breast cancer patients to analyze the expression of DDX27 and its correlation to stemness biomarker. The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database were used to analyze the expression of DDX27 in breast cancer. Kaplan–Meier survival analysis were used to investigate the implication of DDX27 on breast cancer prognosis. Western blot, CCK-8 assay, Transwell assay and wound-healing assay were carried out to clarify the regulation of DDX27 on stem cell-like properties in breast cancer cells. Gene Set Enrichment Analysis (GSEA) was performed to analyze the potential molecular mechanisms of DDX27 in breast cancer. Results DDX27 was significantly high expressed in breast cancer compared with normal tissue. High expression of DDX27 was related to larger tumor size (p = 0.0005), positive lymph nodes (p = 0.0008), higher histological grade (p = 0.0040), higher ki-67 (p = 0.0063) and later TNM stage (p < 0.0001). Patients with high DDX27 expression turned out a worse prognosis on overall survival (OS, p = 0.0087) and disease-free survival (DFS, p = 0.0235). Overexpression of DDX27 could enhance the expression of biomarkers related to stemness and promote stem cell-like activities such as proliferation and migration in breast cancer cells. Conclusion DDX27 can enhance stem cell-like properties and cause poor prognosis in breast cancer, also may be expected to become a potential biomarker for breast cancer therapy.

Introduction: Transmembrane protein 16A (TMEM16A) is a Ca2+-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown. Objective: In this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis. Methods: Wound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl- currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset. Results: TMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival. Conclusion: Our findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

Mitochondria play essential roles in eukaryotic cells for glucose metabolism to produce ATP. In Schizosaccharomyces pombe, transcription factor Rst2 can be activated upon glucose deprivation. However, the link between Rst2 and mitochondrial function remains elusive. Here, we monitored Rst2 transcriptional activity in living cells using a Renilla luciferase reporter system, and found that inhibition of mitochondrial complex III/IV caused cells to produce reactive oxygen species (ROS) and nitric oxide (NO), which in turn activated Rst2. Furthermore, Rst2‐GFP was observed to translocate from cytoplasm to nucleus upon mitochondrial complex III/IV inhibitors treatment, and deletion of genes associated with complex III/IV resulted in delayed process of Rst2‐GFP nuclear exportation under glucose‐rich condition. In particular, we found that Rst2 was phosphorylated following the treatment of complex III/IV inhibitors or SNAP. Altogether, our findings suggest that mitochondrial complex III/IV participates in the activation of Rst2 through ROS and NO generation in Schizosaccharomyces pombe.

The reactions of C60 with acetone were carried out under basic condition in the presence of 1.0 M TBAOH (tetra-n-butylammonium hydroxide) methanol solution and ArCH2Br (Ar = Ph or o-BrPh), where methano[60]fulleroids with a novel 1,1,4,9,9,25-configuration were obtained and structurally characterized by single crystal diffraction. The product was formed via the ring-opening reaction of the [5,6]-cyclopropane by the nucleophilic addition of MeO-, which is different from the reactions of other ketones reported previously.