Betulinic acid in the treatment of breast cancer: Application and mechanism progress.

Betulinic acid (BA) is a pentacyclic triterpene compound, which can be obtained by separation, chemical synthesis and biotransformation. BA has excellent biological activities, especially its role in the treatment of breast cancer deserves attention. Its mechanisms mainly include inducing mitochondrial oxidative stress, regulating specific protein (Sp) transcription factors, inhibiting breast cancer metastasis, inhibiting glucose metabolism and NF-κB pathway. In addition, BA can also increase the sensitivity of breast cancer cells to other chemotherapy drugs such as paclitaxel and reduce its toxic side effects. This article reviews the application and possible mechanism of BA in the treatment of breast cancer.

Use of honokiol in lung cancer therapy: a mini review of its pharmacological mechanism.

Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,2'-diol) is a biologically active natural product derived from Magnolia and has been shown to have excellent biological activities. This paper discusses research progress on the use of honokiol in the treatment of lung cancer, as studies have confirmed that honokiol can exert anti-lung-cancer effects through multiple pathways and multiple signaling pathways, such as inhibiting angiogenesis, affecting mitochondrial function and apoptosis, regulating of autophagy and epithelial-mesenchymal transition (EMT). In addition, honokiol combined with other chemotherapy drugs is also a way in which it can be applied.

In vivo and in vitro binding of [125 I]I-R-(+)-TISCH: A dopamine D1 receptor ligand for studying pancreatic ß-cell mass.

Diabetes mellitus (DM) and insulinoma are mainly affected by the status of pancreatic ß-cell mass (BCM). Development of imaging agents for BCM allows to study pancreatic ß cells and the relationship between ß cells and DM or insulinoma. In this study, we investigated the density of dopamine D1 receptor on the ß cells and measured BCM by statistical image processing. The pancreatic uptakes of [125 I]I-R-(+)-7-chloro-8-hydroxy-1-(3'-iodopheny1)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ([125 I]I-R-(+)-TISCH), dopamine D1 receptor tracer, in normal and diabetic rats displayed significant differences at 30 min (1.11 ± 0.08% ID/g vs. 0.63 ± 0.09% ID/g, p < 0.0001). In the presence of SCH23390, the pancreatic uptake of [125 I]I-R-(+)-TISCH at 30 min in normal rats was lower (1.01 ± 0.04% ID/g, p < 0.05). Although the blocking was not complete, [125 I]I-R-(+)-TISCH showed specific binding signals to the pancreas. Furthermore, the uptakes of [125 I]I-R-(+)-TISCH in INS-1 cells were reduced in the presence of SCH23390 at different concentrations. [125 I]I-R-(+)-TISCH displayed a respectable uptake in insulinoma. Overall, [125 I]I-R-(+)-TISCH provided specific binding signals to pancreatic ß cells. Although the specific signal may not be sufficient for imaging in vivo, the dopamine D1 receptor can still be considered as a potential target for studying BCM. Further investigation will be required to optimize the ligand.

[18F]BIBD-239: 18F-Labeled ER176, a Positron Emission Tomography Tracer Specific for the Translocator Protein.

[11C]ER176 has adequate sensitivity to image the human brain translocator protein (TSPO) in all three genotypes by positron emission tomography (PET). However, its clinical application is limited by the short half-life of 11C (20.38 min). To overcome the deficiency of [11C]ER176 and keep the pharmacophore features of ER176 to the maximum extent, we designed four fluorine-labeled ER176 derivatives using the deuterium method. In vitro competition binding confirmed that the designed compounds had high affinity for TSPO. Biodistribution experiments showed that tissues with high expression of TSPO had high uptake of these compounds, as well as that the compound showed high brain penetration and mild defluorination in vivo. Therefore, [18F]BIBD-239 with simple synthesis conditions was selected for further biological evaluation. Theoretical simulations showed that BIBD-239 and ER176 have similar binding modes and sites to Ala147-TSPO and Thr147-TSPO, which indicated that the tracers may have consistent sensitivity to the three affinity genotypes. In vitro autoradiography and in vivo PET studies of the ischemic rat brain showed dramatically higher uptake of [18F]BIBD-239 on the lesion site compared to the contralateral side with good brain kinetics. Additionally, [18F]BIBD-239 provided clear tumor PET images in a GL261 glioma model. Importantly, PET imaging and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) results showed that in vivo defluorination and other metabolites of [18F]BIBD-239 did not interfere with brain imaging. Conclusively, [18F]BIBD-239, similar to ER176 with low polymorphism sensitivity, has simple labeling conditions, high labeling yield, high affinity, and high specificity for TSPO, and it is planned for further evaluation in higher species.

Novel 18F-Labeled PET Tracers Specific to Aromatase: Design, Synthesis, and Biological Evaluation.

The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of 18F-labeled and 68Ga-labeled potential aromatase-binding candidate compounds were designed and synthesized based on the structures of aromatase inhibitors. Competitive inhibition experiments in vitro and molecular docking showed that BIBD-069 and BIBD-071 have high affinity for aromatase. The radiolabeling conditions of [18F]BIBD-069 and [18F]BIBD-071 were simple, and the yields were high. Biodistribution and in vivo inhibition experiments confirmed that [18F]BIBD-069 and [18F]BIBD-071 specifically bind to aromatase. [18F]BIBD-069 and [18F]BIBD-071 selectively imaged the amygdala and nucleus of the stria terminalis, which is similar to the imaging result of [11C]vorozole. Radiometabolites of [18F]BIBD-069 and [18F]BIBD-071 did not bind to aromatase and interfered with brain imaging. MicroPET-CT imaging further confirmed that [18F]BIBD-069 and [18F]BIBD-071 can specifically bind to aromatase and were not defluorinated in vivo. Given that [18F]BIBD-069 and [18F]BIBD-071 exhibit excellent aromatase binding affinities, mild radiolabeling conditions, and good pharmacokinetics, they can be important tools for the diagnosis and treatment of aromatase-related diseases.

Omarigliptin ameliorated high glucose-induced nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation through activating adenosine monophosphate-activated protein kinase α (AMPKα) in renal glomerular endothelial cells.

Diabetic nephropathy (DN) is a complication of diabetes that induces the development of end-stage renal disease (ESRD). The pathogenesis of DN is reported to be closely related to the activation of the NOD-like receptor 3 (NLRP3) inflammasome in renal glomerular endothelial cells. Omarigliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the management of type II diabetes, it has been recently reported to possess a significant anti-inflammatory property. This study aims to explore the potential therapeutic effects of Omarigliptin on DN. We established an in vitro injury model in human renal glomerular endothelial cells (HrGECs) using high glucose (HG). The severe cytotoxicity and increased oxidative stress in HrGECs induced by HG were pronouncedly reversed by the introduction of Omarigliptin. Furthermore, the activated NLRP3 inflammasome and the excessive production of interleukin 18 (IL-18) and interleukin 1ß (IL-1ß) in HrGECs induced by incubation with HG were pronouncedly reversed by the introduction of Omarigliptin, accompanied by the activation of the AMPK/mTOR signaling pathway. After the co-administration of the adenosine monophosphate-activated protein kinase α (AMPKα) inhibitor, compound C, the protective effects of Omarigliptin against HG-induced NLRP3 inflammasome activation and production of pro-inflammatory factors were dramatically abolished. Taken together, our data revealed that Omarigliptin ameliorated HG-induced inflammation in renal glomerular endothelial cells through suppressing NLRP3 inflammasome activation mediated by AMPKα.

The Role of Tumor Inflammatory Microenvironment in Lung Cancer.

Lung cancer is the most common and fatal malignant tumor in the world. The tumor microenvironment (TME) is closely related to the occurrence and development of lung cancer, in which the inflammatory microenvironment plays an important role. Inflammatory cells and inflammatory factors in the tumor inflammatory microenvironment promote the activation of the NF-κB and STAT3 inflammatory pathways and the occurrence, development, and metastasis of lung cancer by promoting immune escape, tumor angiogenesis, epithelial-mesenchymal transition, apoptosis, and other mechanisms. Clinical and epidemiological studies have also shown a strong relationship among chronic infection, inflammation, inflammatory microenvironment, and lung cancer. The relationship between inflammation and lung cancer can be better understood through the gradual understanding of the tumor inflammatory microenvironment, which is advantageous to find more therapeutic targets for lung cancer.

Synthesis and preliminary evaluation of a PET-FI bimodal imaging agent targeting estrogen receptor.

Estrogen receptor is an attractive target for the diagnosis and treatment of breast cancer. This article reports for the first time a dual-modality imaging agent targeting estrogen receptor that can use PET imaging to diagnose breast cancer and utilize fluorescence imaging to achieve intraoperative navigation. Fluorescence experiments show that [natGa] 1 has typical aggregate induced emission characteristics. Above the critical concentration, [natGa] 1 can form biocompatible nanomicelles. [natGa] 1 can quickly light up estrogen receptor positive MCF-7 cells. Cell uptake experiments show that [68Ga] 1 is mediated by estrogen receptor. Therefore, [nat/68Ga] 1 shows the characteristics of highly sensitive diagnosis and visualization of breast cancer, and can be used as a lead compound for the development of a novel PET-FI bimodal imaging agent targeting the estrogen receptor.

Retracted: Naringenin Inhibits Cell Migration, Invasion, and Tumor Growth by Regulating circFOXM1/miR-3619-5p/SPAG5 Axis in Lung Cancer.

Cancer Biotherapy and Radiopharmaceuticals officially retracts the article entitled, "Naringenin Inhibits Cell Migration, Invasion, and Tumor Growth by Regulating circFOXM1/miR-3619-5p/SPAG5 Axis in Lung Cancer" by Zhaofeng Tan, Yuli Sun, Mei Liu, Lei Xia, Fang Cao, Yuanfu Qi, and Yonglei Song, (Cancer Biother Radiopharm; E-pub 27 Jun 2020; doi: 10.1089/cbr.2019.3520) at the authors' request: "...we feel that we have not yet studied our work completely and some new great results are discovered. So after carefully thinking, we are going to rearrange this manuscript and try to give more precise model. Thus we decided to withdraw this manuscript with great pity. We sincerely say sorry for all the staffs involved this manuscript including editors, reviewers etc. because of our action."[sic] After careful consideration, the Editor agreed to retract the paper. The Editor and Publisher of Cancer Biotherapy and Radiopharmaceuticals are committed to preserving the scientific literature and the community it serves.

PET probe with Aggregation Induced Emission characteristics for the specific turn-on of aromatase.

Aromatase is an attractive target for the diagnosis and treatment of breast cancer. To combine the anti-photobleaching properties of Aggregation Induced Emission (AIE) with the high sensitivity and whole-body imaging characteristics of positron emission tomography (PET), we designed a bifunctional complexing agent with AIE characteristics by modifying the structure of tetraphenylethene, which is linked with triazole derivatives capable of complexing with natGa3+/68Ga3+ to obtain [natGa/68Ga] 2 for targeting the aromatase. [natGa] 2 has typical AIE characteristics, which can form uniform nanomicelles above the critical micelle concentration, and illuminate estrogen receptor (+) MCF-7 cells. [natGa] 2 itself is almost nonemissive in PBS buffer solution, but it turns on its fluorescence upon interaction with human aromatase, with a detection limit of 0.15 µg/mL [68Ga] 2 is easy to prepare and has high stability. Compared to the estrogen receptor that is negatively expressed by MDA-MB-231  cells, MCF-7  cells positively expressing estrogen have a higher uptake of [natGa] 2. The distribution of aromatase in a tumor can be co-localized by using [68Ga] 2. These results can be used to effectively assess estrogen receptor status and aromatase levels at the cellular level. We anticipate that this research could provide a new strategy for the fabrication of PET probes with AIE characteristics, providing useful probes for PET- FL (Fluorescence imaging) bimodal imaging.

Synthesis and biological evaluation of [18F](2S,4S)4-(3-fluoropropyl) arginine as a tumor imaging agent.

Designing novel 18F-labeled amino acid derivatives for targeted amino acid transporters is an attractive strategy for the development of therapeutic and diagnostic agents for cancer therapy. In this work, we have developed a novel 3-fluoropropyl analog of arginine, namely, (2S,4S)4-[18F]FPArg, [18F]1, to be used as a probe for studying arginine metabolism. Optically pure and labeled with 18F and 19F, (2S,4S)4-(3-fluoropropyl)arginine was synthesized and isolated in high radiochemical purity (>95%). In vitro uptake assays in human MCF-7 cells revealed that [18F]1 enters cells mainly via sodium-independent cationic amino acid transporters and was inhibited >62% by arginine. [18F]1 showed a high cellular uptake of 7.3 ±â€¯0.24% and 6.07 ±â€¯0.3% uptake/100 mg protein after incubation in MCF-7 and MDA-MB-231 cells for 120 min, respectively. In vivo biodistribution studies demonstrated that [18F]1 provided high tumor uptake and high tumor to muscle ratios (5:1 at the 30 and 60 min time points). In vivo PET imaging studies demonstrated tumor-specific uptake in nude mice bearing MCF-7 breast tumors with an excellent tumor-to-muscle ratio. These results suggest that [18F]1 is a promising tracer for clinical breast cancer imaging and may be used to diagnose and monitor diseases that are associated with arginine metabolism.

Detection rate and proximal shift tendency of adenomas and serrated polyps: a retrospective study of 62,560 colonoscopies.

PURPOSE: The purpose of this study is to estimate the detection rates of adenomas and serrated polyps and to identify proximalization and associate risk factors in patients from Southern China. METHODS: Consecutive patients undergoing colonoscopy from 2004 to 2013 in Guangzhou were included. The proportions of proximal adenomas to advanced adenomas and serrated polyps were compared and potential predictors were evaluated. RESULTS: Colonoscopies (n = 62,560) were performed, and 11,427 patients were diagnosed with polyps. Detection rates for adenomas, hyperplastic polyps, and serrated adenomas were 12.0, 2.5, and 0.2 patients per 100 colonoscopies. When comparing the 1st (2004-2008) to the 2nd period (2009-2013), adenoma and serrated polyp detection in proximal and distal colon both increased significantly (proximal colon [adenoma 3.9 vs. 6.1 patients/100 colonoscopies, P < 0.001; serrated polyp 0.4 vs. 1.1 patients/100 colonoscopies, P < 0.001]; distal colon [adenoma 6.6 vs. 7.2 patients/100 colonoscopies, P = 0.003; serrated polyp 1.2 vs. 2.4 patients/100 colonoscopies, P < 0.001]). Advanced adenoma detection increased over these two periods only in proximal colon (1st vs. 2nd period: 1.5 vs. 2.4 patients/100 colonoscopies, P < 0.001), not the distal colon (P = 0.114). Multivariate analyses showed that diagnostic period was an independent predictor for adenoma proximalization (OR = 1.36, 95% CI 1.25-1.48, P < 0.001), but not for advanced adenomas (P = 0.117) or serrated polyps (P = 0.928). CONCLUSIONS: Adenomas and serrated polyps were increasingly detected throughout the colon, whereas advanced adenomas were only in proximal colon. A proximal shift tendency detected by colonoscopy was observed for adenomas, but not advanced adenomas or serrated polyps, in Southern China. The screening for proximal polyps should be emphasized and colonoscopy might be a preferred initial screening tool.

Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells.

The integrity of intestinal barrier is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of various gastrointestinal diseases. Aside from serving as substrates for protein biosynthesis, amino acids also maintain the health of intestinal mucosal barrier. However, the underlying mechanisms remain unclear. We aimed to determine the effect and mechanism of non-essential amino acid (NEAA) deprivation on intestinal tight junction permeability using porcine intestinal epithelial cells as a model. We found that NEAA deprivation led to an impairment of barrier function as evidenced by increased permeability, decreased trans-epithelial resistance, and decreased expression of tight junction proteins claudin-1 and ZO-1. Importantly, NEAA deprivation induced both apoptosis and autophagy as shown by caspase-3 activation, and poly ADP-ribose polymerase cleavage; and LC3II lipidation and p62 degradation, hallmarks of apoptosis and autophagy, respectively. Importantly, we showed that the autophagy induced by NEAA deprivation counteracts apoptosis. Abrogation of autophagy by 3-methyladenine enhanced NEAA deprivation-induced barrier dysfunction and apoptosis; whereas, activation of autophagy by rapamycin partially rescued NEAA deprivation-induced barrier dysfunction and apoptosis. Taken together, our results demonstrate a critical role of NEAA on the mucosal integrity by regulating cell death and survival signaling pathways.

Pediatric colonoscopy in South China: a 12-year experience in a tertiary center.

OBJECTIVE: To investigate: 1) the demographics and clinical characteristics, 2) the findings, and 3) the safety and effectiveness in a cohort of Chinese pediatric patients undergoing colonoscopy. METHODS: The study participants were consecutive patients aged ≤14 years old that underwent their first colonoscopy in the endoscopy center at the First Affiliated Hospital, Sun Yat-sen University between Jan. 1, 2001 and Dec. 31, 2012. Demographic, clinical, endoscopic, and pathological findings were collected. RESULTS: The cohort consisted of 322 patients, including 218 boys (67.7%) and 104 girls (32.3%). The median age was 8.0 years old and ranged from 9 months to 14 years old. Hematochezia (48.8%) and abdominal pain/discomfort (41.3%) were the most common presentations preceding pediatric colonoscopy. The caecal intubation success rate was 96.3%. No serious complications occurred during the procedures. A total of 227 patients (70.5%) received a positive diagnosis under endoscopy, including 138 patients with polyps and 53 patients with inflammatory bowel disease (IBD). Among the patients with polyps, 71.0% were juvenile polyps. Comparisons between years 2001-2006 and 2007-2012 showed that the IBD detection rate increased significantly (4.6% vs. 22.4%, P<0.001), while the opposite occurred for the polyp detection rate (73.1% vs. 27.6%, P<0.001). CONCLUSION: Colonoscopy in pediatric patients is a safe and effective procedure. Polyps are the primary finding during colonoscopy. In South China there has been an increase in pediatric patients diagnosed with IBD over the past decade. However, a large epidemiological study is needed to confirm our findings.

Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, the relevance of rare exonic single-base substitutions at nucleotide positions close to splice sites that are predicted to result in missense or silent (SNP) variants or substitutions in introns at splice-site positions that are not highly conserved has not been systematically examined in FAP patients. In 34 index patients, we identified 26 different heterozygous single-base substitutions at or close to the splice sites. We characterized five exonic mutations in exon 4 (c.423G>T), exon 14 (c.1956C>T, c.1957A>G, and c.1957A>C), and exon 15 (c.1959G>A) by transcript analysis and by splice-prediction programs (BDGP, SpliceSiteFinder, and ESEfinder). The splicing patterns of these variants were compared to those of 16 different substitutions at highly or less-conserved intronic splice-site positions, and to normal controls. In addition, we analyzed cosegregation of the variants with affected family members and examined the genotype-phenotype correlation. We could demonstrate that the four unclear variants in exon 4 and 14 that are predicted to result in missense or silent mutations in fact lead to complete exon skipping due to aberrant splicing; one possible explanation for this observed effect might be the disruption of exonic splicing enhancer (ESE) motifs. In contrast, the substitution at the first position of exon 15 seems to actually be a silent variant. We present the first systematic evaluation of different single-base substitutions in APC at or close to splice sites at transcript level. We show that the consequence of exonic mutations cannot be evaluated only by the predicted change in amino acid sequence but rather by the change at DNA level. The functional analysis of variants with unknown pathogenic effect plays an important role in increasing the mutation detection rate and achieving validation of predictive testing.