Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

LncRNA NORAD promotes proliferation, migration and angiogenesis of hepatocellular carcinoma cells through targeting miR-211-5p/FOXD1/VEGF-A axis.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world. Despite improvement in the prevention and treatment of HCC, the clinical prognosis is still poor with increasing mortality. Non-coding RNAs play pivotal roles in HCC oncogenesis, but the detailed mechanism is poorly known. Therefore, the functions and interaction of lncRNA NORAD and miR-211-5p in HCC was investigated in this study. METHODS: Quantitative real-time PCR method was used to analyze the expression of NORAD and miR-211-5p in clinical HCC tissues and cultured cell lines. Knockdown of NORAD and overexpression of miR-211-5p were then carried in HCC cells. Moreover, bioinformatics analysis and luciferase report assays were further employed to analyze the interaction between miR-211-5p and NORAD or FOXD1. RESULTS: Increased lncRNA NORAD and decreased miR-211-5p expression were first detected in HCC compared with the peritumorial area. Further studies showed that knockdown of NORAD or overexpression of miR-211-5p impaired the proliferation, migration and angiogenesis of HCC cells. Mechanistically, we found that NORAD functions as a sponge for miR-211-5p. Moreover, it was revealed that decreased miR-211-5p induced the expression of FOXD1 as well as its downstream target VEGF-A, thereby contributes to enhanced angiogenesis of HCC. CONCLUSION: Elevated NORAD works as a sponge for miR-211-5p in HCC, thus release the inhibition effect of the latter on its downstream target FOXD1 and VEGF-A, which finally promotes angiogenesis. These results provide new insights into the interaction between NORAD and miR-211-5p in HCC and their potential usage as targets for the development of novel therapeutics against HCC.

Efficacy and safety of different ticagrelor regimens versus clopidogrel in patients with coronary artery disease: a retrospective multicenter study (SUPERIOR).

Current guidelines favor dual anti-platelet therapy with ticagrelor 90 mg BID (T90BID) over clopidogrel 75 mg QD (C75QD) in addition to aspirin for acute coronary syndrome. However, an increased risk of ticagrelor-related adverse events prompted the evaluation of low-dose regimens. This study (NCT03381742) retrospectively analyzed the data from 11 hospitals on 3,043 patients with coronary artery disease, who received C75QD, T90BID, ticagrelor 45 mg BID (T45BID), or ticagrelor 90 mg QD (T90QD). Compared with C75QD, both T45BID and T90QD showed significantly higher inhibition of platelet aggregation (P < .0001) and lower platelet-fibrin clot strength (P < .0001) induced by adenosine diphosphate. Furthermore, compared with T90BID, two low-dose regimens had a much lower minor bleeding rate and a significantly higher proportion of patients within the therapeutic window for P2Y12 receptor reactivity. There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite. Similar efficacy and safety outcomes were observed in the propensity score-matched analysis. In conclusion, the low-dose ticagrelor regimen, either T45BID or T90QD, may provide a more attractive benefit-risk profile than C75QD or T90BID.

[Reasearch on lipid metabolism of Plasmodium and antimalarial mechanism of artemisinin].

As a unicellular organism, Plasmodium displays a panoply of lipid metabolism pathways that are seldom found together in a unicellular organism. These pathways mostly involve the Plasmodium-encoded enzymatic machinery and meet the requirements of membrane synthesis during the rapid cell growth and division throughout the life cycle. Different lipids have varied synthesis and meta-bolism pathways. For example, the major phospholipids are synthesized via CDP-diacylglycerol-dependent pathway in prokaryotes and de novo pathway in eukaryotes, and fatty acids are synthesized mainly via type Ⅱ fatty acid synthesis pathway. The available studies have demonstrated the impacts of artemisinin and its derivatives, the front-line compounds against malaria, on the lipid metabolism of Plasmodium. Therefore, this article reviewed the known lipid metabolism pathways and the effects of artemisinin and its derivatives on these pathways, aiming to deepen the understanding of lipid synthesis and metabolism in Plasmodium and provide a theoretical basis for the research on the mechanisms and drug resistance of artemisinin and other anti-malarial drugs.

[Research progress on energy metabolism of Plasmodium at erythrocytic stage].

As a single-cell organism, Plasmodium has a large and complex metabolic network system. There is a close relationship between various metabolic pathways to maintain the transformation of Plasmodium's own energy and substances. Plasmodium energy metabolism pathways mainly include glycolysis and oxidative phosphorylation. Among them, Plasmodium at the erythrocytic stage takes glycolysis as the main energy supply method, and less energy is generated by oxidative phosphorylation. In addition, the two carbon metabolism pathways closely relating to energy metabolism are the tricarboxylic acid(TCA) cycle pathway and glutamate metabolism pathway. As the core of metabolism, the TCA cycle connects glycolysis and glutamate metabolism; glutamate metabolism, as the main carbon metabolism pathway, also participates in various metabolic pathways, such as pyrimidine metabolism, porphyrin metabolism, and protein biosynthesis. This article reviews the energy metabolism pathways of Plasmodium and carbon metabolism pathways that are closely related to energy metabolism, in order to deepen the understanding of the energy metabolism of Plasmodium at the erythrocytic stage, and then provide the theoretical basis and references for studying the mechanisms of action and the drug resistance of antimalarial drugs.

[Research progress on heme metabolism in intraerythrocytic plasmodium].

Heme is a key metabolic factor in all life. Malaria parasite has de novo heme-biosynthetic pathway, however the growth and development of parasite depend on the hemoglobin-derived heme metabolism process during the intraerythrocytic stages, such as the ingestion and degradation of hemoglobin in the food vacuole. The hemoglobin metabolism in the food vesicles mainly includes four aspects: hemoglobin transport and intake, hemoglobin enzymolysis to produce heme, heme polymerization into malarial pigment, and heme transport via the food vacuole. The potential mechanisms of antimalarial drugs,such as chloroquine, artemisinin and atovaquone may be related to this process. The main four aspects of this metabolic process, key metabolic enzymes, effects of antimalarial drugs on the process and their potential mechanism of action would be summarized in this paper, providing ideas for rational use and mechanism exploration of similar drugs.

[Ferroptosis pathway and its intervention regulated by Chinese materia medica].

Ferroptosis is a new form of regulated cell death which is different from apoptosis, necrosis and autophagy, and results from iron-dependent lipidperoxide accumulation. Now, it is found that ferroptosis is involved in multiple physiological and pathological processes, such as cancer, arteriosclerosis, neurodegenerative diseases, diabetes, antiviral immune response, acute renal failure, hepatic and heart ischemia/reperfusion injury. On the one hand, it could be found the appropriate drugs to promote ferroptosis to clear cancer cells and virus infected cells, etc. On the other hand, we could inhibit ferroptosis to protect healthy cells. China has a wealth of traditional Chinese medicine resources. Chinese medicine contains a variety of active ingredients that regulate ferroptosis. Here, this paper reported the research of ferroptosis pathway, targets of its inducers and inhibitors that have been discovered, and the regulatory effects of the discovered Chinese herbs and its active ingredients on ferroptosis to help clinical and scientific research.

Gold-Catalyzed Tandem Cycloisomerization-Halogenation of Chiral Homopropargyl Sulfonamides.

Two new gold-catalyzed tandem cycloisomerization-halogenation reactions of chiral homopropargyl sulfonamides have been developed. Various enantioenriched 3,3-diiodopyrrolidin-2-ols and 3-fluoropyrrolidin-2-ols were obtained in moderate-to-good yields with excellent enantio- and diastereoselectivity.

[Protective effects of three phenylallyl compounds from Guizhi decoction ox-LDL-induced oxidative stress injury of human brain microvascular endothelial cells].

The main objective of this research is to observe protective effects of three phenylallyl compounds(cinnamyl alcohol,cinnamaldehyde and cinnamic acid)from Guizhi decoction against ox-LDL-induced oxidative stress injury on human brain microvascular endothelial cells(HBMEC).In this study,the toxicity and optimal protective concentration of three phenylallyl compounds from Guizhi decoction were determined by MTT assay.The HBMEC were divided into control group(DMSO),model group(ox-LDL),tert-butylhydroquinone (t-BHQ) group,cinnamyl alcohol group, cinnamaldehyde group and cinnamic acid group.The model group were treated with ox-LDL (50 mg•L⁻¹)for 24 h,other groups were separately treated with t-BHQ, cinnamyl alcohol, cinnamaldehyde and cinnamic acid of 20 µmol•L⁻¹, and exposed to ox-LDL (50 mg•L⁻¹) for 24 h at the same time.The survival rate of HBMEC was detected by MTT assay,reactive oxygen species(ROS) production of injured cells were detected using laser scanning confocal microscope (LSCM),the content of SOD, MDA, eNOS and NO in HBMEC was determined by ELISA, and the expressions of Nrf2 mRNA were detected by quantitative Real-time PCR(qRT-PCR).The results shows that oxidative stress injury of HBMEC could be induced by ox-LDL, the three phenylallyl compounds from Guizhi decoction did not affect morphology and viability of normal HBMEC.Compared with model group, the three phenylallyl compounds from Guizhi decoction could improve the above oxidative stress status and up-regulate Nrf2 mRNA expressions in injured HBMEC(P<0.05, P<0.01) .These findings suggested that the three phenylallyl compounds from Guizhi decoction have certain protective effects against ox-LDL-induced oxidative stress injury on HBMEC(cinnamaldehyde> t-BHQ> cinnamic acid>cinnamyl alcohol),the protective mechanism maybe related to regulation of antioxidant enzymes gene expression in HBMEC by Nrf2.

The mechanisms of 5-FU-PLA-O-CMC-NPS-mediated inhibition of the proliferation of colorectal cancer cell line SW480.

We aimed to investigate how 5-FU-PLA-O-CMC-NP (5-FPOCN) inhibits the proliferation of the SW480 colon cancer cell line. Following the treatment of cell line SW480 with 0.1, 1, 10 or 100 µg/ml 5-FPOCN or 5-fluorouracil (fluorouracil, 5-Fu) for 0, 24, 48, or 72, the rate of cell was tested by the tetrazolium assay (MTT). After the SW480 cells were treated with 5-FPOCN or 5-FU for 72 h, the growth rate and apoptosis were detected. After the SW480 cells were treated with 5-FPOCN or 5-FU for 24, 48, 72, or 120, flow cytometry (FCM) was used to determine the cell cycle distribution. The changes in the expression of P21, CyclinD1 and Rb were detected by Western blotting and real-time PCR. We found that different doses of 5-FPOCN can significantly inhibit the growth rate of SW480 cells, and this effect is dose and time dependent. However, there is no significant difference from 72 to 120 h (P>0.05). After 5-FPOCN treatment for 72 h, there is a negative correlation between the concentration of 5-FPOCN and the activity of SW480 cells and a positive correlation between the concentration of 5-FPOCN and SW480 cell apoptosis. G1 phase was significantly increased, and S phase was significantly decreased in 5-FPOCN-treated SW480 cells at 72 h compared to the control group (P<0.05); there was a positive correlation between the concentration of 5-FPOCN and the above changes. It was suggested that 5-FPOCN can delay G1/S phase and that this is a dose-dependent effect. The expression of P21 protein and messenger RNA (mRNA) and Rb protein and mRNA was significantly increased in 5-FPOCN-treated SW480 cells at 72 h compared to the control group, and this was a dose- and time-dependent effect. CyclinD1 protein and mRNA expression was reduced as the dose increased, and its expression was negatively associated with the increased expression of P21. We concluded that 5-FPOCN can significantly inhibit the growth of colon cancer SW480 cells. 5-FPOCN increased P21 expression and decreased cyclin family and pRb expression to promote cell cycle delay and apoptosis.

Gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water.

A gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water has been developed, which provides ready access to highly functionalized indole derivatives from o-alkynyl anilines and ynamides. Importantly, gold serves dual catalytic roles to mediate both the cycloisomerization of o-alkynyl anilines and the intermolecular oxidation of ynamides at the same time, thus providing a new type of concurrent tandem catalysis. The use of readily available starting materials, a simple procedure, and mild reaction conditions are other notable features of this method.

Copper-Catalyzed [3 + 2] Annulation of O-Acyl Oximes with 4-Sulfonamidophenols for the Synthesis of 5-Sulfonamidoindoles and 2-Amido-5-sulfonamidobenzofuran-3(2H)-ones.

A copper-catalyzed [3 + 2] annulation of O-acyl oximes with 4-sulfonamidophenols is developed. The advantage of this method lies in the concurrent double activation of two substrates to form nucleophilic enamines and electrophilic quinone monoimines. The substituent on the α-carbon of O-acyl oxime determines two different reaction pathways, thereby leading to the selective generation of 5-sulfonamidoindoles and 2-amido-5-sulfonamidobenzofuran-3(2H)-ones.

Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Laser directed lithography of asymmetric graphene ribbons on a polydimethylsiloxane trench structure.

Recently, manipulating heat transport by asymmetric graphene ribbons has received significant attention, in which phonons in the carbon lattice are used to carry energy. In addition to heat control, asymmetric graphene ribbons might also have broad applications in renewable energy engineering, such as thermoelectric energy harvesting. Here, we transfer a single sheet of graphene over a 5 µm trench of polydimethylsiloxane (PDMS) structure. By using a laser (1.77 mW, 1 µm diameter spot size, 517 nm wavelength) focusing on one side of the suspended graphene, a triangular shaped graphene ribbon is obtained. As the graphene has a negative thermal expansion coefficient, local laser heating could make the affected graphene area shrink and eventually break. Theoretical calculation shows that the 1.77 mW laser could create a local hot spot as high as 1462.5 °C, which could induce an asymmetric shape structure. We also find the temperature coefficient (-13.06 cm(-1) mW) of suspended graphene on PDMS trench substrate is ten times higher than that reported on SiO2/Si trench substrate. Collectively, our results raise the exciting prospect that the realization of graphene with asymmetric shape on thermally insulating substrate is technologically feasible, which may open up important applications in thermal circuits and thermal management.

An ultra-high element density pMUT array with low crosstalk for 3-D medical imaging.

A ~1 MHz piezoelectric micromachined ultrasonic transducer (pMUT) array with ultra-high element density and low crosstalk is proposed for the first time. This novel pMUT array is based on a nano-layer spin-coating lead zirconium titanium film technique and can be fabricated with high element density using a relatively simple process. Accordingly, key fabrication processes such as thick piezoelectric film deposition, low-stress Si-SOI bonding and bulk silicon removal have been successfully developed. The novel fine-pitch 6 × 6 pMUT arrays can all work at the desired frequency (~1 MHz) with good uniformity, high performance and potential IC integration compatibility. The minimum interspace is ~20 µm, the smallest that has ever been achieved to the best of our knowledge. These arrays can be potentially used to steer ultrasound beams and implement high quality 3-D medical imaging applications.

Integrated analysis of bulk RNA-seq and single-cell RNA-seq reveals the function of pyrocytosis in the pathogenesis of abdominal aortic aneurysm.

Pyrocytosis is involved in the development of abdominal aortic aneurysm (AAA), we explored the pyrocytosis-related hub genes in AAA and conducted a diagnostic model based on the pyrocytosis-related genes score (PRGs). A total of 2 bulk RNA-seq (GSE57691 and GSE47472) datasets and pyrocytosis-related genes were integrated to obtain 24 pyrocytosis-related different expression genes (DEGs). The LASSO Cox regression analysis was conducted to filter out 7 genes and further establish the nomogram signature based on the PRGs that exhibited a good diagnosis value. Weighted gene co-expression network analysis (WGCNA) established 14 gene modules and further identified 6 hub genes which were involved in the regulatory process of pyrocytosis in AAA. At the single cell level, we further identified 3 immune cells were highly associated with the pyrocytosis process in AAA. Finally, the cell-cell communication demonstrated that fibroblasts and endothelial cells and myeloid cells maintained close communications. Here, we identified the dysfunctional expressed pyrocytosis-related genes and immune cells in AAA, which provide a comprehensive understanding of the pathogenesis of AAA.

Development and validation of an online calculator to predict the pathological nature of colorectal tumors.

BACKGROUND: No single endoscopic feature can reliably predict the pathological nature of colorectal tumors (CRTs). AIM: To establish and validate a simple online calculator to predict the pathological nature of CRTs based on white-light endoscopy. METHODS: This was a single-center study. During the identification stage, 530 consecutive patients with CRTs were enrolled from January 2015 to December 2021 as the derivation group. Logistic regression analysis was performed. A novel online calculator to predict the pathological nature of CRTs based on white-light images was established and verified internally. During the validation stage, two series of 110 images obtained using white-light endoscopy were distributed to 10 endoscopists [five highly experienced endoscopists and five less experienced endoscopists (LEEs)] for external validation before and after systematic training. RESULTS: A total of 750 patients were included, with an average age of 63.6 ± 10.4 years. Early colorectal cancer (ECRC) was detected in 351 (46.8%) patients. Tumor size, left semicolon site, rectal site, acanthosis, depression and an uneven surface were independent risk factors for ECRC. The C-index of the ECRC calculator prediction model was 0.906 (P = 0.225, Hosmer-Lemeshow test). For the LEEs, significant improvement was made in the sensitivity, specificity and accuracy (57.6% vs 75.5%; 72.3% vs 82.4%; 64.2% vs 80.2%; P < 0.05), respectively, after training with the ECRC online calculator prediction model. CONCLUSION: A novel online calculator including tumor size, location, acanthosis, depression, and uneven surface can accurately predict the pathological nature of ECRC.

[Efficacies of lactulose plus live combined Bacillus subtilis and Enterococcus faecium capsules in the treatment of functional constipation: a multicenter, randomized, double blind, controlled trial].

OBJECTIVE: To explore the efficacies of live combined Bacillus subtilis (B. subtilis) and Enterococcus faecium (E. faecium) capsules plus lactulose in the treatment of functional constipation. METHODS: A total of 216 patients fulfilling the diagnostic criteria of functional constipation (slow transit pattern) were randomly enrolled from 9 participating hospitals and allocated into treatment group and control group. The patients of treatment group received lactulose plus live combined B. subtilis and E. faecium capsules for 14 days and only took the latter during the following 14 days. The patients of control group received lactulose plus placebo for 2 weeks and then only took placebo continually for the following 2 weeks. RESULTS: A total of 216 patients were analyzed (treatment group n = 104, control group n = 112). The effective rates of 7-day treatment were 88.46% (n = 92) and 84.82% (n = 95) for treatment and control groups respectively. And those of 28-day treatment were 87.50% (n = 91) and 81.25% (n = 91)respectively. And the inter-group differences were not statistically significant (all P > 0.05). Fecal form, frequency, difficulty, urgency, distension, abdominal pain and expelling rates of barium enema were not statistically significant (all P > 0.05). Comparing the effective rates of 28-day with that of 14-day, differences were not statistically significant in A group (S = 0.5, P = 0.4795), but in B group the effective rates of 28-day were lower than that of 14-day statistically(S = 11, P = 0.0009). CONCLUSION: The regiment of live combined B. subtilis and E. faecium capsules plus lactulose offers better efficacies in the treatment of functional constipation.

Highly Site-Selective Oxidative Cyclization of Ene-ynamides via Non-Noble-Metal Catalysis: Access to Functionalized Lactams.

Herein, an unprecedented non-noble-metal-catalyzed oxidation/cyclization of ene-ynamides is developed, allowing the synthesis of diversely functionalized lactams in moderate to good yields with excellent diastereoselectivities without the observation of typical cyclopropanation products. In combination with Ellman's tert-butylsulfinimine chemistry, chiral γ-lactams containing three contiguous stereocenters are obtained with high diastereo- and enantioselectivity. Moreover, density functional theory (DFT) calculations indicate that this protocol probably undergoes a carbon cation or proton transfer process.

Endoscopic classification and pathological features of primary intestinal lymphangiectasia.

BACKGROUND: The appearance of the intestinal mucosa during endoscopy varies among patients with primary intestinal lymphangiectasia (PIL). AIM: To classify the endoscopic features of the intestinal mucosa in PIL under endoscopy, combine the patients' imaging and pathological characteristics of the patients, and explain their causes. METHODS: We retrospectively analyzed the endoscopic images of 123 patients with PIL who were treated at the hospital between January 1, 2007 and December 31, 2018. We compared and analyzed all endoscopic images, classified them into four types according to the endoscopic features of the intestinal mucosa, and analyzed the post-lymphographic computed tomography (PLCT) and pathological characteristics of each type. RESULTS: According to the endoscopic features of PIL in 123 patients observed during endoscopy, they were classified into four types: nodular-type, granular-type, vesicular-type, and edematous-type. PLCT showed diffuse thickening of the small intestinal wall, and no contrast agent was seen in the small intestinal wall and mesentery in the patients with nodular and granular types. Contrast agent was scattered in the small intestinal wall and mesentery in the patients with vesicular and edematous types. Analysis of the small intestinal mucosal pathology revealed that nodular-type and granular-type lymphangiectasia involved the small intestine mucosa in four layers, whereas ectasia of the vesicular- and edematous-type lymphatic vessels largely involved the lamina propria mucosae, submucosae, and muscular layers. CONCLUSION: Endoscopic classification, combined with the patients' clinical manifestations and pathological examination results, is significant and very useful to clinicians when scoping patients with suspected PIL.