Genome-wide identification of pan-cancer common and cancer-specific alternative splicing events in 9 types of cancer.

Alternative splicing (AS) has significant clinical relevance with cancers and is a potential source of neoepitopes. In this study, RNA-seq data of 94 solid tumor and matched adjacent normal tissues from 47 clinical patients covering nine cancer types were comprehensively analyzed using SUVA developed by ourselves. The results identified highly conserved pan-cancer differential alternative splicing (DAS) events and cancer-specific DAS events in a series of tumor samples, which in turn revealed the heterogeneity of AS post-transcriptional regulation across different cancers. The co-disturbed network between spliceosome factors (SFs) and common cancer-associated DAS was further constructed, suggesting the potential possibility of the regulation of differentially expressed SFs on DAS. Finally, the common cancer-associated DAS events were fully validated using the TCGA dataset, confirming the significant correlation between cancer-associated DAS and prognosis. Briefly, our study elucidates new insights into conservatived and specific DAS in cancer, providing valuable resources for cancer therapeutic targets.

Lycium barbarum polysaccharide ameliorates the accumulation of lipid droplets in adipose tissue via an ATF6/SIRT1-dependent mechanism.

Lipid droplets (LDs) are dynamic organelles that store neutral lipids and are closely linked to obesity. Previous studies have suggested that Lycium barbarum polysaccharide (LBP) supplements can ameliorate obesity, but the underlying mechanisms remain unclear. In this study, we hypothesize that LBP alleviates LD accumulation in adipose tissue (AT) by inhibiting fat-specific protein 27 (Fsp27) through an activating transcription factor-6 (ATF6)/small-molecule sirtuin 1 (SIRT1)-dependent mechanism. LD accumulation in AT is induced in high-fat diet (HFD)-fed mice, and differentiation of 3T3-L1 preadipocytes (PAs) is induced. The ability of LBP to alleviate LD accumulation and the possible underlying mechanism are then investigated both in vivo and in vitro. The influences of LBP on the expressions of LD-associated genes ( ATF6 and Fsp27) are also detected. The results show that HFD and PA differentiation markedly increase LD accumulation in ATs and adipocytes, respectively, and these effects are markedly suppressed by LBP supplementation. Furthermore, LBP significantly activates SIRT1 and decreases ATF6 and Fsp27 expressions. Interestingly, the inhibitory effects of LBP are either abolished or exacerbated when ATF6 is overexpressed or silenced, respectively. Furthermore, SIRT1 level is transcriptionally regulated by LBP through opposite actions mediated by ATF6. Collectively, our findings suggest that LBP supplementation alleviates obesity by ameliorating LD accumulation, which might be partially mediated by an ATF6/SIRT1-dependent mechanism.

STS1 and STS2 Phosphatase Inhibitor Baicalein Enhances the Expansion of Hematopoietic and Progenitor Stem Cells and Alleviates 5-Fluorouracil-Induced Myelosuppression.

STS1 and STS2, as the protein phosphatases that dephosphorylate FLT3 and cKIT, negatively regulate the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs). To obtain the small molecule inhibitors of STS1/STS2 phosphatase activity used to expand HSPCs both in vitro and in vivo, we establish an in vitro phosphatase assay using the recombinant proteins of the STS1/STS2 histidine phosphatase (HP) domain, by which we screened out baicalein (BC) as one of the effective inhibitors targeting STS1 and STS2. Then, we further demonstrate the direct binding of BC with STS1/STS2 using molecular docking and capillary electrophoresis and verify that BC can restore the phosphorylation of FLT3 and cKIT from STS1/STS2 inhibition. In a short-term in vitro culture, BC promotes profound expansion and enhances the colony-forming capacity of both human and mouse HSPCs along with the elevation of phospho-FLT3 and phospho-cKIT levels. Likewise, in vivo administration with BC significantly increases the proportions of short-term hematopoietic stem cells (ST-HSCs), multipotent progenitors (MPPs) and especially long-term HSCs (LT-HSCs) in healthy mouse bone marrow and increases the numbers of colony-forming units (CFU) formed by HSPCs as well. More importantly, pre-administration of BC significantly enhances the survival of mice with lethal 5-fluorouracil (5-FU) injection due to the alleviation of 5-FU-induced myelosuppression, as evidenced by the recovery of bone marrow histologic injury, the increased proportions of LT-HSCs, ST-HSCs and MPPs, and enhanced colony-forming capacity. Collectively, our study not only suggests BC as one of the small molecule candidates to stimulate HSPC expansion both in vitro and in vivo when needed in either physiologic or pathologic conditions, but also supports STS1/STS2 as potential therapeutic drug targets for HSPC expansion and hematopoietic injury recovery.

Convergence Analysis of Distributed Gradient Descent Algorithms With One and Two Momentum Terms.

For the centralized optimization, it is well known that adding one momentum term (also called the heavy-ball method) can obtain a faster convergence rate than the gradient method. However, for the distributed counterpart, there is quite few results about the effect of added momentum terms on the convergence rate. This article is aimed at studying the issue in the distributed setup, where N agents minimize the sum of their individual cost functions using local communication over a network. The cost functions are twice continuously differentiable. We first study the algorithm with one momentum term and develop a distributed heavy-ball (D-HB) method by adding one momentum term on to the distributed gradient algorithm. By borrowing tools from the control theory, we provide a simple convergence proof and an explicit expression of the optimal convergence rate. Furthermore, we consider adding two momentum terms case and propose a distributed double-heavy-ball (D-DHB) method. We show that adding one momentum term allows faster convergence while adding two momentum terms does not perform any superiorities. Finally, simulation examples are given to illustrate our findings.

Regional Differential Decomposition and Formation Mechanism of Dynamic Carbon Emission Efficiency of China's Logistics Industry.

Among China's five major industries, the logistics industry is the only one in which carbon emission intensity is continuing to increase, so it is of great importance in developing a low-carbon economy for China. Thus, some scholars have learned about carbon emission efficiency (CEE) in logistic industry recently; however, few of them have considered the inner structure, regional differentiation, or dynamic items of CEE. To fill this gap, we first calculate the dynamic carbon emission efficiency of China's logistics industry (CEELI) (2001-2017) using the three-stage DEA-Malmquist model, and then using the Dagum Gini coefficient method, the Kernel Density Estimation (KDE), and the panel vector auto-regression (PVAR) model to analyze regional differential decomposition and their formation mechanism. The results indicate that the dynamic CEELI is 'inefficient' overall; it shows a decreasing trend, and the decline of dynamic efficiency mainly comes from technical backwardness rather than efficiency decline. Moreover, the domestic differences are gradually narrowing; the Gini inequality between regions and the density of trans-variation between regions are the main reasons for the gap between different regions and different periods.

Ursolic Acid Targets Glucosyltransferase and Inhibits Its Activity to Prevent Streptococcus mutans Biofilm Formation.

Streptococcus mutans (S. mutans), the prime pathogen of dental caries, can secrete glucosyltransferases (GTFs) to synthesize extracellular polysaccharides (EPSs), which are the virulence determinants of cariogenic biofilms. Ursolic acid, a type of pentacyclic triterpene natural compound, has shown potential antibiofilm effects on S. mutans. To investigate the mechanisms of ursolic acid-mediated inhibition of S. mutans biofilm formation, we first demonstrated that ursolic acid could decrease the viability and structural integrity of biofilms, as evidenced by XTT, crystal violet, and live/dead staining assays. Then, we further revealed that ursolic acid could compete with the inherent substrate to occupy the catalytic center of GTFs to inhibit EPS formation, and this was confirmed by GTF activity assays, computer simulations, site-directed mutagenesis, and capillary electrophoresis (CE). In conclusion, ursolic acid can decrease bacterial viability and prevent S. mutans biofilm formation by binding and inhibiting the activity of GTFs.

Analysis of Bulk RNA Sequencing Data Reveals Novel Transcription Factors Associated With Immune Infiltration Among Multiple Cancers.

Tumor-infiltrating immune cells shape the tumor microenvironment and are closely related to clinical outcomes. Several transcription factors (TFs) have also been reported to regulate the antitumor activity and immune cell infiltration. This study aimed to quantify the populations of different immune cells infiltrated in tumor samples based on the bulk RNA sequencing data obtained from 50 cancer patients using the CIBERSORT and the EPIC algorithm. Weighted gene coexpression network analysis (WGCNA) identified eigengene modules strongly associated with tumorigenesis and the activation of CD4+ memory T cells, dendritic cells, and macrophages. TF genes FOXM1, MYBL2, TAL1, and ERG are central in the subnetworks of the eigengene modules associated with immune-related genes. The analysis of The Cancer Genome Atlas (TCGA) cancer data confirmed these findings and further showed that the expression of these potential TF genes regulating immune infiltration, and the immune-related genes that they regulated, was associated with the survival of patients within multiple cancers. Exome-seq was performed on 24 paired samples that also had RNA-seq data. The expression quantitative trait loci (eQTL) analysis showed that mutations were significantly more frequent in the regions flanking the TF genes compared with those of non-TF genes, suggesting a driver role of these TF genes regulating immune infiltration. Taken together, this study presented a practical method for identifying genes that regulate immune infiltration. These genes could be potential biomarkers for cancer prognosis and possible therapeutic targets.

SUVA: splicing site usage variation analysis from RNA-seq data reveals highly conserved complex splicing biomarkers in liver cancer.

Most of the current alternative splicing (AS) analysis tools are powerless to analyse complex splicing. To address this, we developed SUVA (Splice sites Usage Variation Analysis) that decomposes complex splicing events into five types of splice junction pairs. By analysing real and simulated data, SUVA showed higher sensitivity and accuracy in detecting AS events than the compared methods. Notably, SUVA detected extensive complex AS events and screened out 69 highly conserved and dominant AS events associated with cancer. The cancer-associated complex AS events in FN1 and the co-regulated RNA-binding proteins were significantly correlated with patient survival.

KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3.

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/ß-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

Fas and GIT1 signalling in the prefrontal cortex mediate behavioural sensitization to methamphetamine in mice.

PURPOSE: Repeated methamphetamine (METH) administration in mice readily produces behavioural sensitization, but the underlying mechanisms remain elusive. The present research aimed to identify new targets affecting METH-induced behavioural sensitization. METHODS: We first established a mouse model of METH-induced behavioural sensitization. To characterize the animal model, we performed behavioural tests at different stages of behavioural sensitization and simultaneously detected changes in several neurotransmitters in the prefrontal cortex (PFC). Next, we perfromed RNA sequencing (RNA-seq) to screen new targets, which were subsequently and verified by RT-PCR and western blot. Finally, we confirmed the roles of the new targets in METH-induced behavioural sensitization by injection of overexpressed lentiviruses and further detected related protein levels by western blot and histological changes by haematoxylin and eosin (HE) staining. RESULTS: We successfully established a mouse model of METH-induced behavioural sensitization. The locomotor activities of the mice changed at different stages of sensitization, accompanied by changes in the levels of DA, 5-HT, GABA and glutamate. For RNA-seq analysis, we chose Fas as target, meanwhile, we chose GIT1 as target through literature. The detection of gene expression by RT-PCR indicated that METH-sensitized mice exhibited decreased levels of Fas, MEK1 and CREB and increased levels of Erk1/2 in the PFC. Western blot analysis revealed decreased Fas, GIT1, MEK1 and phosphorylated CREB levels and increased phosphorylated Erk1/2 levels in METH-sensitized mice. Injection of Fas and GIT1 injection showed that overexpression of Fas and GIT1 inhibited the induction of METH sensitization and reversed the changes in neurotransmitter levels and related protein levels, including MEK1, phosphorylated CREB and phosphorylated Erk1/2, in METH-sensitized mice. Overexpression of Fas and GIT1 also reduced histological lesions induced by METH. CONCLUSION: The findings indicated that the development of behavioural sensitization to METH may be mediated by Fas and GIT1 through the MEK1-Erk1/2-CREB pathway.

Tectorigenin enhances PDX1 expression and protects pancreatic ß-cells by activating ERK and reducing ER stress.

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet ß-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to ß-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve ß-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for the PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in ß-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of ß-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet ß-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring ß-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD-impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet ß-cells both in vitro and in vivo.

Hypericin attenuates nonalcoholic fatty liver disease and abnormal lipid metabolism via the PKA-mediated AMPK signaling pathway in vitro and in vivo.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and constitutes a major risk factor for progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). The occurrence of NAFLD is closely associated with abnormal lipid metabolism and implies a high risk of type 2 diabetes and cardiovascular disease. Therefore, specific and effective drugs for the prevention and treatment of NAFLD are necessary. Hypericin (HP) is one of the main active ingredients of Hypericum perforatum L., and we previously revealed its protective role in islet ß-cells and its effects against type 2 diabetes. In this study, we aimed to explore the preventive and therapeutic effects of HP against NAFLD and the underlying mechanisms in vitro and in vivo. Here, we demonstrated that HP improved cell viability by reducing apoptosis and attenuated lipid accumulation in hepatocytes both in vitro and in vivovia attenuating oxidative stress, inhibiting lipogenesis and enhancing lipid oxidization. Thus, HP exhibited significant preventive and therapeutic effects against HFHS-induced NAFLD and dyslipidemia in mice. Furthermore, we demonstrated that HP directly bound to PKACα and activated PKA/AMPK signaling to elicit its effects against NAFLD, suggesting that PKACα is one of the drug targets of HP. In addition, the enhancing effect of HP on lipolysis in adipocytes through the activation of PKACα was also elucidated. Together, the conclusions indicated that HP, of which one of the targets is PKACα, has the potential to be used as a preventive or therapeutic drug against NAFLD or abnormal lipid metabolism in the future.

Induced Expression of VEGFC, ANGPT, and EFNB2 and Their Receptors Characterizes Neovascularization in Proliferative Diabetic Retinopathy.

Purpose: To investigate whole transcriptional differences between proliferative diabetic retinopathy (PDR) neovascular membranes (NVMs) and retinas, and the regulatory genes participating in retinal neovascularization in PDR. Methods: We used high-throughput sequencing technology to capture the whole-genome gene expression levels of all participants, including 23 patients with PDR or branch retinal vein occlusion (BRVO), 3 normal retinal samples, and 2 retinal samples from type II diabetic (T2D) eyes by donation, followed by analyses of expression patterns using bioinformatics methods, then validation of the data by in situ hybridization and Western blotting. Results: We showed that transcriptional profiles of the NVMs were distinct from those of the retinas. Angiogenesis growth factors VEGFC, ANGPT1, ANGPT2, and EFNB2, and their receptors FLT4, TIE1, TIE2, and EPHB4, respectively, were overexpressed. Expression of VEGFA was highly upregulated in T2D retina, but low in the NVMs, while angiogenesis transcription factors, including ETS1 and ERG, were coordinately upregulated in NVMs. Conclusions: This study described a PDR neovascularization model in which pathological retina-secreted vascular endothelial growth factor A (VEGFA) enhanced the expression of a set of angiogenesis transcription factors and growth factors, to cooperatively induce the retinal neovascularization. Based on these results, novel potential therapeutic targets and biomarkers for PDR treatment and diagnosis are suggested.

Micro-RNA-27a/b negatively regulates hepatic gluconeogenesis by targeting FOXO1.

In the context of hepatic insulin resistance, hepatic gluconeogenesis is abnormally increased, which results in increased hepatic glucose production and hyperglycemia, but the underlying mechanisms remain to be fully elucidated. Micro-RNAs (miRNAs) have been identified as critical regulators of diabetes and other metabolic disorders. In this study, we found that the expressions of miRNA-27 family members miRNA-27a and miRNA-27b (miR-27a/b) decreased significantly in the livers of diabetic mice. Moreover, the levels of miR-27a/b increased in the serum of patients with type 2 diabetes. Our present results showed that inhibition of miR-27a/b expression led to increased hepatic protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase and enhanced hepatic gluconeogenesis in vitro and in vivo. Overexpression of miR-27a/b suppressed hepatic glucose output and alleviated hyperglycemia in diabetic mice. Further study revealed that forkhead box O1 (FOXO1) is a downstream target of miR-27a/b. Taken together, we found novel evidence suggesting that miR-27a/b contributes to hepatic gluconeogenesis through targeting FOXO1 and provided novel mechanistic insight into the pathophysiology of insulin resistance.

Hypericin maintians PDX1 expression via the Erk pathway and protects islet ß-cells against glucotoxicity and lipotoxicity.

A decrease in islet ß-cell mass is closely associated with the development and progression of diabetes. Therefore, protection against ß-cell loss is an essential measure to prevent and treat diabetes. In this study, we investigated the protective effects of non-photoactivated hypericin, a natural compound, on ß-cells both in vitro and in vivo. In vitro, hypericin greatly improved INS-1 cell viability under high-glucose and high-fatty-acid conditions by inhibiting glucotoxicity- and lipotoxicity-induced apoptosis and nitric oxide (NO) production. Then, we further demonstrated that hypericin elicited its protective effects against glucotoxicity and lipotoxicity in INS-1 cells by attenuating the reduction in pancreatic duodenal homeobox-1 (PDX1) expression and Erk activity. In vivo, prophylactic or therapeutic use of hypericin inhibited islet ß-cell apoptosis and enhanced the anti-oxidative ability of pancreatic tissue in high-fat/high-sucrose (HFHS)-fed mice, thus alleviating ß-cell loss and maintaining or improving ß-cell mass and islet size. More importantly, hypericin treatment decreased fasting blood glucose, improved glucose intolerance and insulin intolerance, and alleviated hyperinsulinaemia in HFHS-fed mice. Therefore, hypericin showed preventive and therapeutic effects against HFHS-induced onset of type II diabetes in mice. Hypericin possesses great potential for development as an anti-diabetes drug in the future.

Dracorhodin perchlorate protects pancreatic ß-cells against glucotoxicity- or lipotoxicity-induced dysfunction and apoptosis in vitro and in vivo.

Glucotoxicity or lipotoxicity leads to hyperglycemia and insulin secretion deficiency, which are important causes for the onset of type 2 diabetes mellitus (T2DM). Thus, the restoration of ß-cell function is a long-sought goal in diabetes research. Previous studies have implicated pancreatic and duodenal homeobox 1 gene (Pdx1) in ß-cell function and insulin secretion. In this study, we established a Pdx1 promoter-dependent luciferase system and identified the natural compound dracorhodin perchlorate (DP) as an effective promotor of Pdx1 expression. We further demonstrated that DP could significantly inhibit ß-cell apoptosis induced by 33 mm glucose or 200 µm palmitate by interfering with endoplasmic reticulum stress and mitochondrial pathways and enhance insulin secretion as well. These effects were associated with enhanced activities of Erk1/2, which in turn promoted Pdx1 expression and increased the ratio of Bcl2/Bax, since inhibition of the Erk1/2 pathway abolished the DP-induced expression of Pdx1 and suppression of apoptosis. In addition, our in vivo results in diabetic mice indicated that DP treatment lowered blood glucose, raised insulin levels, enhanced Pdx1 expression and increased islet size and number in the pancreas of diabetic mice. Our findings suggest that Pdx1 is a potential target molecule of DP in the treatment of T2DM via the inhibition of glucotoxicity- or lipotoxicity- induced ß-cell apoptosis and the attenuation of insulin secretion dysfunction.

Hepatic miR-181b-5p Contributes to Glycogen Synthesis Through Targeting EGR1.

BACKGROUND/AIM: The miR-181 family plays an important role in the regulation of various cellular functions. However, whether miR-181b-5p mediates hepatic insulin resistance remains unknown. In this study, we investigated the effect of miR-181b-5p on the regulation of hepatic glycogen synthesis. METHODS: The miR-181b-5p levels in the livers of diabetic mice were detected by real-time PCR. The glycogen levels and AKT/GSK pathway activation were examined in human hepatic L02 cells and HepG2 cells transfected with miR-181b-5p mimic or inhibitor. The potential target genes of miR-181b-5p were evaluated using a luciferase reporter assay and Western blot analysis. EGR1-specific siRNA and pCMV-EGR1 were used to further determine the role of miR-181b-5p in hepatic glycogen synthesis in vitro. Hepatic inhibition of miR-181b-5p in mice was performed using adeno-associated virus 8 (AAV8) vectors by tail intravenous injection. RESULTS: The miR-181b-5p levels were significantly decreased in the serum and livers of diabetic mice as well as the serum of type 2 diabetes patients. Importantly, inhibition of miR-181b-5p expression impaired the AKT/GSK pathway and reduced glycogenesis in hepatocytes. Moreover, upregulation of miR-181b-5p reversed high-glucose-induced suppression of glycogenesis. Further analysis revealed that early growth response 1 (EGR1) was a downstream target of miR-181b-5p. Silencing of EGR1 expression rescued miR-181b-5p inhibition-reduced AKT/GSK pathway activation and glycogenesis in hepatocytes. Hepatic inhibition of miR-181b-5p led to insulin resistance in C57BL/6 J mice. CONCLUSION: We demonstrated that miR-181b-5p contributes to glycogen synthesis by targeting EGR1, thereby regulating PTEN expression to mediate hepatic insulin resistance.

Anti-biofilm Activities from Bergenia crassifolia Leaves against Streptococcus mutans.

Streptococcus mutans has been reported as a primary cariogenic pathogen associated with dental caries. The bacteria can produce glucosyltransferases (Gtfs) to synthesize extracellular polysaccharides (EPSs) that are known as virulence factors for adherence and formation of biofilms. Therefore, an ideal inhibitor for dental caries is one that can inhibit planktonic bacteria growth and prevent biofilm formation. Bergenia crassifolia (L.), widely used as a folk medicine and tea beverage, has been reported to have a variety of bioactivities. The present study aimed to explore the effect of B. crassifolia (L.) leaf extracts on the biofilm of Streptococcus mutans. The B. crassifolia (L.) leaf extracts showed inhibitory effects by decreasing viability of bacteria within the biofilm, as evidenced by the XTT assay, live/dead staining assay and LDH activity assay, and could decrease the adherence property of S. mutans through inhibiting Gtfs to synthesize EPSs. In addition, the reduced quantity of EPSs and the inhibition of Gtfs were positively correlated with concentrations of test samples. Finally, the MTT assay showed that the extracts had no cytotoxicity against normal oral cells. In conclusion, the extracts and sub-extracts of B. crassifolia leaves were found to be antimicrobial and could reduce EPS synthesis by inhibiting activities of Gtfs to prevent bacterial adhesion and biofilm formation. Therefore, B. crassifolia leaves have potential to be developed as a drug to prevent and cure dental caries.

Efficient Cancer Regression by a Thermosensitive Liposome for Photoacoustic Imaging-Guided Photothermal/Chemo Combinatorial Therapy.

The capacity to specifically destroy cancer cells while avoiding normal tissue is urgently desirable in cancer treatment. Herein, a photothermal-trigger-released system serves as a photoacoustic imaging agent constructed by entrapping diketopyrrolopyrrole-based conjugated polymers and curcumin in a poly(ethylene glycol) (PEG)-protected thermoresponsive liposomal phospholipid bilayer. This lipid nanostructure can improve the bioavailability of hydrophobic agents for photothermal treatment with high efficiency and deliver the anticancer drug curcumin to the tumor site actuated by near-infrared (NIR) irradiation. A significantly enhanced combined therapeutic effect to HepG2 tumor-bearing mice was acquired in contrast to the result of single therapy alone. These liposomes with the capability of photoacoustic imaging, greater EPR-induced accumulation in tumor sites, and hyperthermia ablation for photothermal chemotherapy show potential for photoacoustic imaging-guided photothermal/chemo combined therapeutic applications.

Near-infrared conjugated polymers for photoacoustic imaging-guided photothermal/chemo combination therapy.

Conjugated polymers (CPs) with intensive near-infrared (NIR) absorption and high photothermal conversion efficiency (PCE) have emerged as a new generation of photothermal therapy (PTT) and photoacoustic imaging (PAI) agents for cancer therapy. PTT + chemotherapy has been identified as a powerful modality to offer synergistic effects in the destruction and monitoring of cancer tissues. In this study, diketopyrrolopyrrole-based polymers (DPP) were designed through a combination of donor-acceptor moieties. Then, doxorubicin (DOX) and DPP were co-encapsulated in tocopheryl polyethylene-glycol-succinate-cholesterol (TPGS-CHO) copolymers to build a combined theranostic system for tumor treatment. These combined NPs with high PCE (∼50%) and strong (NIR) absorption exhibit excellent real-time photoacoustic imaging detection and synergistic cancer inhibition.