Takara (Sweden)

Abstract Background: Photosynthetic eukaryotes have evolved through the acquisition of plastids by secondary endosymbiosis, a process that requires several steps. Immediately before plastid acquisition, the genome of the symbiont is known to be dramatically reduced, but few studies have focused on the genomic changes in the symbiont at the early stages of secondary endosymbiosis. Methods: To investigate the genetic basis of the transition from facultative to obligate endosymbiosis, we compared the genomes of Chlorella variabilis, a representative symbiotic alga, with that of Paramecium bursaria, to compare closely related free-living species and transcriptomes between organisms in symbiotic and non-symbiotic conditions. Results: We found that the non-reduced genome of C. variabilis and its genes play a crucial role in endosymbiosis, being involved in cell wall biogenesis and degradation, and metabolic exchanges with the host. Our results suggest that the genetic mechanism underlying the enhancement of photosynthesis under symbiosis is the increasing light absorption efficiency and carbon fixation capacity of the endosymbiont, resulting in an increase in the supply of maltose to P. bursaria.

Objective: The aim of this study is to verify the effects of consuming proanthocyanidins derived from acacia bark on improving blood pressure and blood circulation in healthy Japanese adult subjects. Methods: This was a randomized, double-blind, placebo-controlled, parallel-comparison study involving 66 healthy Japanese adults. Subjects were allocated into either acacia or placebo group (n = 33 each) using a random number generator. Subjects consumed six tablets/day of either acacia bark extract tablets or placebo for 12 weeks. The primary outcome was the measured value of sitting systolic blood pressure at 12 weeks, whereas the secondary outcomes were sitting systolic and diastolic blood pressures, superoxide dismutase activity in blood, and blood flow.Results: The number of subjects analyzed as full analysis set was 33 (20 men and 13 women) in the Acacia group and 31 (23 men and 8 women) in the placebo group. Compared with the placebo group, the measured values and changes from baseline at 4, 8, and 12 weeks of the sitting systolic blood pressure were significantly lower in the Acacia group. Furthermore, “the ratio of the number of subjects whose sitting systolic blood pressure <130 mmHg and diastolic blood pressure ≤89 mmHg at 12 weeks” of the Acacia group was significantly higher than that of the placebo group. No adverse event was observed. Conclusions: Proanthocyanidins derived from acacia bark showed a hypotensive effect. Trial registration: UMIN-CTR: UMIN000039416. Foundation: Acacia-No-Ki Co., Ltd. Keywords: Acacia bark extract, Proanthocyanidins, Systolic blood pressure, Diastolic blood pressure

Background: To prevent diabetes, it is important to control postprandial glycemic levels. Studies have suggested that consuming black tea decreases the risk of type 2 diabetes; however, only a few studies have examined the effects of black tea on postprandial glycemic control after consuming starch-rich foods. In addition, the mechanism underlying the suppression of postprandial glucose levels remains unclear.Objective: To investigate the effects of black tea on postprandial blood glucose levels in healthy humans and to identify the components of black tea that inhibit digestive enzymes.Methods: The inhibitory activity of black tea on digestive enzymes was measured, and the inhibitory components were fractionated. Healthy Japanese adults ingested 200 ml of black tea, and its effect on postprandial blood glucose and insulin levels were investigated. Results: Black tea dose-dependently inhibited α-glucosidase, sucrase, and α-amylase activity. The major components responsible for this inhibition were high–molecular-weight polyphenols. The galloyl moieties present in these compounds play an important role in their inhibitory activities. Two randomized, double-blind, placebo-controlled, crossover studies of healthy human subjects (total n = 46) were conducted to investigate the effect of black tea on blood glucose and insulin levels. Combined data from the two studies showed that black tea ingestion (200 mL) after cooked rice intake (200 g) significantly reduced the incremental area under the curve of glucose (P =.024) and insulin (P =.014) compared to placebo drink.Conclusions: The high–molecular-weight polyphenols in black tea inhibited α-glucosidase, sucrase, and α-amylase activity in a dose-dependent manner. Furthermore, black tea ingestion after eating cooked rice significantly reduced the incremental area under the curve of glucose and insulin. These effects of black tea could be attributed to the inhibition of digestive enzymes by high–molecular-weight polyphenols containing galloyl groups.Keywords: black tea, blood glucose, α-glucosidase, α-amylase, polyphenol

Humanpluripotent stem cell-derived hepatocytes (hPSC-HEP) displaymany properties of mature hepatocytes, including expression of importantgenes of the drug metabolizing machinery, glycogen storage, and productionof multiple serum proteins. To this date, hPSC-HEP do not, however,fully recapitulate the complete functionality of in vivo mature hepatocytes.In this study, we applied versatile bioinformatic algorithms, includingfunctional annotation and pathway enrichment analyses, transcriptionfactor binding-site enrichment, and similarity and correlation analyses,to datasets collected from different stages during hPSC-HEP differentiationand compared these to developmental stages and tissues from fetaland adult human liver. Our results demonstrate a high level of similaritybetween the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis.Importantly, the transcriptional correlation of hPSC-HEP with adultliver (AL) tissues was higher than with fetal liver (FL) tissues (0.83and 0.70, respectively). Functional data revealed mature featuresof hPSC-HEP including cytochrome P450 enzymes activities and albuminsecretion. Moreover, hPSC-HEP showed expression of many genes involvedin drug absorption, distribution, metabolism, and excretion. Despitethe high similarities observed, we identified differences of specificpathways and regulatory players by analyzing the gene expression betweenhPSC-HEP and AL. These findings will aid future intervention and improvementof in vitro hepatocyte differentiation protocol in order to generatehepatocytes displaying the complete functionality of mature hepatocytes.Finally, on the transcriptional level, our results show stronger correlationand higher similarity of hPSC-HEP to AL than to FL. In addition, potentialtargets for further functional improvement of hPSC-HEP were also identified.

There is a strong anticipated future for human pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g. Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, LDL and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker TNFα was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling NASH. Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

A chimeric antigen receptor (CAR) comprises an extracellular ligand recognition domain linked to CD3ζ and induces T-cell activation upon antigen binding. Recently, the potential of CD19-targeted CAR T-cells (CAR-T) to treat multiple myeloma has been explored. A group in the University of Pennsylvania reported that 4 out of 10 patients with refractory myeloma achieved an objective response (sCR: 1, VGPR: 1, and PR: 2). Although the resultant cancer ablation was an arresting sight, it remains unclear whether CD19 is a suitable target for myeloma. Therefore, CAR-T therapy employing alternative target antigens is being attempted. Some current clinical trials are utilizing CAR against differentiation antigens, including CD138, CD38, and kappa light chain. B-cell maturation antigen (BCMA) is also a potential candidate. A group in the NCI described 12 patients with refractory myeloma enrolled in a BCMA-CAR phase 1 clinical trial. Two patients receiving the highest dosage attained an objective response. Nevertheless, considerable research is required for CAR immunotherapy to become universally available to patients with myeloma. The current enthusiasm for the development of this cutting-edge technology is justified because extraordinary evidence indicates that it is effective, although this may not apply to every case. CAR-T therapy for myeloma is currently undergoing rapid, wide-scale growth both in academia and in industry-sponsored clinical development.

Gut microbiota are deeply associated with the prevalence of obesity. Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGO). This study evaluated the effects of AGO on obese phenotype and gut microbial composition in mice. Mice were administered AGO in drinking water (AGO-receiving mice). 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Serum bile acids were ascertained using a LC-MS/MS system. Compared to the control group, AGO administration significantly reduced epididymal adipose tissue weights and serum non-esterified fatty acid concentrations, but the cecal content weights were increased. Data from the serum bile acid profile show that concentrations of primary bile acids (cholic acid and chenodeoxycholic acid), but not those of secondary bile acids (deoxycholic acid, lithocholic acid, and ursodeoxycholic acid), tended to increase in AGO-receiving mice. 16S rRNA gene sequencing analyses showed that the relative abundances of 15 taxa differed significantly in AGO-receiving mice. Of these, the relative abundances of Rikenellaceae and Lachnospiraceae were found to be positively correlated with epididymal adipose tissue weight. The relative abundances of Bacteroides and Ruminococcus were correlated negatively with epididymal adipose tissue weight. Although the definitive role of gut microbes of AGO-received mice is still unknown, our data demonstrate the possibility that AGO administration affects the gut microbial composition and inhibits obesity in mice.

Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.