SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AIM: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. METHODS: DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) ß-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. RESULTS: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. ß-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. CONCLUSION: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.

Gap-free genome assembly and comparative analysis reveal the evolution and anthocyanin accumulation mechanism of Rhodomyrtus tomentosa.

Rhodomyrtus tomentosa is an important fleshy-fruited tree and a well-known medicinal plant of the Myrtaceae family that is widely cultivated in tropical and subtropical areas of the world. However, studies on the evolution and genomic breeding of R. tomentosa were hindered by the lack of a reference genome. Here, we presented a chromosome-level gap-free T2T genome assembly of R. tomentosa using PacBio and ONT long read sequencing. We assembled the genome with size of 470.35 Mb and contig N50 of ~43.80 Mb with 11 pseudochromosomes. A total of 33 382 genes and 239.31 Mb of repetitive sequences were annotated in this genome. Phylogenetic analysis elucidated the independent evolution of R. tomentosa starting from 14.37MYA and shared a recent WGD event with other Myrtaceae species. We identified four major compounds of anthocyanins and their synthetic pathways in R. tomentosa. Comparative genomic and gene expression analysis suggested the coloring and high anthocyanin accumulation in R. tomentosa tends to be determined by the activation of anthocyanin synthesis pathway. The positive selection and up-regulation of MYB transcription factors were the implicit factors in this process. The copy number increase of downstream anthocyanin transport-related OMT and GST gene were also detected in R. tomentosa. Expression analysis and pathway identification enriched the importance of starch degradation, response to stimuli, effect of hormones, and cell wall metabolism during the fleshy fruit development in Myrtaceae. Our genome assembly provided a foundation for investigating the origins and differentiation of Myrtaceae species and accelerated the genetic improvement of R. tomentosa.

Chinese English as a Foreign Language Teachers' Wellbeing and Motivation: The Role of Mindfulness.

Teaching is a career with great instances of anxiety and exhaustion in all stages of education with particular difficulties associated with the attribute of language instruction. The notion of motivation might be a significant fundamental mechanism since demotivated educators are distressed due to the anxious feature of the instructing career. Moreover, educators' wellbeing has been demonstrated to have a pivotal function in the path of instruction and learners' success. On the other hand, to mitigate both motivation and wellbeing among teachers, one of the mental traits in this filed, namely, mindfulness can be effective as it is a technique that link to positive effects when used as an administrative strategy for alleviating stress and concern that bring about motivation and wellbeing. As a result, the purpose of the study is to investigate the predictor role of mindfulness on teachers' motivation and wellbeing. In this study, 577 teachers (235 males and 342 females) Chinese English as a foreign language (EFL) teachers at different colleges, universities, and institutes in 13 provinces among which Jiangsu and Zhejiang province accounted for 26.69%, while other provinces made up 65.86% and 2 municipalities directly under the central government (Beijing and Chongqing; 7.45%). were kindly accepted to participate in the present study, and they answered the three questionnaires, namely, motivation, mindfulness, and wellbeing. The results of the study through a linear regression analysis indicated that teachers' mindfulness could significantly predict both teachers' wellbeing and motivation. According to the results, some pedagogical suggestions for the policymakers, educator trainers, materials developers, and language educators are offered. Ultimately, guidance for further studies is proposed to L2 scholars who are interested.

Heterologous Expression and Biochemical Characterization of Two Lipoxygenases in Oriental Melon, Cucumis melo var. makuwa Makino.

Lipoxygenases (LOXs) are a class of non-heme iron-containing dioxygenases that catalyse oxidation of polyunsaturated fatty acids to produce hydroperoxidation that are in turn converted to oxylipins. Although multiple isoforms of LOXs have been detected in several plants, LOXs in oriental melon have not attracted much attention. Two full-length LOX cDNA clones, CmLOX10 and CmLOX13 which have been isolated from oriental melon (Cucumis melo var. makuwa Makino) cultivar "Yumeiren", encode 902 and 906 amino acids, respectively. Bioinformatics analysis showed that CmLOX10 and CmLOX13 included all of the typical LOX domains and shared 58.11% identity at the amino acid level with each other. The phylogenetic analysis revealed that CmLOX10 and CmLOX13 were members of the type 2 13-LOX subgroup which are known to be involved in biotic and abiotic stress. Heterologous expression of the full-length CmLOX10 and truncated CmLOX13 in Escherichia coli revealed that the encoded exogenous proteins were identical to the predicted molecular weights and possessed the lipoxygenase activities. The purified CmLOX10 and CmLOX13 recombinant enzymes exhibited maximum activity at different temperature and pH and both had higher affinity for linoleic acid than linolenic acid. Chromatogram analysis of reaction products from the CmLOX10 and CmLOX13 enzyme reaction revealed that both enzymes produced 13S-hydroperoxides when linoleic acid was used as substrate. Furthermore, the subcellular localization analysis by transient expression of the two LOX fusion proteins in tobacco leaves showed that CmLOX10 and CmLOX13 proteins were located in plasma membrane and chloroplasts respectively. We propose that the two lipoxygenases may play different functions in oriental melon during plant growth and development.

Nitinol stents loaded with a high dose of antitumor 5-fluorouracil or paclitaxel: esophageal tissue responses in a porcine model.

BACKGROUND: A poor prognosis associated with esophageal cancer leads to surgical resection not suitable for most patients. Nitinol stents loaded with 50% 5-fluorouracil (5-FU) or paclitaxel (PTX), functioning both as a stent and local chemotherapy, could provide a new therapy modality for these patients. OBJECTIVE: To investigate esophageal tissue responses to nitinol stents loaded with 50% 5-FU or PTX implanted in the esophagus of healthy pigs. DESIGN: Twenty-three healthy Bama mini-pigs were randomly divided into 4 groups for stent implantation: group A (PTX stent, n = 13), group B (5-FU stent, n = 8), group C (blank film-covered stent, n = 1), and group D (bare stent, n = 1). Tissue responses were observed by endoscopy or pathologic analyses, and 5-FU or PTX concentrations were measured in the esophagus at the stent implantation site at different time points. SETTING: Animal laboratory. INTERVENTIONS: Endoscopic placement of esophagus stent. MAIN OUTCOME MEASUREMENTS: Endoscopic examination, histology, and drug concentration analysis. RESULTS: In general, the esophageal tissue responses varied according to different parts of 5-FU or PTX stent (middle part [drug-containing part] and bare ends [drug-free part]). Severe tissue responses at the bare ends of the stent included inflammation, ulceration, and granulation. However, the tissue responses were greatly reduced in the middle part of the stent. The drug concentrations in the esophagus that had contact with the 5-FU stent or PTX stent were very high, especially for the first period after implantation, which did not cause obvious tissue damage. LIMITATION: Some subjects had incomplete follow-up because of unexpected deaths and stent migration. CONCLUSION: The nitinol stents loaded with 50% 5-FU or PTX did not cause severe esophageal tissue responses, although there was a large concentration of the drug in these tissues.

Enhancing curcumin anticancer efficacy through di-block copolymer micelle encapsulation.

We report herein the development of a novel aqueous formulation and improved antitumor activity for curcumin by encapsulating it into a biocompatible and biodegradable poly(L-lactic acid) based poly(anhydride-ester)-b-poly(ethylene glycol) (PAE-b-PEG) micelle. The resulting curcumin loaded micelles were completely water-dispersible, overcoming the problem of poor water solubility that limited its efficacy and bioavailability. In vitro cellular studies revealed that the curcumin-loaded micelles were taken up mainly via endocytosis route and exhibited higher cytotoxicities toward model cancer cell lines (HeLa and EMT6) than free curcumin. An in vivo biodistribution study revealed that the curcumin-loaded micelles displayed significantly enhanced accumulation inside the tumor of EMT6 breast tumor-bearing mice. More impressively, the curcumin-loaded micelles showed stronger antitumor activity, higher anti-angiogenesis effects and induced apoptosis on the EMT6 breast tumor model bearing mice than free curcumin. Furthermore, the curcumin-loaded micelles showed no significant toxicity towards hemotological system, major organs or tissues in mice. Combined with a high antitumor activity and low toxic side-effects, the curcumin-loaded micelles developed here thus appear to be a highly attractive nanomedicine for effective, targeted cancer therapy.

Recent progress in studying curcumin and its nano-preparations for cancer therapy.

A hydrophobic polyphenol compound extracted from turmeric, curcumin has been widely utilized as traditional medicines for centuries in China and India. Over the last decades, because of its low toxicity, extensive studies have been focused on its physicochemical properties and pharmacological activities on various diseases, such as cancer, cardio-vascular disease, inflammatory bowel, wound healing, Alzheimer's disease, rheumatoid arthritis, and diabetes. In particular, bioactivities of curcumin as an effective chemopreventive agent, chemo-/radio-sensitizer for tumor cells, and chemo-/radio-protector for normal organs, are of extraordinary research interests in the literature. Despite these advantages, applications of curcumin are limited in clinical trials because of its poor water solubility and low oral bioavailability. Nano-preparations as an emerging platform for the efficient delivery of anti-cancer drugs should overcome these problems. In this review, we at first briefly revisit important properties of curcumin as well as its uses in cancer treatments, and then overview various nano-preparations of curcumin for cancer therapy, including nanoparticles, liposomes, micelles, nanoemulsions, cyclodextrin complexes, nanodisks, nanofibres, solid lipid nanoparticles, and curcumin conjugates.

[Therapeutic effect of Haobieyangyinruanjianfang on the mouse liver fibrosis caused by schistosomiasis].

OBJECTIVE: To explore therapeutic effect of Haobieyangyinruanjianfang (HBYYRJ) on mouse liver fibrosis by schistosomiasis. METHODS: Mice except for normal control were infected with Japanese schistosome cercarias, after 12 weeks, infected mice were divided into 7 groups: low HBYYRJ group, middle HBYYRJ group, high HBYYRJ group, Fufangbiejiaruangan tablet (FFBJRG) group, colchicine group, 3 months infection group and 6 months infection group. Hepatic fibrosis was found in 3 months infection group. Liver hydroxyproline (Hyp) was determined, matrix metalloproteinase-2 and 9 (MMP-2, MMP-9) were detected with gelatin zymography, serum hyaluronic acid (HA) and precollagen III (PC-III) were detected using RIA. RESULTS: HBYYRJ obviously reduced hepatic fibrosis (probability value less than 0.01). Collagen and HA in 3 months infection group and 6 months infection group were higher than that in normal group (probability value less than 0.01), collagen in high and middle HBYYRJ groups and HA in middle and low HBYYRJ groups were lower than that in 6 months infection group (P less than 0.01, probability value less than 0.05). The expression of MMP-9 and MMP-2 in 3 months infection group and 6 months infection group was higher than that in normal group (probability value less than 0.01), The expression of MMP-9 in three HBYYRJ groups and the expression of MMP-2 in high HBYYRJ group were lower than that in 6 months infection group (probability value less than 0.05). CONCLUSION: HBYYRJ can reduce liver fibrosis caused by schistosomiasis.

Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.

Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.