Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study

Background & aimsThere are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies.MethodsThis study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM.ResultsThe mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24).ConclusionsIn this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design

In vitro antiproliferative and apoptosis-inducing properties of a mononuclear copper(II) complex with dppz ligand, in two genotypically different breast cancer cell lines

In the background that there is concerted effort to discover newer metal-based cancer chemotherapeutic agents that could overcome the limitations in cisplatin and that copper, a biocompatible and redox-active metal, offers potential as alternative to cisplatin, the present study was undertaken to investigate the in vitro anti-proliferative properties of the mononuclear copper(II)complex [Cu(L)(diimine)] + where LH = 2-[(2-dimethylaminoethylimino)methyl]phenol and diimine = dipyrido[3,2-a:2',3'-c]phenazine (dppz) using breast cancer cell lines MCF-7 (ER+ve and p53(WT)) and MDA-MB-231(ER-ve and p53(mutant)) when cisplatin was used as positive control. The complex affected the viability of both the cell lines in dose-as well as duration-dependent manner as revealed in the MTT assay. The 24 and 48 h IC50 of the complex were several times lesser than those of cisplatin, and within this huge difference the efficacy of the complex was much superior with MCF-7 cell compared to MDA-MB-231 cell. The cell death was preferentially apoptosis, though necrosis also occurred to a certain extent. These inferences were substantiated by AO/EB fluorescent staining, Hoechst staining, assessment of mitochondrial transmembrane potential, comet assay for DNA damage, DCFH assay for reactive oxygen species (ROS) generation and Western blot of apoptosis-related proteins. Thus, the copper(II) dppz complex under investigation is much more efficient than cisplatin in affecting viability of the breast cancer cells. The underlying mechanism appears to be DNA damage-primed (in view of the known intercalation mode of binding of the complex with DNA) and ROS-associated mitochondria-mediated intrinsic apoptosis to a great extent but necrosis also has a role to a certain extent, which may also be a PARP-mediated cell death independent of apoptosis. Within the purview of this conclusion, the results indicate that the ER and/or p53 genotypes have a bearing on the efficacy of the complex as a cytotoxic agent since the response in the ER-ve and p53(mutant) MDA-MB-231 cell was not so prominent as in ER+ve and p53(WT) MCF-7 cell. Taken together, the complex has been shown to be a potential DNA damaging agent and, in the light of the superiority of the complex over cisplatin, we are further investigating the possibility of targeted nano-delivery of the complex to the tumor cells. When tested on a normal cell, 3T3, Cu(II)dppz was found to affect its viability but at concentrations very high compared to those for the breast cancer cells. Yet, this is a cause of concern and, therefore, we are working out a strategy for targeted delivery of this complex to the cancer cells only

Not Available

Not AvailableNew plant type core set comprising indica and tropical japonica accessions along with checks were evaluated for yield and culm strength related traits and characterized with gene specific markers viz., Gn1a, DEP1, Ghd7, SPL14, GS5, TGW6 and SCM2. Analysis of variance revealed significant differences as well as presence of variability among the genotypes for all the traits. Seven genotypes (IRGC25510, IRGC1742, Haorei machang, Azhoghi, Thangmoi, BPT5204 and Swarnadhan) do not possess similar allele as that of the assessed genes based on combined analysis for all the traits and genes. Of them, four genotypes IRGC1742, Azhoghi, BPT5204 and Swarnadhan possess ideal trait combination (90–100 days to 50% flowering, 100–120 cm plant height, grain number of > 200, 11–15 productive tillers) but with weak culm can be ideal sources for identification of new genes for yield attributing traits and direct introgression of SCM2. Based on single trait-gene analysis, nine trait wise donors with high value for the trait (also with desirable plant type) but without similar allele of the corresponding gene were identified. One genotype IRGC7486 with high grain number (300), four genotypes (IRGC50448, IRGC43741, IRGC15147 and IRGC39111) with strong culm (1195–2655 g.f), three genotypes viz., IRGC15147, IRGC39111 and IRGC10658 with high panicle weight and one genotype Solumpiket with high 1000-grain weight and high panicle weight can be considered for identification of novel gene(s) for respective traits.Not Availabl

Not Available

Not AvailableNew plant type core set comprising indica and tropical japonica accessions along with checks were evaluated for yield and culm strength related traits and characterized with gene specific markers viz., Gn1a, DEP1, Ghd7, SPL14, GS5, TGW6 and SCM2. Analysis of variance revealed significant differences as well as presence of variability among the genotypes for all the traits. Seven genotypes (IRGC25510, IRGC1742, Haorei machang, Azhoghi, Thangmoi, BPT5204 and Swarnadhan) do not possess similar allele as that of the assessed genes based on combined analysis for all the traits and genes. Of them, four genotypes IRGC1742, Azhoghi, BPT5204 and Swarnadhan possess ideal trait combination (90–100 days to 50% flowering, 100–120 cm plant height, grain number of 200, 11–15 productive tillers) but with weak culm can be ideal sources for identification of new genes for yield attributing traits and direct introgression of SCM2. Based on single trait-gene analysis, nine trait wise donors with high value for the trait (also with desirable plant type) but without similar allele of the corresponding gene were identified. One genotype IRGC7486 with high grain number (300), four genotypes (IRGC50448, IRGC43741, IRGC15147 and IRGC39111) with strong culm (1195–2655 g.f), three genotypes viz., IRGC15147, IRGC39111 and IRGC10658 with high panicle weight and one genotype Solumpiket with high 1000-grain weight and high panicle weight can be considered for identification of novel gene(s) for respective traits.Not Availabl

Not Available

Not AvailableMajor biotic stresses viz., bacterial blight (BB) and blast and brown plant hopper (BPH) coupled with abiotic stresses like drought stress, significantly affect rice yields. To address this, marker-assisted intercross (IC) breeding involving multiple donors was used to combine three BB resistance genes—xa5, xa13 and Xa21, two blast resistance genes—Pi9 and Pi54, two BPH resistance genes—Bph20 and Bph21, and four drought tolerant quantitative trait loci (QTL)—qDTY1.1, qDTY2.1, qDTY3.1 and qDTY12.1—in the genetic background of the elite Indian rice cultivar ‘Krishna Hamsa’. Three cycles of selective intercrossing followed by selfing coupled with foreground selection and phenotyping for the target traits resulted in the development of 196 introgression lines (ILs) with a myriad of gene/QTL combinations. Based on the phenotypic reaction, the ILs were classified into seven phenotypic classes of resistance/tolerance to the following: (1) BB, blast and drought—5 ILs; (2) BB and blast—10 ILs; (3) BB and drought—9 ILs; (4) blast and drought—42 ILs; (5) BB—3 ILs; (6) blast—84 ILs; and (7) drought—43 ILs; none of the ILs were resistant to BPH. Positive phenotypic response (resistance) was observed to both BB and blast in 2 ILs, BB in 9 ILs and blast in 64 ILs despite the absence of corresponding R genes. Inheritance of resistance to BB and/or blast in such ILs could be due to the unknown genes from other parents used in the breeding scheme. Negative phenotypic response (susceptibility) was observed in 67 ILs possessing BB-R genes, 9 ILs with blast-R genes and 9 ILs harboring QTLs for drought tolerance. Complex genic interactions and recombination events due to the involvement of multiple donors explain susceptibility in some of the marker positive ILs. The present investigation successfully demonstrates the possibility of rapid development of multiple stress-tolerant/resistant ILs in the elite cultivar background involving multiple donors through selective intercrossing and stringent phenotyping. The 196 ILs in seven phenotypic classes with myriad of gene/QTL combinations will serve as a useful genetic resource in combining multiple biotic and abiotic stress resistance in future breeding programs.Not Availabl

Cellular responses induced by Cu(II) quinolinonato complexes in human tumor and hepatic cells

<p>Abstract</p> <p>Background</p> <p>Inspired by the unprecedented historical success of cisplatin, one of the most important research directions in bioinorganic and medicinal chemistry is dedicated to the development of new anticancer compounds with the potential to surpass it in antitumor activity, while having lower unwanted side-effects. Therefore, a series of copper(II) mixed-ligand complexes of the type [Cu(qui)(L)]Y · <it>x</it>H₂O (1–6), where Hqui = 2-phenyl-3-hydroxy-4(1<it>H</it>)-quinolinone, Y = NO₃ (1, 3, 5) or BF₄ (2, 4, 6), and L = 1,10-phenanthroline (phen) (1, 2), 5-methyl-1,10-phenanthroline (mphen) (3, 4) and bathophenanthroline (bphen) (5, 6), was studied for their <it>in vitro</it> cytotoxicity against several human cancer cell lines (A549 lung carcinoma, HeLa cervix epitheloid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia).</p> <p>Results</p> <p>The tested complexes displayed a stronger cytotoxic effect against all the cancer cells as compared to cisplatin. The highest cytotoxicity was found for the complexes 4 (IC₅₀ = 0.36 ± 0.05 μM and 0.56 ± 0.15 μM), 5 (IC₅₀ = 0.66 ± 0.07 μM and 0.73 ± 0.08 μM) and 6 (IC₅₀ = 0.57 ± 0.11 μM and 0.70 ± 0.20 μM) against A2780, and A2780cis respectively, as compared with the values of 12.0 ± 0.8 μM and 27.0 ± 4.6 μM determined for cisplatin. Moreover, the tested complexes were much less cytotoxic to primary human hepatocytes than to the cancer cells. The complexes 5 and 6 exhibited significantly high ability to modulate secretion of the pro-inflammatory cytokines TNF-α (2873 ± 238 pg/mL and 3284 ± 139 pg/mL for 5, and 6 respectively) and IL-1β (1177 ± 128 pg/mL and 1087 ± 101 pg/mL for 5, and 6 respectively) tested on the lipopolysaccharide (LPS)-stimulated THP-1 cells as compared with the values of 1173 ± 85 pg/mL and 118.5 ± 4.8 pg/mL found for the commercially used anti-inflammatory drug prednisone. The ability of the tested complexes to interact with sulfur-containing biomolecules (cysteine and reduced glutathione) at physiological levels was proved by electrospray-ionization mass spectrometry.</p> <p>Conclusions</p> <p>Overall positive results of the biological activity studies revealed that the presented complexes may represent good candidates for non-platinum anticancer drugs, however, we are aware of the fact that further and deeper studies mainly in relation to the elucidation of their mechanisms of antiproliferative action will be necessary.</p

Nutrition assessment and MASH severity in children using the Healthy Eating Index

BackgroundPediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.MethodsDiet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components.ResultsIn all, 119 children were included (13.3 ± 2.7&nbsp;y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI &lt; 47.94 (n = 39), mid HEI ≥ 47.94 and &lt; 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120&nbsp;mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43&nbsp;mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04).ConclusionsIn children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD