Carbazole based Electron Donor Acceptor (EDA) catalysis for the synthesis of biaryl and aryl-heteroaryl compounds.

A highly regioselective, carbazole based Electron Donor Acceptor (EDA) catalyzed synthesis of biaryl and aryl-heteroaryl compounds is described. Various indole and carbazole derivatives were screened for the Homolytic Aromatic Substitution (HAS) reaction. Tetrahydrocarbazole (THC) was very efficient for the HAS transformation and proceeded via a complex formation between diazonium salt and electron rich tetrahydrocarbazole. The UV-Vis spectroscopy technique has been used to confirm the complex formation. The in situ generated EDA complex even in a catalytic amount is found to be efficient for the Single Electron Transfer (SET) process without any photoactivation. Biaryl compounds, 2-phenylfuran, 2-phenylthiophene, and 2-phenylpyrrole and bioactive compounds such as dantrolene and canagliflozin have been synthesized in moderate to excellent yields.

Inhibitory potential of EGCG on Streptococcus mutans biofilm: A new approach to prevent Cariogenesis.

Dental caries is a common cause for tooth loss and Streptococcus mutans is identified as the etiologic pathogen. This study evaluates the inhibitory potential of Epigallocatechin gallate (EGCG) on S.mutans glucansucrase enzyme and its biofilm. Glucansucrase binding and the inhibitory potential of EGCG was validated using AutoDock tool and enzyme inhibitory assay. Biofilm inhibitory potential was also confirmed using Scanning Electron Microscopic (SEM) analysis in human tooth samples. Molecular docking revealed that EGCG interacted with GLU 515 and TRP 517 amino acids and binds to glucansucrase. SEM analysis revealed inhibition of S.mutans biofilm by various concentrations of EGCG on surfaces of tooth samples. Bioinformatics and biological assays confirmed that EGCG potentially binds to the S. mutans glucansucrase and inhibits its enzymatic activity. Enzymatic inhibition of glucansucrase attenuated biofilm formation potential of S. mutans on tooth surface. Thus, we conclude that EGCG inhibitory potential of S. mutans biofilm on the tooth surface is a novel approach in prevention of dental caries.

Cell death of intestinal epithelial cells in intestinal diseases / 生理学报

Gut injury continues to be the devastating and unpredictable critical illness associated with increased cell death of intestinal epithelial cells (IECs). The IECs, immune system and microbiome are the interrelated entities to maintain normal intestinal homeostasis and barrier integrity. In response to microbial invasion, IEC cell death occurs to maintain intestinal epithelium function and retain the continuous renewal and tissue homeostasis. But the imbalance of IEC cell death results in increased intestinal permeability and barrier dysfunction that leads to several acute and chronic intestinal diseases, such as intestinal ischemia/reperfusion (I/R), sepsis, inflammatory bowel diseases (IBD), necrotizing enterocolitis (NEC), etc. During the pathophysiological state, the excessive IEC apoptotic cell death leads to a chronic inflammatory condition, later switches to necroptotic cell death mechanism that induces more pathological features than apoptosis and may also induce other lytic cell death mechanisms like pyroptosis and ferroptosis to increase the pathogenesis of the intestinal diseases. But still, there remains gaps in the fundamental knowledge about the IEC cell death mechanisms in chronic intestinal diseases. Together, a deep understanding of the specific cell death mechanisms underlying chronic intestinal diseases, including sepsis, IBD, NEC, and intestinal I/R, is desperately needed to develop emerging novel promising therapeutic strategies. This review aims to show how the acute and critical illness in the gut are driven by IEC cell death mechanism, such as apoptosis, necrosis, necroptosis, pyroptosis, and ferroptosis.

Graded Incorporation of Defatted Yellow Mealworm (Tenebrio molitor) in Rainbow Trout (Oncorhynchus mykiss) Diet Improves Growth Performance and Nutrient Retention.

Insects are emerging as a sustainable alternative to fishmeal and fish oil in aquafeeds. This study assessed the effect of graded incorporation levels of defatted yellow mealworm (Tenebrio molitor) protein meal on juvenile rainbow trout (Oncorhynchus mykiss) growth performance, body composition, and apparent nutrient digestibility. The trial comprised five dietary treatments: control diet with 25% fishmeal, and four experimental diets with yellow mealworm protein meal at 5%, 7.5%, 15%, or 25%, which corresponded to a fishmeal replacement of 20%, 30%, 60%, or 100%, respectively. After 90 days, the graded incorporation of insect protein meal led to a significant stepwise increase in final body weight, and a significant improvement of specific growth rate, feed conversion ratio, and protein efficiency ratio compared to the control treatment. Regardless of the incorporation level, the insect protein meal had no effects on fish whole-body composition and apparent digestibility coefficients of dry matter, protein, fat, phosphorus, and energy. Protein, phosphorus, and energy retention significantly increased in fish fed the diets with an insect protein meal. In conclusion, the yellow mealworm protein meal could effectively replace 100% of fishmeal in the diet of juvenile rainbow trout with positive effects on its overall zootechnical performance.

Muscle growth mechanisms in response to isoenergetic changes in dietary non-protein energy source at low and high protein levels in juvenile rainbow trout.

This study investigates muscle growth mechanisms in juvenile rainbow trout in response to isoenergetic changes in dietary non-protein energy (NPE) source (F, fat vs. C, carbohydrates) at two levels of digestible protein to digestible energy (DP/DE) ratio. Fish (initial weight 32.4 g) were fed four diets having similar DE levels (~18 kJ g-1) with a high (HP/E~26 mg kJ-1) vs. low (LP/E~14 mg kJ-1) DP/DE ratio using F or C as major NPE source (7 week-experiment). The lowering of dietary DP/DE ratio increased myoblast determination protein 1a (myod1a) and decreased myostatin 1b (mstn1b) and cathepsin D (ctsd) muscle mRNA levels. The isoenergetic change in dietary NPE from F to C decreased myod1a and proliferative cell nuclear antigen (pcna) muscle mRNA levels. An interaction between DP/DE ratio and NPE source was observed in muscle transcript levels of myogenic factor 6 (mrf4/myf6), fast myosin heavy chain (fmhc) and fast myosin light chain 2 (fmlc2). White muscle total cross-sectional area decreased at low dietary DP/DE ratio and also when NPE source changed from F to C, linked i) to a decreased total number of white muscle fibres, indicating that low dietary DP/DE restricted muscle hyperplasia and that dietary carbohydrate were less efficiently used than fat to sustain muscle hyperplasia, and ii) to decreased percentage of large muscle fibres, indicating limited fibre hypertrophy. Not only the DP level or the DP/DE ratio, but also the isoenergetic change in dietary NPE source (fat vs carbohydrates) thus appears as a potent regulator of muscle hyperplasia and hypertrophy.

Pinocembrin, a novel histidine decarboxylase inhibitor with anti-allergic potential in in vitro.

Pinocembrin (5, 7- dihydroxy flavanone) is the most abundant chiral flavonoid found in propolis, exhibiting antioxidant, antimicrobial and anti-inflammatory properties. However, the effect of Pinocembrin on allergic response is unexplored. Thus, current study aimed at investigating the effects of Pinocembrin on IgE-mediated allergic response in vitro. A special emphasis was directed toward histidine decarboxylase (HDC) and other pro-allergic and pro-inflammatory mediators. Preliminary studies, using a microbiological model of Klebsiella pneumoniae, provided first evidences that suggest Pinocembrin as a potential thermal stable inhibitor for HDC. Applying docking analysis revealed possible interaction between Pinocembrin and mammalian HDC. In vitro studies validated the predicted interaction and showed that Pinocembrin inhibits HDC activity and histamine in IgE-sensitized RBL-2H3 in response to dinitrophenol (DNP)-bovine serum albumin (BSA) stimulation. In addition, Pinocembrin mitigated the damage in the mitochondrial membrane, formation of cytoplasmic granules and degranulation as indicated by lower ß-hexoseaminidase level. Interestingly, it reduced range of pro-inflammatory mediators in the IgE-mediated allergic response including tumor necrosis factor (TNF)-α, interleukin (IL)-6, nitric oxide (NO), inducible NO synthase (iNOS), phosphorylation of inhibitory kappa B (IкB)-α, prostaglandin (PGE)-2 and cyclooxygenase (COX)-2. In conclusion, current study suggests Pinocembrin as a potential HDC inhibitor, and provides the first evidences it is in vitro anti-allergic properties, suggesting Pinocembrin as a new candidate for natural anti-allergic drugs.

In Silico Identification of Human miR 3654 and its Targets Revealed its Involvement in Prostate Cancer Progression.

BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs known to control a broad range of biological functions such as cellular proliferation, differentiation and programmed cell death. Recent reports showed that miRNAs can act as oncogenes or tumor suppressors, thereby, playing an important role in cancer initiation and progression. Moreover, we know that Expressed sequence tags (ESTs) are random single pass sequence reads, which displays the condition/tissue specific transcripts (coding and non-coding) of an organism. METHODS: In the present study, we have applied the bioinformatics approach to identify miRNA from prostate cancer using EST resource and its expressions were analyzed by quantitative reverse transcription PCR (qRT-PCR). RESULTS: Analysis of transcriptomics resource from the LNCaP cells revealed the presence of an EST encoding hsa-miR-3654. Presence of the premature candidate of miR-3654, demonstrates its expression in LNCaP cells. We further indentified that the expression level (Fold Induction) of miR-3654 in LNCaP was higher than the normal and androgen insensitive prostate cancer cell lines (PNT1A, PC-3). CONCLUSION: we have identified the miR-3654 involved in prostate cancer progression using computational approach and hypothesized that the down regulation of miR-3654 could be responsible for a solid tumor to get cancer stem-like cell phenotype. Further studies are required to investigate the molecular mechanisms behind the STAT3 mediated miR-3654 repression and the associated metastasis.

Identification of evolutionarily conserved Momordica charantia microRNAs using computational approach and its utility in phylogeny analysis.

Momordica charantia (bitter gourd, bitter melon) is a monoecious Cucurbitaceae with anti-oxidant, anti-microbial, anti-viral and anti-diabetic potential. Molecular studies on this economically valuable plant are very essential to understand its phylogeny and evolution. MicroRNAs (miRNAs) are conserved, small, non-coding RNA with ability to regulate gene expression by bind the 3' UTR region of target mRNA and are evolved at different rates in different plant species. In this study we have utilized homology based computational approach and identified 27 mature miRNAs for the first time from this bio-medically important plant. The phylogenetic tree developed from binary data derived from the data on presence/absence of the identified miRNAs were noticed to be uncertain and biased. Most of the identified miRNAs were highly conserved among the plant species and sequence based phylogeny analysis of miRNAs resolved the above difficulties in phylogeny approach using miRNA. Predicted gene targets of the identified miRNAs revealed their importance in regulation of plant developmental process. Reported miRNAs held sequence conservation in mature miRNAs and the detailed phylogeny analysis of pre-miRNA sequences revealed genus specific segregation of clusters.

Role of microRNA 21 in mesenchymal stem cell (MSC) differentiation: a powerful biomarker in MSCs derived cells.

The significant role of microRNAs (miRNAs) in stem cell development has been expansively discussed in recent publications and they are noticed to be involved in post transcriptional regulation of gene expression by its affinity towards the 3'UTR of target mRNA. Since the expression of miR-21 was high in cells that were derived from MSCs, recent evidence indicates that miR-21 plays a vital role in mesenchymal stem cells (MSCs) differentiation. Despite the fact that miR-21 can be considered as a powerful biomarker for MSCs differentiation, the number of studies related to the above scenario is very limited. This review highlights the recent publications related to the importance of miR-21 specifically in differentiation of MSCs.

Relevance of miR-21 in HIV and non-HIV-related lymphomas.

The critical role of microRNAs (miRNAs) in cell differentiation, homeostasis and cancer development has been extensively discussed in recent publications. The microRNAs with RISC enzyme complex allow it to find its complementary sequence, which is usually located in the 3'-untranslated region (UTR) of the target messenger RNA (mRNA). This is followed by inhibition of protein translation or promotion, resulting in degradation of the target gene. miR-21 has been mapped at chromosome 17q23.2, where it overlaps with the protein coding gene vacuole membrane protein 1 (VMP1), a human homologue of rat vacuole membrane protein. Recent evidence indicates that miR-21 plays a vital role in tumour cell proliferation, apoptosis and invasion. The inhibition of miR-21 may induce cell cycle arrest and increased chemosensitivity to anticancer agents, providing evidence that miR-21 functions as an oncogene in human cancer. Increased expression levels of miR-21 were observed in tumours arising from diverse tissue types. This also includes tumours of haematological origin, such as chronic lymphatic leukaemia, diffuse large B cell lymphomas (DLBCLs), acute myeloid leukaemia and Hodgkin lymphomas. Recently, it has been shown that high levels of B cell activation were induced by miR-21 in circulating B cells and are seen in HIV-infected individual. Notably, miR-21 is overexpressed in activated B cells, suggesting its assistance in maintaining B cell hyperactivation, which plays a pivotal role in HIV-infected cells. Therefore, miR-21 can be considered as a powerful biomarker in HIV-related lymphomas. The number of studies related to the role of miR-21 in HIV-related lymphomas is sparse; therefore, this mini review highlights the recent publications related to clinical impact and significance of miR-21, specifically in HIV- and non-HIV-related lymphomas.

Oxygen consumption constrains food intake in fish fed diets varying in essential amino acid composition.

Compromisation of food intake when confronted with diets deficient in essential amino acids is a common response of fish and other animals, but the underlying physiological factors are poorly understood. We hypothesize that oxygen consumption of fish is a possible physiological factor constraining food intake. To verify, we assessed the food intake and oxygen consumption of rainbow trout fed to satiation with diets which differed in essential amino acid (methionine and lysine) compositions: a balanced vs. an imbalanced amino acid diet. Both diets were tested at two water oxygen levels: hypoxia vs. normoxia. Trout consumed 29% less food under hypoxia compared to normoxia (p<0.001). Under both hypoxia and normoxia trout significantly reduced food intake by 11% and 16% respectively when fed the imbalanced compared to the balanced amino acid diet. Oxygen consumption of the trout per unit body mass remained identical for both diet groups not only under hypoxia but also under normoxia (p>0.05). This difference in food intake between diets under normoxia together with the identical oxygen consumption supports the hypothesis that food intake in fish can be constrained by a set-point value of oxygen consumption, as seen here on a six-week time scale.

Hepatoprotective role of Abelmoschus esculentus (Linn.) Moench., on carbon tetrachloride-induced liver injury.

CONTEXT: Chronic liver disease has become a global health problem. The research for prominent herbal agents for the management of liver diseases is widely increased. OBJECTIVE: The root of Abelmoschus esculentus (Linn.) Moench., (Malvaceae) has been used as a remedy for liver disorders. The aim of the present study was to evaluate the antioxidant and hepatoprotective effects of the ethanol extract of A. esculentus root. MATERIALS AND METHOD: The antioxidant effect was assessed using DPPH and hydroxy radical scavenging assays. The hepatoprotective effect of the extract was evaluated using CCl4 intoxicated HepG2 cell line and Wistar rats by estimating the levels of hepatic and antioxidant markers. RESULTS: The extract of A. esculentus showed IC50 values of 270.99 and 532.86 µg/mL for DPPH and hydroxy radical scavenging assays, respectively. The incubation of HepG2 cells with CCl4 drastically decreased the cell viability and increased the leakage of transaminases. Pre-treatment with the extract significantly restored the cell death by 31.25 and 39.04% at 200 and 400 µg/mL concentrations, respectively. The reduction of ALT leakage by the treatment was 18.62, 38.59 and 52.15% compared to the CCl4 treated cells at 100, 200 and 400 µg/mL, respectively. In in-vivo experiments also the treatment reduced the levels of transaminases, ALP, MDA, total bilirubin and hepatic TNFα levels as well as increased the antioxidant levels in a dose dependent manner. Histological observations of liver sections showed reduction in steatosis, necrosis and inflammation. CONCLUSION: The results substantiated the hepatoprotective activity of A. esculentus through its antioxidant capacity.

Voluntary feed intake in rainbow trout is regulated by diet-induced differences in oxygen use.

This study investigated the hypothesis that the voluntary feed intake in fish is regulated by diet-induced differences in oxygen use. Four diets were prepared with a similar digestible protein:digestible energy ratio (18 mg/kJ), but which differed in the composition of nonprotein energy source. This replacement of fat (F) by starch (S) was intended to create a diet-induced difference in oxygen use (per unit of feed): diets F30-S70, F50-S50, F65-S35, and F80-S20 with digestible fat providing 28, 49, 65, and 81% of the nonprotein digestible energy (NPDE), respectively. Each diet was fed to satiation to triplicate groups of 20 rainbow trout for 6 wk. As expected, diet-induced oxygen use decreased linearly (R(2) = 0.89; P < 0.001) with increasing NPDE as fat. The digestible and metabolizable energy intakes of trout slightly increased with increasing NPDE as fat (i.e., decreasing starch content) (R(2) = 0.30, P = 0.08; and R(2) = 0.34, P = 0.05, respectively). Oxygen consumption of trout fed to satiation declined with increasing dietary NPDE as fat (R(2) = 0.48; P = 0.01). The inverse relation between digestible energy intake of trout and the diet-induced oxygen use (R(2) = 0.33; P = 0.05) suggests a possible role of diet-induced oxygen use in feed intake regulation as shown by the replacement of dietary fat by starch.

Computational approach for identification of Anopheles gambiae miRNA involved in modulation of host immune response.

MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in regulating gene expression in animals, plants, and viruses, which involves in biological processes including development, cancer, immunity, and host-microorganism interactions. In this present study, we have used the computational approach to identify potent miRNAs involved in Anopheles gambiae immune response. Analysis of 217,261 A. gambiae ESTs and further study of RNA folding revealed six new miRNAs. The minimum free energy of the predicted miRNAs ranged from -27.2 to -62.63 kcal/mol with an average of -49.38 kcal/mol. While its A + U % ranges from 50 to 65 % with an average value of 57.37 %. Phylogenetic analysis of the predicted miRNAs revealed that aga-miR-277 was evolutionary highly conserved with more similarity with other mosquito species. Observing further the target identification of the predicted miRNA, it was noticed that the aga-miR-2304 and aga-miR-2390 are involved in modulation of immune response by targeting the gene encoding suppressin and protein prophenoloxidase. Further detailed studies of these miRNAs will help in revealing its function in modulation of A. gambiae immune response with respect to its parasite.

A comparative study of the metabolic response in rainbow trout and Nile tilapia to changes in dietary macronutrient composition.

Metabolic mechanisms underlying the divergent response of rainbow trout (Oncorhynchus mykiss) and Nile tilapia (Oreochromis niloticus) to changes in dietary macronutrient composition were assessed. Fish were fed one of four isoenergetic diets having a digestible protein-to-digestible energy (DP:DE) ratio above or below the optimal DP:DE ratio for both species. At each DP:DE ratio, fat was substituted by an isoenergetic amount of digestible starch as the non-protein energy source (NPE). Dietary DP:DE ratio did not affect growth and only slightly lowered protein gains in tilapia. In rainbow trout fed diets with low DP:DE ratios, particularly with starch as the major NPE source, growth and protein utilisation were highly reduced, underlining the importance of NPE source in this species. We also observed species-specific responses of enzymes involved in amino acid catabolism, lipogenesis and gluconeogenesis to dietary factors. Amino acid transdeamination enzyme activities were reduced by a low dietary DP:DE ratio in both species and in tilapia also by the substitution of fat by starch as the NPE source. Such decreased amino acid catabolism at high starch intakes, however, did not lead to improved protein retention. Our data further suggest that a combination of increased lipogenic and decreased gluconeogenic enzyme activities accounts for the better use of carbohydrates and to the improved glycaemia control in tilapia compared with rainbow tront fed starch-enriched diets with low DP:DE ratio.

Constraints on energy intake in fish: the link between diet composition, energy metabolism, and energy intake in rainbow trout.

The hypothesis was tested that fish fed to satiation with iso-energetic diets differing in macronutrient composition will have different digestible energy intakes (DEI) but similar total heat production. Four iso-energetic diets (2 × 2 factorial design) were formulated having a contrast in i) the ratio of protein to energy (P/E): high (H(P/E)) vs. low (L(P/E)) and ii) the type of non-protein energy (NPE) source: fat vs. carbohydrate which were iso-energetically exchanged. Triplicate groups (35 fish/tank) of rainbow trout were hand-fed each diet twice daily to satiation for 6 weeks under non-limiting water oxygen conditions. Feed intake (FI), DEI (kJ kg(-0.8) d(-1)) and growth (g kg(-0.8) d(-1)) of trout were affected by the interaction between P/E ratio and NPE source of the diet (P<0.05). Regardless of dietary P/E ratio, the inclusion of carbohydrate compared to fat as main NPE source reduced DEI and growth of trout by ~20%. The diet-induced differences in FI and DEI show that trout did not compensate for the dietary differences in digestible energy or digestible protein contents. Further, changes in body fat store and plasma glucose did not seem to exert a homeostatic feedback control on DEI. Independent of the diet composition, heat production of trout did not differ (P>0.05). Our data suggest that the control of DEI in trout might be a function of heat production, which in turn might reflect a physiological limit related with oxidative metabolism.

Macronutrient-induced differences in food intake relate with hepatic oxidative metabolism and hypothalamic regulatory neuropeptides in rainbow trout (Oncorhynchus mykiss).

This study examines how dietary macronutrient-induced changes in voluntary food intake (FI) relate to changes in markers of hepatic oxidative metabolism and in the expression of FI regulatory neuropeptides in a teleost model, the rainbow trout. Rainbow trout were fed for 6weeks with one of four iso-energetic diets (2×2 factorial design), containing either a high (HP, ~500 g·kg(-1) DM) or a low (LP, ~250 g·kg(-1) DM) protein level (PL) with, at each PL, fat (diets HP-F and LP-F) being substituted by an iso-energetic amount of gelatinized corn starch (diets HP-St and LP-St) as non-protein energy source (ES). Irrespective of the dietary PL, FI (g·kg(-0.8)·d(-1)) and digestible energy intake (DEI, kJ·kg(-0.8)·d(-1)) were significantly (P<0.05) reduced by the iso-energetic replacement of fat by starch as non-protein ES. Interestingly, trout fed these St-diets had higher gene expression of markers of hepatic oxidative phosphorylation (OxPhos), i.e., ubiquinol-cytochrome c reductase subunit 2 (UCR2) and cytochrome oxidase subunit 4 (COX4) and of aerobic oxidative capacity (CS, citrate synthase), which paralleled glucokinase (GK) transcription. This positive relation suggests that glucose phosphorylation and markers of mitochondrial OxPhos are linked at the hepatic level and possibly triggered the observed reduction in FI. Moreover, trout displaying the reduced FI had higher cocaine amphetamine regulator transcript (CART) mRNA in hypothalamus, whereas neuropeptide Y (NPY) mRNA did not follow the macronutrient-induced changes in FI. Further studies are needed to unravel the mechanisms by which diet-induced changes in hepatic metabolism inform central feeding centers involved in the regulation of FI in fish.

Therapeutic effect of Saraca asoca (Roxb.) Wilde on lysosomal enzymes and collagen metabolism in adjuvant induced arthritis.

Rheumatoid arthritis is a chronic, progressive and systemic inflammatory disorder mainly affecting the synovial joints. In the present study, we evaluated the anti-arthritic effect of the methanol extract of Saraca asoca (Roxb.) Wilde., (Fabaceae) on adjuvant induced arthritis by assessing paw swelling, body weight, the levels of lysosomal enzymes, protein bound carbohydrates, serum cytokines, urinary collagen and histopathology of joints. It was found that S. asoca methanol extract at doses of 50, 100 and 200 mg/kg reduced the paw thickness and elevated the mean body weight of arthritic rats. The treatment of S. asoca showed a significant reduction in the levels of both plasma and liver lysosomal enzymes. The protein bound carbohydrates and urinary collagen contents were also decreased at a significant level by the treatment of S. asoca methanol extract. The histopathological study of the joints showed the anti-arthritic property of S. asoca which nearly normalized the histological architecture of the joints. Further, we established the anti-arthritic activity of S. asoca methanol extract by measuring the levels of cytokines in both arthritic and treated rats. The treatment of S. asoca reduced the levels of pro-inflammatory cytokines. In conclusion, S. asoca methanol extract was capable of ameliorating the conditions of arthritis in adjuvant induced arthritic rats.