Gentaur Pub

#32746439   2020/08/03 To Up

Resveratrol isomeric switching during bioreduction of gold nanoparticles: a gateway for-resveratrol.

Resveratrol, a polyphenolic and biocompatible molecule, exhibit significant pharmacological effects but has poor bioavailability and metabolic stability. It appears in two isomeric forms-(E)-resveratrol (tRes) and-(Z)-resveratrol (cRes). Many pharmacological activities studied so far are of tRes and is the most stable, predominant, and natural form. cRes is not commercially available due to difficulty in its purification and hence not explored much for its biological activities. Therefore, our study focuses on investigating the stability and therapeutic potential of cRes through its bio-conjugation to nanomaterial. In this study, tRes reduces gold ions to gold nanoparticles (GNPs) and itself get oxidized to its isomeric form cRes. The isomeric switching was evidenced through cRes characteristic spectral differences and chromatographic elution pattern. The monodispersed GNPs of 25.6 ± 0.4 nm size was formed having zeta potential of -19 ± 3.82 mV confirming it to be a stable formulation. The stability studies were further extended to be tested under different physiological fluids. The cRes loaded GNPs (cRGNPs) reflecting the biological activity of cRes presented equivalent antioxidant property to that of tRes even at low concentrations. Also, cRGNPs showed the hemocompatibility by presenting no hemotoxicity and simultaneousanti-hemolytic activity. Therefore, the stability provided to cRes upon conjugating to GNPs can further be exploited to study the biological activities of cRes through its nano-conjugated delivery.
Archita Gupta, Padmini Padmanabhan, Sneha Singh

2216 related Products with: Resveratrol isomeric switching during bioreduction of gold nanoparticles: a gateway for-resveratrol.

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#32745585   2020/07/31 To Up

Metabolic fate in adult and pediatric population of steviol glycosides produced from stevia leaf extract by different production technologies.

More than 60 naturally occurring steviol glycosides in the Stevia rebaudiana Bertoni plant share a similar molecular structure with an aglycone steviol backbone conjugated with β- and α-glycosidic bonds to different sugar moieties. These glycosides are naturally produced in different quantities within the stevia leaf. Certain minor glycosides with superior sensory attributes, such as Reb D and Reb M, are found less than 0.1% in traditional stevia leaves. New technologies can now produce better tasting steviol glycosides by using enzymatic conversion of stevioside and Reb A, which are abundant in stevia leaf. Several regulatory authorities recently evaluated steviol glycosides produced by enzymatic conversion of stevia leaf extract and approved them safe for human consumption. Steviol glycosides undergo microbial hydrolysis in the colon to generate steviol, which is absorbed and metabolized into steviol glucuronide, and excreted primarily via human's urine. Previous studies have shown the hydrolysis of highly purified individual steviol glycosides extracted from stevia leaf are converted to steviol in the presence of colonic microbiota of adults. Since colonic microbiota of children may be different from adults, this study investigates the metabolic fate in the colonic microbiota of adults and children of the minor steviol glycosides produced by extraction and enzymatic conversion of major steviol glycosides from stevia leaf. Several in vitro incubation tests were conducted in human fecal homogenates collected from adult and pediatric populations with steviol glycoside test samples comprised of a complex stevia leaf extract, a blend of minor glycosides isolated from stevia extract and two mixtures of steviol glycosides produced by enzymatic conversion of Reb A to larger molecules by attaching glucose units via β- or α-glycosidic bonds. Results from these studies clearly demonstrate steviol glycosides produced by extraction from stevia leaf, or enzymatic conversion of stevia leaf extract, share the same metabolic fate in the human gut microbiota from adults and children. Considering a common metabolite structure and a shared metabolic fate in all ages, safety data for individual steviol glycosides can be used to support safety of all steviol glycosides produced by extraction and enzymatic conversion of stevia leaf extract.
Sidd Purkayastha, David Kwok

1764 related Products with: Metabolic fate in adult and pediatric population of steviol glycosides produced from stevia leaf extract by different production technologies.

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#32744767   2020/08/03 To Up

Concatenation of Diborane Leads to New Planar Boron Chemistry.

Diborane has long been realized to be analogous to ethylene in terms of its bonding MOs, both as to symmetries and splitting patterns. This naturally suggests an investigation to see whether other similar conjugated hydrocarbons manifest a similar boron-substituted and H 2 supplemented borane. That is, for a conjugated hydrocarbon structure with a neighbor-paired resonance pattern, we propose to look at boranes where each carbon atom is replaced by a boron atom, and an H-atom pair is added to each double bond of the resonance structure, with one H above the molecular plane and one below. This construction of con-catenated diboranes is uniformly different than that for the previously known stable boranes of 4 or more B atoms. We find from quantum-chemical computations that our so constructed polyboranes are stable. All this suggests a possible novel new chapter in borane chemistry - a chapter with some promise of understandings related to that for (alternant) conjugated hydrocarbons.
Josep M Oliva-Enrich, Takahiro Kondo, Ibon Alkorta, José Elguero, Douglas Klein

1430 related Products with: Concatenation of Diborane Leads to New Planar Boron Chemistry.

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#32744157   // To Up

Conjugation of a peptide to an antibody engineered with free cysteines dramatically improves half-life and activity.

The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the complementarity-determining regions (CDRs) of an immunologically silent IgG4. A cysteine-containing heavy chain CDR3 variant was identified that provided clean conjugation to a bromoacetylated peptide without interference from any of the endogenous mAb cysteine residues. The resulting mAb-peptide homodimer has high potency at both target receptors (glucagon receptor, GCGR, and glucagon-like peptide 1 receptor, GLP-1R) driven by an increase in receptor avidity provided by the spatially defined presentation of the peptides. Interestingly, the avidity effects are different at the two target receptors. A single dose of the long-acting peptide conjugate robustly inhibited food intake and decreased body weight in insulin resistant diet-induced obese mice, in addition to ameliorating glucose intolerance. Inhibition of food intake and decrease in body weight was also seen in overweight cynomolgus monkeys. The weight loss resulting from dosing with the bivalently conjugated dual agonist was significantly greater than for the monomeric analog, clearly demonstrating translation of the measured in vitro avidity to in vivo pharmacology.
Raul C Camacho, Seohee You, Katharine E D'Aquino, Wenyu Li, Yuanping Wang, Joseph Gunnet, James Littrell, Jian Shen Qi, Lijuan Kang, Wenying Jian, Mary MacDonald, Timothy Tat, Derek Steiner, Yue-Mei Zhang, James Lanter, Raymond Patch, Rui Zhang, Jiali Li, Suzanne Edavettal, Wilson Edwards, Thai Dinh, Li Ying Wang, Judy Connor, Michael Hunter, Ellen Chi, Ronald V Swanson, James N Leonard, Martin A Case

2515 related Products with: Conjugation of a peptide to an antibody engineered with free cysteines dramatically improves half-life and activity.

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#32744096   2020/08/03 To Up

Neurodegeneration in juvenile Iberian pigs with diet-induced non-alcoholic fatty liver disease.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced non-alcoholic fatty liver disease (NAFLD), cholestasis and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC), and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 weeks either a control (CON) or high-fructose high-fat diet (HFF) with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had decreased number of neurons and an increase in reactive astrocytes in FC tissue. We found also a decrease in one-carbon metabolites choline and betaine, and a marked accumulation of bile acids, cholesteryl esters, and polyol-pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test, and FC levels of amyloid β and phosphorylated Tau did not differ between diets, while probiotics increased amyloid β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs, and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.
Nicole Zeltser, Isabell Meyer, Gabriella V Hernandez, Matthew J Trahan, Rob K Fanter, Mohammed Abo Ismail, Hunter Glanz, Christine R Strand, Douglas G Burrin, Michael R La Frano, Rodrigo Manjarin, Magdalena Maj

2227 related Products with: Neurodegeneration in juvenile Iberian pigs with diet-induced non-alcoholic fatty liver disease.

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#32743864   2020/08/02 To Up

Tocilizumab-Conjugated Polymer Nanoparticles for NIR-II Photoacoustic-Imaging-Guided Therapy of Rheumatoid Arthritis.

The progressive debilitating nature of rheumatoid arthritis (RA) combined with its unknown etiology and initial similarity to other inflammatory diseases makes early diagnosis a significant challenge. Early recognition and treatment of RA is essential for achieving effective therapeutic outcome. NIR-II photoacoustic (PA) molecular imaging (PMI) is emerging as a promising new strategy for effective diagnosis and treatment guidance of RA, owing to its high sensitivity and specificity at large penetration depth. Herein, an antirheumatic targeted drug tocilizumab (TCZ) is conjugated to polymer nanoparticles (PNPs) to develop the first NIR-II theranostic nanoplatform, named TCZ-PNPs, for PA-imaging-guided therapy of RA. The TCZ-PNPs are demonstrated to have strong NIR-II extinction coefficient, high photostability and excellent biocompatibility. NIR-II PMI results reveal the excellent targeting abilities of TCZ-PNPs for the effective noninvasive diagnosis of RA joint tissue with a high signal-to noise ratio (SNR) of 35.8 dB in 3D PA tomography images. Remarkably, one-month treatment and PA monitoring using TCZ-PNPs shows RA is significantly suppressed. In addition, the therapeutic evaluation of RA mice by NIR-II PMI is shown to be consistent with clinical micro-CT and histological analysis. The TCZ-PNPs-assisted NIR-II PMI provides a new strategy for RA theranostics, therapeutic monitoring and the beyond.
Jingqin Chen, Ji Qi, Chao Chen, Jianhai Chen, Liangjian Liu, Rongkang Gao, Tiantian Zhang, Liang Song, Dan Ding, Peng Zhang, Chengbo Liu

2944 related Products with: Tocilizumab-Conjugated Polymer Nanoparticles for NIR-II Photoacoustic-Imaging-Guided Therapy of Rheumatoid Arthritis.

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#32743177   2020/07/16 To Up

Novel Disulfide-Bridged Bioresponsive Antisense Oligonucleotide Induces Efficient Splice Modulation in Muscle Myotubes in Vitro.

Splice-modulating antisense therapy has shown tremendous potential in therapeutic development in recent years with four FDA-approved antisense drugs since 2016. However, an efficient and nontoxic antisense oligonucleotide (AO) delivery system still remains as a major obstacle in nucleic acid therapeutics field. Vitamin-E (α-tocopherol) is an essential dietary requirement for human body. This fat-soluble compound is one of the most important antioxidants which involves in numerous biological pathways. In this study, for the first time, we explored the scope of using α-tocopherol-conjugated bioresponsive AOs to induce splice modulation in mouse muscle myotubes . Our results showed that the bioresponsive construct efficiently internalized into the cell nucleus and induced exon 23 skipping in mouse myotubes. Based on our exciting new results, we firmly believe that our findings could potentially benefit toward establishing a delivery approach to advance the field of splice-modulating AO therapy.
Bao T Le, Tamer R Kosbar, Rakesh N Veedu

1148 related Products with: Novel Disulfide-Bridged Bioresponsive Antisense Oligonucleotide Induces Efficient Splice Modulation in Muscle Myotubes in Vitro.

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#32742864   2020/06/29 To Up

Cholestasis of Sepsis: A Case Report.

A 46-year-old man presented with fever, general lethargy, and weight loss over the last few months. He started to develop jaundice and his condition worsened. Blood tests confirmed rising levels of conjugated bilirubin with near-normal alanine aminotransferase, alkaline phosphatase, and prothrombin time. Imaging of the liver and biliary system, including ultrasound, computed tomography (CT), and magnetic resonance cholangiopancreatography (MRCP), did not show any focal lesion or biliary obstruction. Human immunodeficiency virus (HIV) and hepatitis screening were negative. A chest x-ray showed no consolidation. An echocardiogram showed no evidence of endocarditis. An ultrasound of the neck and axilla did not show any enlarged lymph nodes. A chest CT scan revealed a mediastinal abscess that contained acid-fast bacilli when aspirated and stained. The patient was started on first-line antituberculous treatment. The jaundice was thought to be secondary to cholestasis of sepsis and resolved completely over the subsequent weeks. His bilirubin levels returned to normal after treatment initiation.
Atit Ghoda, Manoj Ghoda

1168 related Products with: Cholestasis of Sepsis: A Case Report.

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#32741899   // To Up

Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.

Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.
Shingo Oda, Nanaka Miyazaki, Koichi Tsuneyama, Tsuyoshi Yokoi

1554 related Products with: Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.

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