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Communications Biology Jun 2024Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours...
Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D. Here, we describe the combined ability of low pH, zinc, and insulin to inhibit hIAPP fibrillation. Insulin dose-dependently slows hIAPP aggregation near neutral pH but had less effect on the aggregation kinetics at acidic pH. We determine that insulin alters hIAPP aggregation in two manners. First, insulin diverts the aggregation pathway to large nonfibrillar aggregates with ThT-positive molecular structure, rather than to amyloid fibrils. Second, soluble insulin suppresses hIAPP dimer formation, which is an important early aggregation event. Further, we observe that zinc significantly modulates the inhibition of hIAPP aggregation by insulin. We hypothesize that this effect arose from controlling the oligomeric state of insulin and show that hIAPP interacts more strongly with monomeric than oligomeric insulin.
Topics: Islet Amyloid Polypeptide; Hydrogen-Ion Concentration; Humans; Zinc; Insulin; Protein Aggregates; Diabetes Mellitus, Type 2; Kinetics; Amyloid; Protein Aggregation, Pathological
PubMed: 38937578
DOI: 10.1038/s42003-024-06388-y -
Biomedicine & Pharmacotherapy =... Jun 20241,25(OH)D is a fat-soluble vitamin, involved in regulating Ca homeostasis in the body. Its storage in adipose tissue depends on the fat content of the body. Obesity is... (Review)
Review
BACKGROUND
1,25(OH)D is a fat-soluble vitamin, involved in regulating Ca homeostasis in the body. Its storage in adipose tissue depends on the fat content of the body. Obesity is the result of abnormal lipid deposition due to the prolonged positive energy balance and increases the risk of several cancer types. Furthermore, it has been associated with vitamin D deficiency and defined as a low 25(OH)D blood level. In addition, 1,25(OH)D plays vital roles in Ca-P and glucose metabolism in the adipocytes of obese individuals and regulates the expressions of adipogenesis-associated genes in mature adipocytes.
SCOPE AND APPROACH
The present contribution focused on the VDR mediated mechanisms interconnecting the obese condition and cancer proliferation due to 1,25(OH)D-deficiency in humans. This contribution also summarizes the identification and development of molecular targets for VDR-targeted drug discovery.
KEY FINDINGS AND CONCLUSIONS
Several studies have revealed that cancer development in a background of 1,25(OH)D deficient obesity involves the VDR gene. Moreover, 1,25(OH)D is also known to influence several cellular processes, including differentiation, proliferation, and adhesion. The multifaceted physiology of obesity has improved our understanding of the cancer therapeutic targets. However, currently available anti-cancer drugs are notorious for their side effects, which have raised safety issues. Thus, there is interest in developing 1,25(OH)D-based therapies without any side effects.
PubMed: 38936194
DOI: 10.1016/j.biopha.2024.117001 -
Poultry Science Jun 2024A total of 378 Cobb-500 male broilers were used to evaluate the effects of 2 fiber sources, differing in hydration capacity and fermentability, on gastrointestinal tract...
Effect of dietary supplementation of two fiber sources differing on fermentability and hydration capacity on performance, nutrient digestibility and cecal fermentation in broilers from 1 to 42 d of age.
A total of 378 Cobb-500 male broilers were used to evaluate the effects of 2 fiber sources, differing in hydration capacity and fermentability, on gastrointestinal tract development, apparent ileal digestibility and performance from 1 to 42d of age. There were 9 replicates per each of the 3 dietary treatments, all in mash form: a wheat-soybean control (CON) diet, CON diet diluted with 1.5% of wood lignocellulose (LC diet) as a non-fermentable insoluble fiber with high hydration capacity; and CON diluted with 1.5% of a mixture of fibers (ISFC diet) containing both lignified insoluble fiber and a prebiotic soluble fiber fraction from fructooligosaccharides. Additionally, the fermentability of both fiber sources (LC and ISFC) was determined by in vitro using cecal inoculum from broilers fed the experimental diets. Both LC and ISFC treatments impaired by 4% feed conversion ratio only during the first 7d (P = 0.003) compared with CON group. In the grower period (21-42d), the ISFC group showed the best growth (P = 0.039), and at 42d tended to show the highest body weight (P = 0.095). This agrees well with the highest ileal dry matter (P = 0.033) and organic matter (P = 0.043) digestibility observed in ISFC group and the similar trend observed for ileal protein digestibility (P = 0.099) at 42d. Also, at 42 d, absolute and relative (% body weight) digestive tract weights (P ≤ 0.041) and empty gizzard weights (P ≤ 0.034) were greater for LC and ISFC groups compared to CON. The cecal molar proportion of valeratewas greatest in ISFC group (P = 0.039). In vitro gas production was higher for ISFC than for LC substrate when using either a diet-adapted or non-adapted cecal inoculum (P < 0.05). These results show the interest in combining IF with prebiotic highly fermentable fiber, such as fructooligosaccharides, in broilers to improve nutrient digestibility and finishing performance.
PubMed: 38936073
DOI: 10.1016/j.psj.2024.103957 -
BJS Open May 2024Posthepatectomy liver failure remains a potentially life-threatening complication after hepatectomy. Soluble suppression of tumourigenicity 2 is an injury-related...
BACKGROUND
Posthepatectomy liver failure remains a potentially life-threatening complication after hepatectomy. Soluble suppression of tumourigenicity 2 is an injury-related biomarker. The aim of the study was to assess soluble suppression of tumourigenicity 2 elevation after hepatectomy and whether it can predict posthepatectomy liver failure.
METHODS
This was a single-centre retrospective study including all patients who underwent a liver resection between 2015 and 2019. Plasma concentrations of soluble suppression of tumourigenicity 2 were measured before surgery and at postoperative days 1, 2, 5 and 7. Posthepatectomy liver failure was defined according to the International Study Group of Liver Surgery and the morbidity rate was graded according to the Clavien-Dindo classification.
RESULTS
A total of 173 patients were included (75 underwent major and 98 minor resection); plasma levels of soluble suppression of tumourigenicity 2 increased from 43.42 (range 18.69-119.96) pg/ml to 2622.23 (range 1354.18-4178.27) pg/ml on postoperative day 1 (P < 0.001). Postoperative day 1 soluble suppression of tumourigenicity 2 concentration accurately predicted posthepatectomy liver failure ≥ grade B (area under curve = 0.916, P < 0.001) and its outstanding performance was not affected by underlying disease, liver pathological status and extent of resection. The cut-off value, sensitivity, specificity, positive predictive value and negative predictive value of postoperative day 1 soluble suppression of tumourigenicity 2 in predicting posthepatectomy liver failure ≥ grade B were 3700, 92%, 85%, 64% and 97% respectively. Soluble suppression of tumourigenicity 2high patients more frequently experienced posthepatectomy liver failure ≥ grade B (64.3% (n = 36) versus 2.6% (n = 3)) and Clavien-Dindo IIIa higher morbidity rate (23.2% (n = 13) versus 5.1% (n = 6)) compared with soluble suppression of tumourigenicity 2low patients.
CONCLUSIONS
Soluble suppression of tumourigenicity 2 may be a reliable predictor of posthepatectomy liver failure ≥ grade B as early as postoperative day 1 for patients undergoing liver resection. Its role in controlling hepatic injury/regeneration needs further investigation. Registration number: ChiCTR-OOC-15007210 (www.chictr.org.cn/).
Topics: Humans; Male; Female; Hepatectomy; Retrospective Studies; Middle Aged; Liver Failure; Postoperative Complications; Aged; Biomarkers; Adult; Liver Neoplasms; Predictive Value of Tests
PubMed: 38935425
DOI: 10.1093/bjsopen/zrae043 -
Indian Journal of Dental Research :... Jan 2024Wet oral environment may have deleterious effects on performance of the composites due to influences of water sorption and solubility. The study evaluated the hydrolytic...
INTRODUCTION
Wet oral environment may have deleterious effects on performance of the composites due to influences of water sorption and solubility. The study evaluated the hydrolytic degradation caused because of water sorption and solubility of silorane and methacrylate-based dental composites.
METHODS
Ten disc samples (2 mm × 10 mm) were prepared. Samples were analyzed for water solubility and sorption according to ISO 4049:2000 regulations and tested for mass gain or loss following immersion in water or in artificial saliva at 1 day, 15 days, and 30 days period. Student's 't' test, repeated measures analysis of variance (ANOVA), and Tukey's post-hoc tests determined statistical significance of the experimental results with global significance set at P = 0.05.
RESULTS
Considerable sorption and solubility was observed with time in both materials on immersion. Silorane composites showed lower water sorption and solubility than methacrylate-based composite (MBC). Artificial saliva demonstrated higher sorption and solubility compared to distilled water.
CONCLUSION
Silorane composites display enhanced hydrolytic stability even after a month of immersion in contrast to conventional methacrylate-based composites (MBCs), making it a better alternative to MBC resins clinically.
Topics: Solubility; Methacrylates; Composite Resins; Water; Silorane Resins; Saliva, Artificial; Materials Testing; Hydrolysis; Dental Materials
PubMed: 38934754
DOI: 10.4103/ijdr.ijdr_195_23 -
Cancer Research Communications Jun 2024To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin Lymphoma (HL) and immune checkpoint modulation induced by...
PURPOSE
To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin Lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA-4 and PD1.
PATIENTS AND METHODS
Phase 1/2, multicenter, open-label, trial NCT01896999 enrolled patients with refractory or relapsed HL (R/R HL) after one or more lines of therapy, with adequate performance status and organ function. Using peripheral blood, we assessed soluble proteins, cell composition, T cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial.
RESULTS
NCT01896999 reported high (>75%) overall objective response rates with brentuximab-vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed durable increase in soluble PD-1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV+N and BV+I+N) compared with BV+I (p<0.05). Non-responders and patients with short progression free-survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (p<0.05).
CONCLUSIONS
The results suggest a circulating tumor-immune-derived signature of BV±I+N treatment resistance that may be useful for patient stratification in combination checkpoint therapy.
PubMed: 38934093
DOI: 10.1158/2767-9764.CRC-24-0252 -
ACS Food Science & Technology Jun 2024Poorly water-soluble iron-containing compounds are promising iron fortificants. However, ensuring high bioaccessibility and low reactivity of iron is challenging. We...
Poorly water-soluble iron-containing compounds are promising iron fortificants. However, ensuring high bioaccessibility and low reactivity of iron is challenging. We present the potential application of ferrous pyrophosphate (Fe(II)PP) and Fe(II)-containing MFe PO salts (0 < < 1, M = Ca, Zn, or Mn) for delivery of iron and a second essential mineral (M). After preparation by a facile and environment-friendly coprecipitation method, the salts were investigated for their composition, pH-dependent dissolution, iron-mediated discoloration of a black tea solution, and oxidation of vitamin C. Our results suggest that these salts are possible dual-fortificants with tunable composition that compared to Fe(II)PP (i) show lower (<0.5 mM) and enhanced (to 5 mM) iron dissolution in moderate and gastric pH, respectively, (ii) exhibit less discoloration and dissolved iron in tea when = 0.470 for M = Ca or Zn and = 0.086 for M = Mn, and (iii) do not increase the oxidation extent of vitamin C over 48 h when = 0.06, 0.086, or 0.053 for M = Ca, Zn, or Mn, respectively.
PubMed: 38934009
DOI: 10.1021/acsfoodscitech.4c00050 -
Frontiers in Pharmacology 2024Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and...
Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C) and the area under the concentration-time curve (AUC) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. http://www.chinadrugtrials.org.cn, identifier CTR20210064.
PubMed: 38933676
DOI: 10.3389/fphar.2024.1359939 -
F1000Research 2023Strawberry is a fruit with a high antioxidant capacity due to its richness in phenolic compounds that suffer a rapid post-harvest deterioration. Spray drying is an...
Strawberry is a fruit with a high antioxidant capacity due to its richness in phenolic compounds that suffer a rapid post-harvest deterioration. Spray drying is an alternative to reduce losses; however, these powders present problems of instantanisation, making it necessary to implement agglomeration processes. During storage, powdered food products can undergo a series of changes in their amorphous state from a product initially in a vitreous state to a gummy state, where all properties are substantially modified due to the increased mobility of water in the matrix. The research objective was to evaluate the storage stability (6 months) of a fluidized bed agglomerated strawberry powder mixture at three temperatures (15, 25 and 25°C), a controlled environment at 65% relative moisture, and PET laminated film bags as packaging. Moisture, water activity, and compacted density, Carr and Hausner indices, solubility, hygroscopicity, wettability, angle of repose, antioxidant capacities, total phenols, anthocyanins, vitamin C, color (CIE-Lab) and particle size were monitored. ANOVA showed statistically significant differences (p<0.05) for all dependent variables concerning storage time; storage temperature had no significant effect on S, ABTS, DPPH and Hu. The time-temperature interaction during storage had no significant effect (p>0.05) on S, ABTS, DPPH, Hu and L. The agglomerate showed moisture and aw values that confer excellent stability against deterioration reactions; it retained good fluidity, low cohesiveness, and retentions above 50% for antioxidant capacity, 76% for total phenols, 39% for anthocyanins, and 40% for vitamin C; particle size was retained during the evaluation. The color was only affected in the 35°C treatment from the fifth month onwards. The study will serve as a tool for the determination of the shelf life of the chipboard once the critical values of the attributes selected as predictors of shelf life are defined.
Topics: Fragaria; Antioxidants; Powders; Food Storage; Phenols; Temperature; Spray Drying; Particle Size; Anthocyanins; Ascorbic Acid
PubMed: 38933490
DOI: 10.12688/f1000research.138509.1 -
Frontiers in Plant Science 2024is one of the most important oil crops in the world. Breeding oilseed rape with colorful flowers can greatly enhance the ornamental value of and thus improve the...
is one of the most important oil crops in the world. Breeding oilseed rape with colorful flowers can greatly enhance the ornamental value of and thus improve the economic benefits of planting. As water-soluble flavonoid secondary metabolites, anthocyanins are very important for the synthesis and accumulation of pigments in the petals of plants, giving them a wide range of bright colors. Despite the documentation of over 60 distinct flower shades in , the intricacies underlying flower color variation remain elusive. Particularly, the mechanisms driving color development across varying flower color backgrounds necessitate further comprehensive investigation. This research undertook a comprehensive exploration through the integration of transcriptome and metabolome analyses to pinpoint pivotal genes and metabolites underpinning an array of flower colors, including beige, beige-red, yellow, orange-red, deep orange-red, white, light-purple, and purple. First, we used a two-way BLAST search to find 275 genes in the reference genome of Darmor v10 that were involved in making anthocyanins. The subsequent scrutiny of RNA-seq outcomes underscored notable upregulation in the structural genes and , alongside the , , and transcriptional regulators within petals, showing anthocyanin accumulation. By synergizing this data with a weighted gene co-expression network analysis, we identified , , , , and as the key players driving anthocyanin synthesis in beige-red, orange-red, deep orange-red, light-purple, and purple petals. By integrating transcriptome and weighted gene co-expression network analysis findings with anthocyanin metabolism data, it is hypothesized that the upregulation of , which, in turn, enhances expression, plays a pivotal role in the development of pigmented oilseed rape flowers. These findings help to understand the transcriptional regulation of anthocyanin biosynthesis in and provide valuable genetic resources for breeding varieties with novel flower colors.
PubMed: 38933465
DOI: 10.3389/fpls.2024.1419508