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Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM).
OBJECTIVE
To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM).
METHODS
Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1, 2017 to December 31, 2022. According to drug prescription records, the patients were divided into metformin plus sitagliptin group (combination group) and metformin monotherapy group(monotherapy group). A series of retrospective cohorts were constructed according to the index date.Finally, full retrospective cohorts were constructed according to propensity score model, including baseline covariates that might be related to outcomes, to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics. The participants were followed up from the index date until the first occurrence of the following events: Diagnosis of outcomes, death, or the end of the study period (December 31, 2022). Cox proportional risk model was used to estimate the hazard ratio()and 95% confidence interval () of sitagliptin added to metformin on 3-point major adverse cardiovascular events (3P-MACE) combination outcome and secondary cardiovascular outcomes.
RESULTS
Before propensity score matching, the proportion of the patients in combination group using insulin, α glucosidase inhibitors, sodium-glucose transporter 2 inhibitors (SGLT-2I) and glienides at baseline was higher than that in monotherapy group, and the baseline fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels in combination group were higher than those in monotherapy group. After propensity score matching, 5 416 subjects were included in the combination group and the monotherapy group, and baseline characteristics were effectively balanced between the groups. The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 person years, respectively. Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy (=1.00, 95% : 0.91-1.10). In secondary outcomes analysis, the incidence of cardiovascular death was lower in the combination group than in the monotherapy group (=0.59, 95% : 0.41-0.85), and no association was found between sitagliptin and the risk of myocardial infarction and stroke (=1.12, 95% : 0.89-1.41; =0.99, 95% : 0.91-1.12).
CONCLUSION
In T2DM patients in Yinzhou district of Ningbo, compared with metformin alone, sitagliptin added to metformin may reduce the risk of cardiovascular death, and do not increase the incidence of overall cardiovascular events. The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.
Topics: Humans; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Metformin; Retrospective Studies; Hypoglycemic Agents; Male; Female; Drug Therapy, Combination; Cardiovascular Diseases; Middle Aged; Propensity Score; Proportional Hazards Models; Aged
PubMed: 38864127
DOI: 10.19723/j.issn.1671-167X.2024.03.008 -
BMC Endocrine Disorders Jun 2024Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph...
OBJECTIVE
Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs.
METHODS
Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases.
RESULTS
In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas.
CONCLUSION
Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.
Topics: Humans; Ubiquitin Thiolesterase; Iran; Endosomal Sorting Complexes Required for Transport; Pituitary ACTH Hypersecretion; Adult; Female; Male; Endopeptidases; Mutation; Middle Aged; ACTH-Secreting Pituitary Adenoma; Middle Eastern People
PubMed: 38862897
DOI: 10.1186/s12902-024-01619-z -
Analytical Chemistry Jun 2024Low-field (LF) MRI promises soft-tissue imaging without the expensive, immobile magnets of clinical scanners but generally suffers from limited detection sensitivity and...
Low-field (LF) MRI promises soft-tissue imaging without the expensive, immobile magnets of clinical scanners but generally suffers from limited detection sensitivity and contrast. The sensitivity boost provided by hyperpolarization can thus be highly synergistic with LF MRI. Initial efforts to integrate a continuous-bubbling SABRE (signal amplification by reversible exchange) hyperpolarization setup with a portable, point-of-care 64 mT clinical MRI scanner are reported. Results from H SABRE MRI of pyrazine and nicotinamide are compared with those of benchtop NMR spectroscopy. Comparison with MRI signals from samples with known HO/DO ratios allowed quantification of the SABRE enhancements of imaged samples with various substrate concentrations (down to 3 mM). Respective limits of detection and quantification of 3.3 and 10.1 mM were determined with pyrazine H polarization () enhancements of ∼1900 ( ∼0.04%), supporting ongoing and envisioned efforts to realize SABRE-enabled MRI-based molecular imaging.
Topics: Magnetic Resonance Imaging; Point-of-Care Systems; Niacinamide; Molecular Imaging; Pyrazines; Humans
PubMed: 38857182
DOI: 10.1021/acs.analchem.4c01299 -
Acta Crystallographica Section B,... Jun 2024A new Zn coordination polymer (CP) based on 2,3-pyrazine dicarboxylic acid (Hpzdc) and 4,4'-bipyridine (bpy) (ZCP) was synthesized using a facile slow evaporation...
A new Zn coordination polymer (CP) based on 2,3-pyrazine dicarboxylic acid (Hpzdc) and 4,4'-bipyridine (bpy) (ZCP) was synthesized using a facile slow evaporation method. Single-crystal X-ray diffraction revealed that ZCP is a two-dimensional porous CP, [Zn(pzdc)(bpy)(HO)], with van der Waals forces as the dominant interaction within its layers forming a 6 network. Employing energetic ultrasound irradiation, nanoscale ZCP (nZCP) was successfully synthesized and Eu ions were incorporated within its host lattice (Eu@nZCP). The resulting platform exhibits superior fluorescence characteristics and demonstrates notable optical durability. Therefore, it was used as a dual detection fluorescent sensing platform for the detection of mercury and L-cysteine (L-Cys) in aqueous media through a turn-off/on strategy. In the turn-off process, the fluorescence emission of Eu@nZCP progressively quenches by the addition of Hg via a photo-induced electron transfer (PET) mechanism. The fluorescence of Eu@nZCP is quenched to establish a low fluorescence background through the incorporation of Hg. This devised turn-on fluorescent system is suitable for the recognition of L-Cys (based on the strong affinity of L-Cys to the Hg ion) through a quencher detachment mechanism. This method attained a relatively wide linear range, spanning from 0.001 to 25 µM, with the low detection limit of 5 nM for the sensing of Hg. Also, the corresponding limit of detection (LOD) for L-Cys is 8 nM in a relatively wide linear range, spanning from 0.001 to 40 µM.
PubMed: 38856649
DOI: 10.1107/S2052520624003019 -
Scientific Reports Jun 2024The European brittle star Amphiura filiformis emits blue light, via a Renilla-like luciferase, which depends on the dietary acquisition of coelenterazine. Questions...
The European brittle star Amphiura filiformis emits blue light, via a Renilla-like luciferase, which depends on the dietary acquisition of coelenterazine. Questions remain regarding luciferin availability across seasons and the persistence of luminous capabilities after a single boost of coelenterazine. To date, no study has explored the seasonal, long-term monitoring of these luminous capabilities or the tracking of luciferase expression in photogenic tissues. Through multidisciplinary analysis, we demonstrate that luminous capabilities evolve according to the exogenous acquisition of coelenterazine throughout adult life. Moreover, no coelenterazine storage forms are detected within the arms tissues. Luciferase expression persists throughout the seasons, and coelenterazine's presence in the brittle star diet is the only limiting factor for the bioluminescent reaction. No seasonal variation is observed, involving a continuous presence of prey containing coelenterazine. The ultrastructure description provides a morphological context to investigate the green autofluorescence signal attributed to coelenterazine during luciferin acquisition. Finally, histological analyses support the hypothesis of a pigmented sheath leading light to the tip of the spine. These insights improve our understanding of the bioluminescence phenomenon in this burrowing brittle star.
Topics: Animals; Seasons; Pyrazines; Imidazoles; Echinodermata; Luminescence; Luciferases; Luminescent Measurements; Light
PubMed: 38853171
DOI: 10.1038/s41598-024-64010-x -
International Journal of Food... Jun 2024The impact of paprika and dextrose addition on the surface of dry cured loins was analysed attending to differences in microbiota composition and aroma profile. Three...
The impact of paprika and dextrose addition on the surface of dry cured loins was analysed attending to differences in microbiota composition and aroma profile. Three different types of loins containing either dextrose (D), paprika (P) or a mixture of dextrose and paprika (DP) were manufactured. The loins were characterized using physic-chemical parameters, free amino acids, volatile compounds and aroma sensorial analysis, as well as applying microbiological counts and metagenomics of the 16S rRNA gene and its rDNA region. The analysis of volatile compounds clearly distinguished all loins, whereas the total content of free amino acids only separated P from D and DP loins. The main sensory differences were linked to paprika addition, which increased the perception of paprika and smoky odors as well as cured, savoury and cheesy notes. Microbial counts analysis could not differentiate between the three loin types; however, metagenomics analysis revealed clear differences in key bacterial and fungal genera among the three loins. Paprika addition favoured dominance of Latilactobacillus in the microbiota of P loins. On the contrary, dextrose addition caused the dominance of Staphylococcus in the microbiota of D loins. In DP loins, both genera were similarly represented in the bacterial community. Regarding fungi, large differences could be observed within the P and D loins, whereas the proportion of Debaryomyces in DP loins increased. The microbiota composition of DP loins controlled the lipid oxidation phenomenon, reducing the generation of derived volatiles producing rancid notes and increase the volatile compounds derived from amino acids such as branched aldehydes, pyrazines and pyrroles, providing particular aroma notes to the loins.
PubMed: 38851175
DOI: 10.1016/j.ijfoodmicro.2024.110782 -
Phytomedicine : International Journal... Aug 2024A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce...
BACKGROUND
A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear.
PURPOSE
We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors.
METHODS
Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured.
RESULTS
Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTEN tumor cells were resistant to celastrol, while PTEN cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTEN CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTEN CCA cells. Disrupting the autophagic pathway in PTEN CCA cells enhanced the cytotoxic effect of celastrol.
CONCLUSION
PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTEN CCA.
Topics: Cholangiocarcinoma; Pentacyclic Triterpenes; PTEN Phosphohydrolase; Humans; Cell Line, Tumor; Bile Duct Neoplasms; Triterpenes; Molecular Docking Simulation; Tripterygium; Antineoplastic Agents, Phytogenic; Proteasome Endopeptidase Complex; Autophagy; Bortezomib
PubMed: 38851099
DOI: 10.1016/j.phymed.2024.155790 -
Biochemical and Biophysical Research... Sep 2024Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic...
Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.
Topics: Animals; Caenorhabditis elegans; Mechanistic Target of Rapamycin Complex 1; Pyrazines; Mitochondria; Signal Transduction; AMP-Activated Protein Kinases; Aging; Caenorhabditis elegans Proteins; Nitrogen Oxides
PubMed: 38850811
DOI: 10.1016/j.bbrc.2024.150220 -
Chemical Record (New York, N.Y.) Jun 2024In the last past twenty years, research on luminescent platinum (II) complexes has been intensively developed for useful application such as organic light emitting... (Review)
Review
In the last past twenty years, research on luminescent platinum (II) complexes has been intensively developed for useful application such as organic light emitting diodes (OLEDs). More recently, new photoluminescent complexes based on diazine ligands (pyrimidine, pyrazine, pyridazine, quinazoline and quinoxaline) have been developed in this context. This review will summarize the photophysical properties of most of the phosphorescent diazine Pt(II) complexes described in the literature and compare the results to pyridine analogues whenever possible. Based on the emission color, and the photoluminescence quantum yield (PLQY) values, the relationship between structure modification, and photophysical properties are highlighted. Tuning of emission color, quantum yields in solution and solid state and, for some complexes, aggregation induced emission (AIE) or thermally activated delayed fluorescence (TADF) properties are described. When emitting OLEDs have been built from diazine Pt(II) complexes, the external quantum efficiency (EQE) values and luminance for different emission wavelengths and in some cases, chromaticity coordinates obtained from devices, are given. Finally, this review highlights the growing interest in studies of new luminescent diazine Pt(II) complexes for OLED applications.
PubMed: 38847061
DOI: 10.1002/tcr.202300335 -
Luminescence : the Journal of... Jun 2024Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA...
Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA products to inhibit viral replication. While, adenine is a purine nucleobase that is found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to generate genetic information. For the first time, the binding mechanism between FVP and adenine was determined using different techniques, including UV-visible spectrophotometry, spectrofluorimetry, synchronous fluorescence (SF) spectroscopy, Fourier transform infrared (FTIR), fluorescence resonance energy transfer (FRET), and metal ion complexation. The fluorescence spectra indicated that FVP is bound to adenine via Van der Waals forces and hydrogen bonding through a spontaneous binding process (ΔG < 0). The quenching mechanism was found to be static. Various temperature settings were used to investigate thermodynamic characteristics, such as binding forces, binding constants, and the number of binding sites. The reaction parameters, including the enthalpy change (ΔH) and entropy change (ΔS), were calculated using Van't Hoff's equation. The findings demonstrated that the adenine-FVP binding was endothermic. Furthermore, the results of the experiments revealed that some metal ions (K, Ca, Co, Cu, and Al) might facilitate the binding interaction between FVP and adenine. Slight changes are observed in the FTIR spectra of adenine, indicating the binding interaction between adenine and FVP. This study may be useful in understanding the pharmacokinetic characteristics of FVP and how the drug binds to adenine to prevent any side effects.
Topics: Pyrazines; Amides; Adenine Nucleotides; Antiviral Agents; Spectroscopy, Fourier Transform Infrared; Thermodynamics; Spectrometry, Fluorescence; Fluorescence Resonance Energy Transfer; Spectrophotometry, Ultraviolet; Binding Sites; Adenine
PubMed: 38845344
DOI: 10.1002/bio.4792