To estimate the effects of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) on proteinuria and oxidative stress expression in type 2 diabetes patients.
68 patients with type 2 diabetes mellitus ...(T2DM) were divided into three groups according urinary albumin-to-creatinine ratio (UACR), including T2DM with non-albuminuria group (UACR < 30 mg/g), T2DM with microalbuminuria group (30 ≤ UACR ≤ 300 mg/g), T2DM with macroalbuminuria group (UACR>300 mg/g). They all received SGLT2 inhibitors (SGLT2i) treatment for 12 weeks. The expression of advanced glycation end products (AGEs) in plasma and 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine were measured as indications of oxidative stress. The 24-hour urine samples were collected to measure the concentration of proteinuria and 8-OHdG before and after 12 weeks SGLT2i treatment. Plasma renin activity (PRA), angiotensin II (Ang II) and Aldosterone (ALD) were measured to evaluate renin angiotensin aldosterone system (RASS) levels.
After 12 weeks SGLT2 inhibitors treatment, the median values of 24-hour proteinuria decreased in macroalbuminuria compared to baseline (970 vs. 821 mg/d, P = 0.006). The median values of AGEs and 8-OHdG decreased in microalbuminuria and macroalbuminuria groups when compared to baseline, AGEs (777 vs. 136 ug/ml, P = 0.003) and (755 vs. 210 ug/ml, P = 0.001), 8-OHdG (8.00 vs. 1.88 ng/ml, P = 0.001) and (11.18 vs. 1.90 ng/ml, P < 0.001), respectively. Partial correlations showed that 8-OHdG were relevant to the baseline 24-h proteinuria (r = 0.389, p = 0.001), the reduction of OHdG (Δ8-OHdG) were positively correlated with the decrease of 24-h proteinuria (Δ24-h proteinuria) after 12 weeks of SGLT2i treatment (r = 0.283, P = 0.031). There was no significant correlation between 24-h proteinuria and AGEs in baseline (r = -0.059, p = 0.640) as well as between ΔAGEs and Δ24-h proteinuria (r = 0.022, p = 0.872) after12 weeks of SGLT2i treatment in T2DM patients.
SGLT2i may reduce proteinuria in diabetic nephropathy patients, potentially by inhibiting renal oxidative stress, but not through the AGEs pathway and does not induce RAAS activation.
This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A cationic three‐dimensional (3D) metal‐organic framework (MOF) sustained by an N,N′‐diethylformamide (DEF)‐solvated zigzag‐shaped Cd5 cluster secondary building unit (SBU), Et2NH22Cd5(BTB)4(DEF)2 ⋅ ...4.75DEF (1 a, H3BTB=benzene‐1,3,5‐tribenzoic acid) shows flexible framework behavior and undergoes solvate exchange with CHCl3 to yield Et2NH22Cd5(BTB)4(DEF)2 ⋅ xCHCl3 (1 b) accompanied by changes to pore sizes and shapes. Unexpectedly, the DEF solvates coordinated to the central Cd2+ could not be replaced by strongly donor pyridyl and dipyridyl ligands. Additionally, more electron‐deficient pyridyls preferentially coordinated to the flanking Cd2+ of the Cd5 SBU, as exemplified by Et2NH22Cd5(BTB)4(DEF)2(PyCHO)2 ⋅ xSol (2 a, PyCHO=4‐pyridinealdehyde) and Et2NH22Cd5(BTB)4(DEF)2(PyAc)2 ⋅ xSol (2 b, PyAc=4‐acetylpyridine). Density functional theory (DFT) calculations were used to understand these counterintuitive observations.
Flexible friend: A metal–organic framework sustained by a Cd5 cluster shows flexible behavior and coordination preference toward electron‐deficient rather than electron‐rich pyridyl ligands. Density functional theory calculations offer binding energies of the electron‐deficient 4‐pyridinealdehyde (1.09 eV) and 4‐acetylpyridine (1.36 eV) to the flanking Cd centers, and are larger than those of the electron‐rich ligands, such as 4‐iodopyridine (0.32 eV) and 4,4′‐bipyridine (0.61 eV).
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Currently, the causal association between sleep disorders and rheumatoid arthritis (RA) has been poorly understood. In this two-sample Mendelian randomization (TSMR) study, we tried to explore ...whether sleep disorders are causally associated with RA. Seven sleep-related traits were chosen from the published Genome-Wide Association Study (GWAS): short sleep duration, frequent insomnia, any insomnia, sleep duration, getting up, morningness (early-to-bed/up habit), and snoring, 27, 53, 57, 57, 70, 274, and 42 individual single-nucleotide polymorphisms (SNPs) (
P
< 5 × 10
−8
) were obtained as instrumental variables (IVs) for these sleep-related traits. Outcome variables were obtained from a public GWAS study that included 14,361 cases and 43,923 European Ancestry controls. The causal relationship between sleep disturbances and RA risk were evaluated by a two-sample Mendelian randomization (MR) analysis using inverse variance weighted (IVW), MR-Egger regression, weighted median, and weight mode methods. MR-Egger Regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to test for horizontal pleomorphism and outliers. There was no evidence of a link between RA and frequent insomnia (IVW, odds ratio (OR): 0.99; 95% interval (CI): 0.84–1.16;
P
= 0.858), any insomnia (IVW, OR: 1.09; 95% CI: 0.85–1.42;
P
= 0.489), sleep duration (IVW, OR: 0.65, 95% CI: 0.38–1.10,
P
= 0.269), getting up (IVW, OR: 0.56, 95% CI: 0.13–2.46,
P
= 0.442), morningness (IVW, OR: 2.59; 95% CI: 0.73–9.16;
P
= 0.142), or snoring (IVW, OR: 0.95; 95% CI: 0.68–1.33;
P
= 0.757). Short sleep duration (6h) had a causal effect on RA, as supported by IVW and weighted median (OR: 1.47, 95% CI: 1.12–1.94,
P
= 0.006; OR: 1.43, 95%CI:1.01–2.05,
P
= 0.047). Sensitivity analysis showed that the results were stable. Our findings imply that short sleep duration is causally linked to an increased risk of RA. Therefore, sleep length should be considered in disease models, and physicians should advise people to avoid short sleep duration practices to lower the risk of RA.
Zinc oxide nanoparticles (ZnO-NPs) have gained significant interest in the agricultural and food industry as a means of killing or reducing the activity of microorganisms. The antibacterial ...properties of ZnO-NPs may improve food quality, which has a direct impact on human health. ZnO-NPs are one of the most investigated inorganic nanoparticles and have been used in various related sectors, with the potential to rapidly gain attention and increase interest in the agriculture and food industries. In this review, we describe various methods for preparing ZnO-NPs, their characterizations, modifications, applications, antimicrobial activity, testing procedures, and effects, including bactericidal and bacteriostatic mechanisms. It is hoped that this review could provide a better understanding of the preparation and application of ZnO nanoparticles in the field of food and agriculture, and promote their development to advance the field of food and agriculture.
Plasmacytoid dendritic cells (pDCs) are a professional type I IFN producer that play critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of the function of ...pDCs and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of the neutrophil cytosolic factor 1 (NCF1) missense variant, which is one of the most significant associated risk variants for lupus, and found that the substitution of arginine (R) for histidine (H) at position 90 in the NCF1 protein (NCF1 p.R90H) led to excessive activation of pDCs. A mechanism study demonstrated that p.R90H reduced the affinity of NCF1 for phospholipids, thereby impairing endosomal localization of NCF1. As NCF1 is a subunit of the NADPH oxidase 2 (NOX2) complex, this impairment led to an acidified endosomal pH and facilitated downstream TLR signaling. Consistently, the homozygous knockin mice manifested aggravated lupus progression in a pDC-dependent lupus model. More important, pharmaceutical intervention revealed that hydroxychloroquine (HCQ) could antagonize the detrimental function of NCF1 p.R90H in the lupus model and systemic lupus erythematosus samples, supporting the idea that NCF1 p.R90H could be identified as a genetic biomarker for HCQ application. Therefore, our study provides insights into the genetic control of pDC function and a paradigm for applying genetic variants to improve targeted therapy for autoimmune diseases.
In this study, a total of 160 experimental data points of Henry's law constant of CO
2
in 32 imidazole ionic liquids (ILs) were collected, with the temperatures range from 283 to 350 K. Herein ...intuitive and explanatory descriptors related to Henry's law constant (HLC) were suggested from the 2D structural features of the ILs according to experimental experience and laws. Temperature was used as another variable due to its significant effect on Henry's law constant. Three machine learning methods were used to construct models to fast predict the HLC based on suggested descriptors. Multi-layer Perceptrowas mainly used to build the model and compared with the results of Random forest and Multiple Linear Regression after investigating the outliers and variable selection. In addition, if only one data point was left at a similar temperature and the reduced dataset was also used to build models in the same procedure, the results were not as good as those of the full dataset but still satisfactory.
Major depression is a serious global health concern; however, the pathophysiology underlying this condition remains unclear. While numerous studies have focused on brain-specific mechanisms, few have ...evaluated the role of peripheral organs in depression. Here, we show that the liver activates an intrinsic metabolic pathway that can modulate depressive-like behavior. We find that chronic stress specifically increases the protein levels of monomeric and oligomeric soluble epoxide hydrolase (sEH), a key enzyme in epoxyeicosatrienoic acid (EET) signaling, in the liver. Hepatic deletion of Ephx2 (which encodes sEH) results in antidepressant-like effects, while the hepatic overexpression of sEH induces depressive phenotypes. The activity of sEH in hepatocytes modulates the plasma levels of 14,15-EET, which then interacts with astrocytes in the medial prefrontal cortex to mediate the effects of hepatic Ephx2 deletion. These results suggest that targeting mechanisms underlying the hepatic response to stress would increase our therapeutic options for the treatment of depression.
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•The expression levels of sEH in the liver increase significantly following CMS•The deletion of hepatic sEH results in antidepressant-like effects•The overexpression of hepatic sEH mimics the effects of chronic stress in mice•Astrocytic EET signaling in mPFC mediates the effects of hepatic Ephx2 deletion
Qin et al. show that the expression levels of hepatic sEH increase following CMS. Deletion of hepatic Ephx2 produces antidepressant-like effects, while the overexpression of Ephx2 induces depressive phenotypes. Collectively, data demonstrate that the liver is able to modulate depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•A synergistic efficacy enhancement route driven through codrug salification is developed.•The first case of dual-drug molecular salification for 5-fluorouracil is assembled.•The molecular salt shows ...optimized physicochemical and pharmacokinetic behaviors.•Synergistically enhanced antitumor effects are achieved in the molecular salt.
In order to exert the ability of biguanide metformin (MET) in optimizing biopharmaceutical properties of conventional antitumor drug 5-fluorouracil (5-FU), and further to explore synergism potentials of the biguanide drugs in the anticancer medications, a synergistic efficacy enhancement route driven through codrug salification is developed, in which the proton transference procedure is actuated through the acid-base gap, which causes optimizations in physicochemical properties and pharmacokinetic behaviors for 5-FU, and furthermore efficacy enhancement by playing adjuvant antitumor effect of biguanide drugs. Under this path, a novel codrug molecular salt metforminium 5-fluorouracilate (FU-MET) is successfully prepared as the first case of dual-drug molecular salification for 5-FU, and subjected to structural characterizations by single-crystal/powder X-ray diffraction and other techniques, confirming the existence of charge-assist hydrogen bonds and secondary helical patterns which affect physicochemical characters. The dissolubility and permeability of 5-FU are proved to be simultaneously improved after assembling the codrug, which are theoretically supported by the results from molecular electrostatic potential, Hirshfeld surface analyses and frontier molecular orbit. Furthermore, the perfection in physicochemical natures of the present codrug also lead to optimization in pharmacokinetic behaviors with prolonged half-life and higher bioavailability over pure 5-FU. More encouragingly, significant reduction in IC50 values against tumor cell lines evidence the strengthened tumor inhibition of the present molecular salt, where the synergetic effect of MET with 5-FU is found according to the CI values less than 1.0. Our present findings not only start a dual-drug molecular salification case for 5-FU with the novel crystalline codrug possessing application foreground, but contribute for exploring the possibilities of biguanide represented by MET in antitumor medication.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Since human coronavirus (HCoV)–like particles were detected in the stool specimens of acute gastroenteritis and necrotizing enterocolitis children with electron microscopy, the relationship between ...HCoV and the pediatric gastrointestinal illness had been recognized. In recent years, the overall detection rates have been low and have varied by region. HCoVs have not been considered as the major pathogens in pediatric acute gastroenteritis. HCoVs detected in children with acute gastroenteritis have included 229E, OC43, HKU1, NL63, and severe acute respiratory syndrome coronavirus, Middle East Respiratory Syndrome Coronavirus and severe acute respiratory syndrome coronavirus-2 have also been associated with gastrointestinal symptoms in children. Although digestive tract has been recognized as an infection route, it has not been possible to fully investigate the association between HCoVs infection and the gastrointestinal symptoms because of the limited number of pediatric cases. Furthermore, pathologic features have not been clear. Till now, our knowledge of severe acute respiratory syndrome coronavirus-2 is limited. However, diarrhea and vomiting have been seen in pediatric cases, particularly in newborns and infants. It has been necessary to pay more attention on gastrointestinal transmission to identify the infected children early and avoid the children without apparent or mild symptoms becoming the sources of infection.
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