Diabetic kidney disease (DKD) is a primary cause of end-stage renal disease (ESRD), and while ferroptosis is known to contribute to DKD pathogenesis, the regulatory role of the NLRP3 inflammasome in this process remains elusive. To address this research gap, we explored whether NLRP3 inhibition alleviates DKD by suppressing ferroptosis using streptozotocin-induced diabetic wild-type and NLRP3-knockout C57BL/6 mice, alongside high-glucose-cultured (30 mM) human renal tubular epithelial (HK-2) cells with or without siNLRP3 transfection. Inflammatory cytokines (IL-6, TNF-α, and IL-1β) were measured using an ELISA; oxidative stress markers (CSSG, MDA, GSH, and ROS) and the iron ion content via colorimetric assays; mitochondrial morphology by transmission electron microscopy (TEM); and ferroptosis-related proteins (ACSL4, COX2, and GPX4) through Western blotting. Our findings demonstrate that NLRP3-knockout diabetic mice displayed markedly reduced urinary albumin excretion and serum creatinine levels (p < 0.01) compared with wild-type diabetic controls, concurrent with suppressed renal iron overload and ferroptosis, diminished inflammatory cytokine levels, and attenuated oxidative stress. Pathological assessments further revealed ameliorated renal fibrosis and preserved mitochondrial ultrastructure in NLRP3-deficient mice. In vitro, siNLRP3 transfection abrogated high-glucose-induced inflammation, oxidative stress, and ferroptosis in HK-2 cells, effects that were reversed by the ferroptosis inducer erastin (p < 0.01). Mechanistically, NLRP3 deficiency was associated with upregulated GPX4 expression and downregulated ACSL4 and COX2 expression. Collectively, these results indicate that inhibition of the NLRP3 inflammasome mitigates DKD progression by suppressing ferroptosis, underscoring its translational potential as a therapeutic target for this condition.

The increasing prevalence of diabetes mellitus (DM) and prediabetes (Pre-DM) in elderly individuals necessitates refined diagnostic tools. The oral glucose tolerance test (OGTT) is cumbersome, and age may alter glycemic parameters, suggesting a need for age-specific thresholds. This study aimed to evaluate the diagnostic performance of glycated hemoglobin (HbA1c) and glycated albumin (GA) for dysglycemia in community-dwelling older adults in Chengdu, China. This was a community-based cross-sectional study that consecutively enrolled eligible community-dwelling residents aged 60 years or older in Chengdu, China. A total of 1,162 participants underwent measurements of fasting plasma glucose (FPG), HbA1c, and GA. A standard 75‑g oral glucose tolerance test (OGTT) with two‑hour post-prandial plasma glucose (2hPG) measurement was performed, and glycemic status was defined according to the World Health Organization (WHO) diagnostic criteria. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cutoff values for HbA1c and GA to detect DM and Pre-DM. Among the 1,162 participants (65.2

A chiral Brønsted acid-catalyzed asymmetric cascade aza-Piancatelli rearrangement/intramolecular Diels-Alder reaction has been developed. This method enables the atom- and step-efficient synthesis of chiral aza-[5,6,5]-tricyclic derivatives with multiple contiguous stereocenters in a highly enantioselective manner from readily available N-pentadienylanilines and 2-furylcarbinols.

Gold redox catalysis, which exploits the ability of strong π-acid activation in combination with redox reactions, has emerged as an attractive synthetic method with unique reactivities compared to other transition metals. However, gold redox chemistry bears the challenge to overcome the high redox potential of Au(I)/Au(III) (1.41 V). The classical strategy of gold redox catalysis applies strong external chemical oxidants which inevitably results in low atom economy and substrate limitations due to incompatibility with functional groups. Here we report a bidentate N-ligand (for example, Phen, Bpy) assisted gold redox catalysis using H2O2 as oxidant, which proved to be generally applicable for many forms of coupling reactions. In addition, C(sp2)–C(sp2) bicyclization coupling (cross-coupling of two cyclized substrates) is accessible under our conditions. Mechanistic studies reveal a redox elimination process in which a bidentate N-ligand is crucial for the catalytic cycle. The formation of alkynyl-AuIII–OH and vinyl-AuIII–OH species is the key process for the synergistic π-bond activation and AuI oxidation. Gold redox catalysis is an attractive synthetic method but challenging due to the high redox potential of Au(I)/Au(III). Now, a bidentate N-ligand-assisted gold redox catalysis using H2O2 as oxidant has been developed. It can be applied to various coupling reactions, including C(sp)–C(sp) cross-coupling, alkynylative cyclization and bicyclization coupling.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

MicroRNA-22 (miR-22) was suggested to be important for type 2 diabetes but its functions for this disease remained unclear. Recombinant adeno-associated virus (rAAV)-mediated miR delivery is a powerful approach to study miR functions in vivo, however, the overexpression of miR-22 by rAAV remains challenging because it is one of the most abundant miRs in the liver. In this study, a series of expression cassettes were designed and compared. It was shown that different lengths of primary miR-22 were overexpressed in HEK293 and HeLa cells but the longer ones were more efficiently expressed. miR-22 may be placed in either introns or the 3' UTR of a transgene for efficient overexpression. RNA polymerase III or II promoters were successfully utilized for miR expression but the latter showed higher expression levels in cell lines. Specifically, miR-22 was expressed efficiently together with an EGFP gene. After screening, a liver-specific TTR promoter was chosen to overexpress miR-22 in diabetic mice fed a high-fat diet. It was shown that miR-22 was overexpressed 2-3 folds which improved the insulin sensitivity significantly. The approach utilized in this study to optimize miR overexpression is a powerful tool for the creation of efficient rAAV vectors for the other miRs.

A highly efficient gold-catalyzed cycloisomerization of 1,5-diynes was developed. Various functional groups are tolerated under the mild reaction conditions, which provides an alternative approach for the synthesis of indeno[1,2-c]furans. On the basis of mechanistic studies, including crossover experiments, deuterium labeling, and computational chemistry, the product formation proceeds via a formal [5,5]-sigmatropic rearrangement, a yet unknown reactivity pattern in gold catalysis. Instead of a synchronous concerted [5,5]-sigmatropic rearrangement and beyond an asynchronous concerted mode, each involving a single transition state, two energetically low transition states (1.8 and 5.6 kJ/mol) and an intermediate associate of the migrating benzyl cation and the vinyl gold species could be located in the computations.

Gold-catalyzed difunctionalizations of o-alkynylbenzenesulfonamides with aryldiazonium salts are reported herein. Upon irradiation with the blue LEDs, benzosultam products were formed via aminoarylation accompanied by the release of N2. Without irradiation, aryldiazonium salts were engaged as efficient electrophiles, facilitating electrophilic deaurations of the vinyl-Au(I) intermediates, followed by tautomerization to give the N-aryl-substituted α-imino (E)-hydrazones. The regioselectivities of 6-endo-dig and 5-exo-dig cyclizations were excellent.

An eosin Y disodium salt-catalyzed photoredox C-H arylation of anthranils is reported. A variety of aryl diazonium tetrafluoroborates were used as aryl sources, providing the C3 cross-coupled products. The in situ generated reactive radicals were trapped by anthranils, providing an alternative method to transition-metal-catalyzed C-H arylations of anthranils. Gold-catalyzed downstream transformations demonstrate the synthetic potential of these valuable building blocks.

AIMS:Although immunoglobulin G Fc receptors with immunoreceptor tyrosine-based activation motifs (ITAM-FcγRs) have been implicated in the mediation of inflammatory responses, the importance of these receptors in the pathogenesis of cognitive impairment in geriatric diabetes remains unclear. The present study investigated the potential role of ITAM-FcγRs in cognitive impairment in geriatric diabetes. METHODS:Diabetes was induced by streptozotocin (STZ) in aged Wistar rats, and cognitive function and cerebral injury were assessed 8 weeks later using the Morris water maze (MWM), real-time PCR and Western blot. In vitro, the inhibition of ITAM-FcγRs was investigated using rat chromaffin cells cultured with high glucose. RESULTS:Aged rats with diabetes exhibited marked and persistent learning and memory impairments. Enhanced cerebral inflammation in the diabetic aged rats was associated with the overactivation of the nuclear factor κB (NF-κB) signaling pathway and the upregulation of inflammatory cytokines (interleukin-6 (IL-6) and tumor nuclear factor-α (TNF-α)) in the hippocampus. Compared to no treatment, the knockdown of FcγRIV (the main isoform of ITAM-FcγRs) markedly attenuated cognitive impairment as well as histologic and ultrastructural pathologic changes in the diabetic rats. The increased expression of inflammatory cytokines and the overactivation of the NF-κB signaling pathway were also significantly alleviated. In vitro, high glucose concentrations significantly activated the NF-κB signaling pathway and increased the expression of inflammatory cytokines. The inhibition of FcγR expression by a small interfering RNA and/or a FcγRI- and FcγRIII-neutralizing antibody significantly ameliorated the effects mediated by high glucose. CONCLUSION:The enhanced activation of the NF-κB signalling pathway may be the mechanism by which ITAM-FcγRs promote cerebral inflammation and cognitive impairment in diabetes. ITAM-FcγRs may be viewed as a potential target for preventative intervention for cognitive impairment in older adults with diabetes.

ABSTRACT Background: To estimate the impact of comorbid diabetes on caregiver stress in Alzheimer's disease (AD) patients from the Impact of Cholinergic Treatment Use (ICTUS) study. Methods: Using the Data from the ICTUS study, diabetes mellitus (DM) was recorded at baseline and caregiver burden was assessed twice per year using the Zarit Burden Interview (ZBI) scale. The three-factorial model of ZBI (the effect on the social and personal life of caregivers, the psychological burden and the feelings of guilt) was adopted. Linear mixed models were used to examine the relation between DM and the scores of ZBI. Results: The present analyses were conducted on 1,264 AD subjects. A total of 156 patients (12.3%) had DM with taking antidiabetic medication and/or self-report of a history. At baseline, the caregivers of patients with or without DM had similar ZBI global scores and similar scores of three different factors of ZBI. Unadjusted and adjusted models both indicated that ZBI global score increased over a 24-month follow-up without significant effect of DM. Similarly, unadjusted model showed that DM was not determining any significant difference in the score of any factor. However, adjusted model indicated that in diabetic patients, the scores of the social and personal life of caregivers and the psychological burden increased more slowly than those in non-diabetic patients (p = 0.04 and 0.01, respectively). Conclusions: DM may affect the caregivers’ daily social and personal life and psychological burden in AD patients. It is necessary for further research.

An efficient catalytic asymmetric cyclization/inverse-electron-demand hetero-Diels-Alder cascade reaction of beta,gamma-unsaturated alpha-ketoesters with alkyl amides or alcohols were accomplished. The process was based on the utilization bimetallic catalyst system with achiral gold(I) catalyst and chiral N,N'-dioxide/Ni(II) catalyst, delivering a variety of fused bicyclic N,O-acetals or O,O-acetals in up to 99% yield and 99% ee with >19:1 dr under mild reaction conditions. Based on the control experiments and previous studies, a possible reaction pathway of bimetallic relay catalysis cascade reactions was presented.

Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A2 (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C2-symmetric jozimine A2 (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A2 (2) represent novel potential candidates for future drug development against pancreatic cancer.

Frailty is described as a clinical state of increased vulnerability to stressors because of homoeostatic impairment and is associated with increased risk of adverse outcomes. 1 Morley J.E. Vellas B. van Kan G.A. et al. Frailty consensus: A call to action. J Am Med Dir Assoc. 2013; 14: 392-397 Abstract Full Text Full Text PDF PubMed Scopus (2257) Google Scholar The best known operationalizations of frailty are the deficit accumulation model proposed by Rockwood et al, 2 Rockwood K. Mitnitski A. Limits to deficit accumulation in elderly people. Mech Ageing Dev. 2006; 127: 494-496 Crossref PubMed Scopus (156) Google Scholar the Frailty Index (FI), and the frailty phenotype proposed by Fried et al. 3 Fried L.P. Tangen C.M. Walston J. et al. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156 Crossref PubMed Google Scholar The FI is an arithmetic/quantitative model with strong biological foundations and has been used as a marker of biological aging. 4 Cesari M. Gambassi G. van Kan G.A. Vellas B. The frailty phenotype and the frailty index: Different instruments for different purposes. Age Ageing. 2014; 43: 10-12 Crossref PubMed Scopus (426) Google Scholar Older persons with diabetes represent a very heterogeneous population exposed to an increased risk of negative health-related outcomes. Grading frailty in older persons with diabetes is extremely important because it potentially allows us to better tailor the offered care according to the individual's biological age. Our previous research has adopted the frailty phenotype to define frailty in older patients with diabetes. 5 Li Y. Zou Y. Wang S. et al. A pilot study of the FRAIL scale on predicting outcomes in Chinese elderly people with type 2 diabetes. J Am Med Dir Assoc. 2015; 16: 714.e7-714.e12 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar However, these 2 instruments are very different and, instead, should be considered complementary. 4 Cesari M. Gambassi G. van Kan G.A. Vellas B. The frailty phenotype and the frailty index: Different instruments for different purposes. Age Ageing. 2014; 43: 10-12 Crossref PubMed Scopus (426) Google Scholar To our knowledge, the operationalization of the FI in older patients with diabetes has never been formally attempted. Hence, in the present study, FI was constructed taking advantage of existing information from a routine comprehensive geriatric assessment conducted in older persons with diabetes. The distribution of the FI and its age-related patterns are investigated.

Basic and clinical research support a link between diabetes mellitus and Alzheimer disease (AD). However, the relationship with AD progression is unclear. This review focuses on the association between diabetes and cognitive decline in patients with AD. The literature published through May 2015 was searched in 3 databases: PubMed, Embase and Cochrane. Studies evaluating the effects of diabetes on patients with AD or cognitive decline were included, and extracted data were analyzed. A total of 10 articles met the inclusion criteria for review. The results of these studies were inconsistent in terms of the association between diabetes and cognitive decline. Only 2 studies demonstrated that the presence of diabetes was independently related to the progression of cognitive decline in the patients with AD, and 3 studies suggested that histories of diabetes were not correlated with the changes in cognitive function in patients with AD. Half of the included studies even indicated that histories of diabetes were associated with lesser declines in cognitive function in patients with AD. Current evidence indicates that the link between diabetes and cognitive decline in patients with AD is uncertain. Further clinical studies are needed, with larger samples, long-term follow up and an extended battery of cognitive assessments.

Although the cognitive impairment in geriatric diabetes is common, its mechanisms remain unclear and therapies are limited. The present study investigated the effects of rosiglitazone on memory impairment in aged rats with diabetes. Diabetes was induced by streptozotocin in aged Wistar rats of 20-22 months. Then, the diabetic rats were divided randomly into the diabetic model group and rosiglitazone treatment group for assessment of cognitive function and cerebral injury at 8 weeks using Morris water maze (MWM) paradigm, real-time PCR and western blot analysis. Wistar rats of the same age were also assessed as control. In vitro, the therapeutic effect of rosiglitazone was investigated using rat chromaffin cell line PC12 cultured with high glucose and/or C-reactive protein (CRP). 8 weeks after diabetes induction aged rats exhibited marked and persistent hyperglycemia, weight loss, higher level of serum CRP and learning impairments. Enhanced cerebral inflammation in aged rats with diabetes was associated with over-activation of the nuclear factor B (NF-B) signalling pathway and upregulation of inflammatory cytokines (IL-6, TNF) in the hippocampus. Compared with the diabetic group, level of serum CRP, inflammatory cytokines and over-activation of NF-B signalling pathway in the hippocampus were restored partially concomitant with attenuation of cognitive dysfunction indicated as markedly decreased escape latency and distance during MWM test in the rosiglitazone treatment group. In vitro, high glucose significantly activated NF-B signalling pathway and upregulated inflammatory cytokines. CRP synergistically promoted high glucose-mediated effects. Rosiglitazone significantly ameliorated the effects mediated by high glucose and CRP.These effects were significantly reversed by co-treatment with the PPAR antagonist T0070907. These results suggest that rosiglitazone can improve cognitive function in aged rats with diabetes by inhibiting the NF-B signal activation and decreasing the expressions of inflammatory cytokines in the hippocampus.

Human cystatin C (HCC), encoded by cystatin 3 gene, is a 13.3kDa endogenous cysteine proteinase inhibitor and an important biomarker of renal function. However, expressing recombinant cystatin C is difficult because of low yield and inclusion bodies in Escherichia coli (E. coli). In this study, we cloned HCC gene into pET-22b vector containing PelB leader signal sequence, which could direct the protein to the bacterial periplasm. Large amounts of soluble HCC could be efficiently expressed in the bacterial periplasm at 16°C with 0.1mM IPTG induction. The recombinant HCC was isolated in high purity by cation exchange chromatography and gel filtration chromatography. Furthermore, the HCC was characterized by circular dichroism (CD) and dynamic light scattering (DLS), and displayed biological activity against papain. Here, we provide a method to produce large amounts of soluble mature HCC in E. coli.

目的 观察罗格列酮对老年糖尿病大鼠认知功能、血清高敏C-反应蛋白(hs-CRP)水平及海马组织核转录因子-κB(NF-κB)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-a)表达的作用.方法 将30只20～22月龄老年Wistar大鼠随机分为3组:对照组(n=6)予生理盐水腹腔注射;糖尿病组(n=12)和罗格列酮组链脲佐菌素55 mg/kg腹腔注射;造模后罗格列酮组以罗格列酮4 mg/(kg·d)+无菌水混悬液灌胃,糖尿病组和对照组以等量无菌水灌胃,共8周.8周后应用Morris水迷宫实验评价各组大鼠的认知功能.检测各组大鼠血清hs-CRP水平、海马区域NF-κB、IL-6、TNF-α的表达.结果 罗格列酮组、糖尿病组Morris水迷宫测试中逃避潜伏期分别较正常对照组延长(P＜0.05);与糖尿病组相比较,罗格列酮组Morris水迷宫测试中潜伏期缩短(P＜0.05),中心区停留时间百分比和通过原平台位置次数增加(P＜0.05).与对照组相比,罗格列酮组和糖尿病组血清hs-CRP水平,NF-κB、IL-6、TNF-α表达升高(P＜0.01);罗格列酮组血清hs-CRP水平、NF-κB、IL-6、TNF-α表达较糖尿病组相比降低(P＜0.05).结论 糖尿病大鼠认知功能受损与血清CRP水平相关.罗格列酮对糖尿病大鼠的认知功能减退有改善作用,其机制可能与降低血清CRP水平,抑制海马组织NF-κB信号,降低IL-6、TNF-a的表达有关.

Ethnopharmacological relevance: Marsdenia tenacissima, a traditional Chinese medicinal herb, endemic to Yunnan Province is widely used to treat cough, asthma, expectorant, esophageal cancer, gastric cancer, lung cancer, and hepatocellular carcinoma. The aim of this study was to evaluate in vitro and in vivo anti-hematologic neoplasm potential of the ethanolic extract of this herb (crude ethanolic extract of Marsdenia tenacissima, CME) and by using different assays to elucidate its possible mechanism of action.Materials and methods: The cytotoxicity of CME on tumor cells and peripheral blood mononuclear cells (PBMCs) was evaluated using MIT and apoptosis assays. We also tested the effect of CME on colony formation inhibition and cell cycle distribution of tumor cells. The protein expressions of Cyclin D1, Bax, Bcl-2, caspase-3 and caspase-9 were detected through Western blotting. In vivo anti-tumor effect was evaluated by measuring tumor volume changes, measuring tumor weight, evaluation of tumor microvessel density (MVD) and TUNEL staining by using immunohistochemistry staining in tumor models of nude mice.Results: Marsdenia tenacissima ethanolic extract exhibited effects of proliferation inhibition and induction of apoptosis on human hematologic neoplasm tumor cells in vitro, as well as hematologic neoplasm growth in vivo.Conclusion: This study clearly indicated that the ethanolic extract of Marsdenia tenacissima displayed strong anti-tumor effects against hematologic neoplasm cells and could induce tumor cells apoptosis in vitro and in vivo, and also had a significant anti-angiogenic effect in vivo against tumor cell apoptosis. Its multi-mechanism of action might be associated with the cell cycle (G0/G1) arrest, induction of apoptosis through up-regulation protein expressions of Bax, caspase-9 and caspase-3 genes and down-regulation of the expressions of Cyclin D1 and Bcl-2 genes, a decrease in tumor microvessel density and an increase of TUNEL-positive cells in vivo. These findings provided the molecular theoretical basis of clinical application. (C) 2014 Elsevier Ireland Ltd. All rights reserved.