Search

Background To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk of incident dementia. Methods The present study is a prospective study of 461 563 participants from the UK Biobank. The age at diabetes diagnosis was determined by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidential intervals (CIs). Results During a median follow-up of 8.1 years, 2 233 dementia cases were recorded. As compared with normoglycemic individuals, individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with participants with diabetes duration of Conclusions Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.

The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFb1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFb1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed with no observable indications of DNA damage response. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, shuttling between the nucleus and cytoplasm, and clustering at the nuclear periphery. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFb1-induced compositional changes in the chromatin and nuclear lamina.

Over the decades, there have been continuous efforts to enhance the quality of human life. Postmenopausal syndrome is a serious concern for the wellbeing of a woman's health. Hormonal therapy is currently the mainstay of treatment for this condition. However, this therapy could lead to estrogen abuse, leading to adverse reactions and side effects. As a result, hormonal therapy has been unsuccessful in ameliorating postmenopausal syndrome. Cistanche deserticola is a classical tonic herb in traditional Chinese medicine. It exhibits significant estrogenic activity. The main active compounds of this herb are glycosides. In a previous experiment, three important factors contributing to the total glycoside yield, acteoside yield, and estrogenic activity were identified, namely, eluent concentration, pH, and eluent volume. In this experiment, an optimal purification process was determined using a central composite design-response surface methodology to obtain glycosides from this herb. An eluent (ethanol) concentration of 85% and volume of 25 BV at a pH of 11 was found to be optimal. Twenty-one active compounds were identified by a high-performance liquid chromatography/ quadrupole time-of-flight mass spectrometry assay. This study provides valuable insights for further in-depth research evaluating the estrogenic activities of total glycosides of Cistanche deserticola.

Methamphetamine (METH)-induced cell death contributes to the pathogenesis of neurotoxicity; however, the relative roles of oxidative stress, apoptosis, and autophagy remain unclear. L-Ascorbate, also called vitamin (Vit.) C, confers partial protection against METH neurotoxicity via induction of heme oxygenase-1. We further investigated the role of Vit. C in METH-induced oxidative stress, apoptosis, and autophagy in cortical cells. Exposure to lower concentrations (0.1, 0.5, 1 mM) of METH had insignificant effects on ROS production, whereas cells exposed to 5 mM METH exhibited ROS production in a time-dependent manner. We confirmed METH-induced apoptosis (by nuclear morphology revealed by Hoechst 33258 staining and Western blot showing the protein levels of pro-caspase 3 and cleaved caspase 3) and autophagy (by Western blot showing the protein levels of Belin-1 and conversion of microtubule-associated light chain (LC)3-I to LC3-II and autophagosome staining by monodansylcadaverine). The apoptosis as revealed by cleaved caspase-3 expression marked an increase at 18 h after METH exposure while both autophagic markers, Beclin 1 and LC3-II, marked an increase in cells exposed to METH for 6 and 24 h, respectively. Treating cells with Vit. C 30 min before METH exposure time-dependently attenuated the production of ROS. Vitamin C also attenuated METH-induced Beclin 1 and LC3-II expression and METH toxicity. Treatment of cells with Vit. C before METH exposure attenuated the expression of cleaved caspase-3 and reduced the number of METH-induced apoptotic cells. We suggest that the protective effect of Vit. C against METH toxicity might be through attenuation of ROS production, autophagy, and apoptosis.

Background: Cistanche deserticola, a traditional Chinese herb medicine, has been widely used for thousands of years with the activities of hormone regulation, immunomodulatory, antioxidative, neuroprotective, anti-inflammatory, and estrogen. Glycosides of Cistanches (GCs) were the main bioactivity components of the herb. Objective: The objective of the study is to study estrogenic activity and the mechanism about estrogen receptors (ERs) of GCs. Materials and Methods: Cell proliferation was measured using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide assay for MCF-7 cells. The cell cycle was detected using flow cytometry, and proliferation index was calculated. The mRNA and protein expressions of ERα and ERβ were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis as the reported method with minor modifications. Results: GCs group at the concentrations of 1.75, 17.5, and 175 μg/mg could enhance proliferation of the MCF-7 cell lines with a time and dosage-dependent manner. Combined medication group (fulvestrant with estradiol [E2] or GCs) could lead to the incline of proliferation rate compared with the individual medication group (P

In recent years, a river-dredging project has been executed in Nantou, Taiwan. A large number of diesel vehicles carrying gravel and sand shuttle back and forth on the main traffic roads (Tai-16 and Tai-21). The purpose of this study is to figure out the levels of metals contributed by those vehicles to the surrounding environment. Eight stations along the roadside of diesel transport routes were selected as exposure sites, while a small village located about 9 km away from the diesel transport routes was selected as the control site. The mass concentrations of coarse and fine particulate matter indicated that contributions from traffic fleets resulted in a higher percentage of coarse particulate matter in the ambient air at exposure sites in comparison with that at control site. Significantly higher values of EC (elemental carbon) concentrations and ratios of EC/OC (organic carbon) at exposure sites indicate that diesel vehicles at exposure sites contributed a greater amount of pollutants than gasoline vehicles. Exposure site concentrations for all metals measured (Fe, Al, Mn, Pb, Zn, Cu, Ni, Mo and As) for fine and coarse particulate matter were all higher than those at the control site. Recorded levels of metal contents in road dust and riverside soil near Tai-16 and Tai-21 showed that while the traffic fleet did not increase the metal contents of crustal elements in the road dust, it did significantly increase the metal contents of traffic-related elements. Enrichment factors (EFs) were calculated with respect to road dust (EFroad) and with respect to the samples of riverside soil (EFriver). Among these metals, Mo was the most highly-enriched metal. The extremely high EFriver value (4300) of Mo indicates that these stations were highly polluted by diesel emission. Whereas the significantly high EFroad value (810) of Mo implies that a considerable of Mo was emitted from tailpipe of diesel vehicles.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Programmed death of neuronal cells plays a crucial role in acute and chronic neurodegeneration following TBI. The tumor suppressor protein p53, a transcription factor, has been recognized as an important regulator of apoptotic neuronal death. The p53 inactivator pifithrin-α (PFT-α) has been shown to be neuroprotective against stroke. A previous cellular study indicated that PFT-α oxygen analogue (PFT-α (O)) is more stable and active than PFT-α. We aimed to investigate whether inhibition of p53 using PFT-α or PFT-α (O) would be a potential neuroprotective strategy for TBI. To evaluate whether these drugs protect against excitotoxicity in vitro, primary rat cortical cultures were challenged with glutamate (50mM) in the presence or absence of various concentrations of the p53 inhibitors PFT-α or PFT-α (O). Cell viability was estimated by LDH assay. In vivo, adult Sprague Dawley rats were subjected to controlled cortical impact (CCI, with 4m/s velocity, 2 mm deformation). Five hours after injury, PFT-α or PFT-α (O) (2 mg/kg, i.v.) was administered to animals. Sensory and motor functions were evaluated by behavioral tests at 24 h after TBI. Apoptotic cells and p53-positive neurons were identified by double staining with cell-specific markers. Levels of mRNA encoding for p53-regulated genes (BAX, PUMA, Bcl-2 and p21) were measured by reverse transcription followed by real time-PCR from TBI animals without or with PFT- α/PFT- α (O) treatment. We found that PFT-α (O) (10uM) enhanced neuronal survival against glutamate-induced cytotoxicity in vitro more effectively than PFT-α (10uM). In vivo PFT-α (O) treatment enhanced functional recovery and decreased contusion volume at 24 h post-injury. Neuroprotection by PFT-α (O) treatment also reduced p53-positive neurons in the cortical contusion region. In addition, p53-regulated PUMA mRNA levels at 8h were significantly reduced by PFT-α (O) administration after TBI. PFT-α (O) treatment also decreased phospho-p53 positive neurons in the cortical contusion region. Our data suggest that PFT-α (O) provided a significant reduction of cortical cell death and protected neurons from glutamate-induced excitotoxicity in vitro, as well as improved neurological functional outcome and reduced brain injury in vivo via anti-apoptotic mechanisms. The inhibition of p53-induced apoptosis by PFT-α (O) provides a useful tool to evaluate reversible apoptotic mechanisms and may develop into a novel therapeutic strategy for TBI.

The xylanase R8 gene (xynR8) from uncultured rumen fungi was cloned and successfully expressed in Lactobacillus reuteri. A xylanase activity of 132.1 U/mL was found in the broth of L. reuteri R8, the transformant containing pNZ3004 vector with xynR8 gene insertion. Two distinct forms of recombinant xylanase with different hydrophobicities and molecular weights were found in the broth after purification. According to the results of Western blotting, only the T7-tag, fused in the N-terminus of XynR8, could be bound to the expressed proteins, which indicated that the C-terminus of XynR8 had been truncated. These results, combined with tryptic digestion and mass spectrometry analyses, allow us to attribute the two xylanase forms to an optional cleavage of C-terminal sequences, and XynR8A, a 13 amino acid residues truncated form, and XynR8B, a 22 amino acid residues truncated form, were the main products in the extracellular fraction of L. reuteri R8. The specific activities of XynR8A and R8B were 1028 and 395 U/mg protein. Both forms of recombinant xylanase displayed a typical endoxylanase activity when they were reacted with xylan, but XynR8A demonstrated a better specific activity, catalytic efficiency and thermostability than XynR8B according to the results of enzyme characterization. These changes in enzyme properties were highly possibly caused by the present of the β-sheet in the C-terminal undeleted fragment of XynR8A. This study demonstrates that modified forms with different enzyme properties could be produced when a gene was recombinantly expressed by a L. reuteri transformant.