Berberine Regulates GPX4 to Inhibit Ferroptosis of Islet ß Cells.

Ferroptosis, as a kind of non-apoptotic cell death, is involved in the pathogenesis of type 1 diabetes mellitus (T1DM). Islet B cells mainly produce insulin that is used to treat diabetes. Berberine (BBR) can ameliorate type 2 diabetes and insulin resistance in many ways. However, a few clues concerning the mechanism of BBR regulating ferroptosis of islet ß cells in T1DM have been detected so far. We measured the effects of BBR and GPX4 on islet ß cell viability and proliferation by MTT and colony formation assays. Western blot and qRT-PCR were utilized to examine GPX4 expression in islet ß cells with distinct treatments. The influence of BBR and GPX4 on ferroptosis of islet ß cells was investigated by evaluating the content of Fe2+ and reactive oxygen species (ROS) in cells. The mechanism of BBR targeting GPX4 to inhibit ferroptosis of islet ß cells was further revealed by the rescue experiment. Our results showed that BBR and overexpression of GPX4 could notably accelerate cell viability and the proliferative abilities of islet ß cells. Moreover, BBR stimulated GPX4 expression to reduce the content of Fe2+ and ROS, thereby repressing the ferroptosis of islet ß cells, which functioned similarly as ferroptosis inhibitor Fer-1. In conclusion, BBR suppressed ferroptosis of islet ß cells via promoting GPX4 expression, providing new insights into the mechanism of BBR for islet ß cells.

Establishment and validation of an AI-aid method in the diagnosis of myocardial perfusion imaging.

BACKGROUND: This study aimed to develop and validate an AI (artificial intelligence)-aid method in myocardial perfusion imaging (MPI) to differentiate ischemia in coronary artery disease. METHODS: We retrospectively selected 599 patients who had received gated-MPI protocol. Images were acquired using hybrid SPECT-CT systems. A training set was used to train and develop the neural network and a validation set was used to test the predictive ability of the neural network. We used a learning technique named "YOLO" to carry out the training process. We compared the predictive accuracy of AI with that of physician interpreters (beginner, inexperienced, and experienced interpreters). RESULTS: Training performance showed that the accuracy ranged from 66.20% to 94.64%, the recall rate ranged from 76.96% to 98.76%, and the average precision ranged from 80.17% to 98.15%. In the ROC analysis of the validation set, the sensitivity range was 88.9 ~ 93.8%, the specificity range was 93.0 ~ 97.6%, and the AUC range was 94.1 ~ 96.1%. In the comparison between AI and different interpreters, AI outperformed the other interpreters (most P-value < 0.05). CONCLUSION: The AI system of our study showed excellent predictive accuracy in the diagnosis of MPI protocols, and therefore might be potentially helpful to aid radiologists in clinical practice and develop more sophisticated models.

Endocrine, genetic, and microbiome nexus of obesity and potential role of postbiotics: a narrative review.

Obesity is a public health crisis, presenting a huge burden on health care and the economic system in both developed and developing countries. According to the WHO's latest report on obesity, 39% of adults of age 18 and above are obese, with an increase of 18% compared to the last few decades. Metabolic energy imbalance due to contemporary lifestyle, changes in gut microbiota, hormonal imbalance, inherent genetics, and epigenetics is a major contributory factor to this crisis. Multiple studies have shown that probiotics and their metabolites (postbiotics) supplementation have an effect on obesity-related effects in vitro, in vivo, and in human clinical investigations. Postbiotics such as the SCFAs suppress obesity by regulating metabolic hormones such as GLP-1, and PPY thus reducing feed intake and suppressing appetite. Furthermore, muramyl di-peptides, bacteriocins, and LPS have been tested against obesity and yielded promising results in both human and mice studies. These insights provide an overview of targetable pharmacological sites and explore new opportunities for the safer use of postbiotics against obesity in the future.

A hierarchical opportunistic screening model for osteoporosis using machine learning applied to clinical data and CT images.

BACKGROUND: Osteoporosis is a common metabolic skeletal disease and usually lacks obvious symptoms. Many individuals are not diagnosed until osteoporotic fractures occur. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the gold standard for osteoporosis detection. However, only a limited percentage of people with osteoporosis risks undergo the DXA test. As a result, it is vital to develop methods to identify individuals at-risk based on methods other than DXA. RESULTS: We proposed a hierarchical model with three layers to detect osteoporosis using clinical data (including demographic characteristics and routine laboratory tests data) and CT images covering lumbar vertebral bodies rather than DXA data via machine learning. 2210 individuals over age 40 were collected retrospectively, among which 246 individuals' clinical data and CT images are both available. Irrelevant and redundant features were removed via statistical analysis. Consequently, 28 features, including 16 clinical data and 12 texture features demonstrated statistically significant differences (p < 0.05) between osteoporosis and normal groups. Six machine learning algorithms including logistic regression (LR), support vector machine with radial-basis function kernel, artificial neural network, random forests, eXtreme Gradient Boosting and Stacking that combined the above five classifiers were employed as classifiers to assess the performances of the model. Furthermore, to diminish the influence of data partitioning, the dataset was randomly split into training and test set with stratified sampling repeated five times. The results demonstrated that the hierarchical model based on LR showed better performances with an area under the receiver operating characteristic curve of 0.818, 0.838, and 0.962 for three layers, respectively in distinguishing individuals with osteoporosis and normal BMD. CONCLUSIONS: The proposed model showed great potential in opportunistic screening for osteoporosis without additional expense. It is hoped that this model could serve to detect osteoporosis as early as possible and thereby prevent serious complications of osteoporosis, such as osteoporosis fractures.

Plasmon-enhanced electrochemical oxidation of 4-(hydroxymethyl)benzoic acid.

Plasmon-mediated electrocatalysis based on plasmonic gold nanoparticles (Au NPs) has emerged as a promising approach to facilitate electrochemical reactions with the introduction of light to excite the plasmonic electrodes. We have investigated the electrochemical oxidation of 4-(hydroxymethyl)benzoic acid (4-HMBA) on gold (Au), nickel (Ni), and platinum (Pt) metal working electrodes in alkaline electrolytes. Au has the lowest onset potential for catalyzing the electrooxidation of 4-HMBA among the three metals in base, whereas Pt does not catalyze the electrooxidation of 4-HMBA under alkaline conditions, although it is conventionally a good electrocatalyst for alcohol oxidation. Both 4-carboxybenzaldehyde and terephthalic acid are detected as the products of electrochemical oxidation of 4-HMBA on the Au working electrode by high-performance liquid chromatography . The electrodeposited Au NPs on indium tin oxide (ITO)-coated glass is further utilized as the working electrode for the 4-HMBA electrooxidation. With its broad absorption in the visible and near-infrared range, we show that the Au NPs on the ITO electrode could enhance the electrochemical oxidation of 4-HMBA under green and red LED light illuminations (505 and 625 nm). A possible reaction mechanism is proposed for the electrochemical oxidation of 4-HMBA on Au working electrodes in an alkaline electrolyte.

Linguistic barriers and healthcare in China: Chaoshan vs. Mandarin.

BACKGROUND: China has 129 dialects with Mandarin as the standard and Chaoshan as the major dialect of the Chaoshan region in Guangdong. This study aimed to describe the dialect competence and usage, communication difficulty, impact of linguistic barriers, and subjective experience in healthcare. METHODS: Healthcare providers (n = 234) and healthcare consumers (n = 483) at two tertiary teaching hospitals in Shantou, Chaoshan region participated in an anonymous survey. RESULTS: Chaoshan and Mandarin were spoken respectively by ca. 80% and 6.1% of the participants. Monolinguals accounted for 28.5%, including 16.8% of Chaoshan-speaking healthcare providers and 18% of Mandarin-speaking healthcare consumers. The monolinguals preferentially used their competent dialect (Ps < 0.001) and had significant communication difficulties (Ps < 0.0001), with the mean (SD) score of 3.06 (0.96) out of 4 with Mandarin for healthcare providers and 2.18 (1.78) and 1.64 (1.40) with Mandarin and Chaoshan, respectively, for healthcare consumers. The monolingual healthcare providers perceived significant negative impacts of linguistic barriers on the entire healthcare delivery process (Ps < 0.0001). Regression analyses showed the length of stay in the Chaoshan region as a protective factor of linguistic barrier with a limited protective effect. CONCLUSIONS: This is the first report of significant linguistic barriers in healthcare imposed by Mandarin and Chaoshan dialects in Chaoshan, China. With perceived adverse impacts on the entire healthcare delivery and risks to the healthcare quality and burden, interventions such as professional interpreter service, service-learning interpreter program, or mobile interpreting apps that are medically accurate and culturally sensitive are suggested for dialectally diverse China.

LncRNA DLEU2 accelerates the tumorigenesis and invasion of non-small cell lung cancer by sponging miR-30a-5p.

Long non-coding RNAs (lncRNAs) have been reported to participate in the pathogenesis of non-small cell lung cancer (NSCLC). However, how lncRNA deleted in lymphocytic leukaemia 2 (DLEU2) contributes to NSCLC remains undocumented. The clinical significance of lncRNA DLEU2 and miR-30a-5p expression in NSCLC was analysed by using fluorescence in situ hybridization and TCGA cohorts. Gain- and loss-of-function experiments as well as a NSCLC tumour model were executed to determine the role of lncRNA DLEU2 in NSCLC. DLEU2-sponged miR-30a-5p was verified by luciferase reporter, and RIP assays. Herein, the expression of lncRNA DLEU2 was elevated in NSCLC tissues, and its high expression or low expression of miR-30a-5p acted as an independent prognostic factor of poor survival and tumour recurrence in NSCLC. Silencing of lncRNA DLEU2 repressed the tumorigenesis and invasive potential of NSCLC, whereas re-expression of lncRNA DLEU2 showed the opposite effects. Furthermore, lncRNA DLEU2 harboured a negative correlation with miR-30a-5p expression in NSCLC tissues and acted as a sponge of miR-30a-5p, which reversed the tumour-promoting effects of lncRNA DLEU2 by targeting putative homeodomain transcription factor 2 in NSCLC. Altogether, lncRNA DLEU2 promoted the tumorigenesis and invasion of NSCLC by sponging miR-30a-5p.

A Gcn5-Related N-Acetyltransferase (GNAT) Capable of Acetylating Polymyxin B and Colistin Antibiotics in Vitro.

Deeper exploration of uncharacterized Gcn5-related N-acetyltransferases has the potential to expand our knowledge of the types of molecules that can be acylated by this important superfamily of enzymes and may offer new opportunities for biotechnological applications. While determining native or biologically relevant in vivo functions of uncharacterized proteins is ideal, their alternative or promiscuous in vitro capabilities provide insight into key active site interactions. Additionally, this knowledge can be exploited to selectively modify complex molecules and reduce byproducts when synthetic routes become challenging. During our exploration of uncharacterized Gcn5-related N-acetyltransferases from Pseudomonas aeruginosa, we identified such an example. We found that the PA3944 enzyme acetylates both polymyxin B and colistin on a single diaminobutyric acid residue closest to the macrocyclic ring of the antimicrobial peptide and determined the PA3944 crystal structure. This finding is important for several reasons. (1) To the best of our knowledge, this is the first report of enzymatic acylation of polymyxins and thus reveals a new type of substrate that this enzyme family can use. (2) The enzymatic acetylation offers a controlled method for antibiotic modification compared to classical promiscuous chemical methods. (3) The site of acetylation would reduce the overall positive charge of the molecule, which is important for reducing nephrotoxic effects and may be a salvage strategy for this important class of antibiotics. While the physiological substrate for this enzyme remains unknown, our structural and functional characterization of PA3944 offers insight into its unique noncanonical substrate specificity.

Bioinspired Peptide-Coated Superhydrophilic Poly(vinylidene fluoride) Membrane for Oil/Water Emulsion Separation.

Polyvinylidene fluoride (PVDF) membranes are limited in the field of oil-in-water emulsion treatment because the intrinsic hydrophobicity of PVDF can cause serious membrane fouling. Here, a superhydrophilic PVDF membrane (PVDF@PDA-GSH) was fabricated using a facile, versatile, mussel-inspired method. The pristine PVDF membrane was coated with dopamine under mild alkaline conditions by a dip-coating method, followed by addition of glutathione (GSH) via a simple reaction. GSH was successfully coated onto the membrane surface and confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray spectrometry. Hierarchical surface structure and superhydrophilicity were examined by scanning electron microscopy and contact angle, respectively, giving the PVDF@PDA-GSH membrane excellent wettability and antifouling ability. The water flux of PVDF@PDA-GSH was several-fold higher than conventional filtration membranes, and the oil rejection ratio was nearly 99%. The PVDF@PDA-GSH membrane also showed favorable reusability because the flux recovery ratio (FRR) remained above 90% after five cycles. In general, these results indicated that this modification might provide a good method for the fabrication of superhydrophilic PVDF membranes with good prospects for water filtration applications.

Cationic Palladium(II)-Catalyzed Reductive Cyclization of Alkynyl Cyclohexadienones.

A cationic palladium(II)-catalyzed reductive cyclization of cyclohexadienone-containing 1,6-enynes by using ethanol as a hydrogen donor and solvent was successfully developed. This procedure offers convenient access to cyclohexenone-annulated heterocycles under mild reaction conditions. The reaction was initiated by hydropalladation of the alkyne and was quenched by addition of the intramolecular conjugate alkene. This possible mechanism was preliminarily demonstrated by deuterium-labeling experiments.

Downregulation of C-Terminal Tensin-Like Protein (CTEN) Suppresses Prostate Cell Proliferation and Contributes to Acinar Morphogenesis.

C-terminal tensin-like protein (CTEN) is a member of tensin family, which is crucial for the assembly of cell-matrix adhesome. Unlike other tensins, CTEN is selectively expressed only in a few tissues such as the prostate. However, the biological relevance of CTEN in normal prostate is poorly understood. In this study, we revealed that CTEN is selectively expressed in the prostate epithelial cells and enriched in the basal compartment. Knockdown of CTEN in RWPE-1 cells suppresses cell proliferation and results in G1/S cell cycle arrest as well as the accumulation of cyclin-dependent kinase (CDK) inhibitors, p21 and p27. Moreover, the expression of CTEN is decreased during acinar morphogenesis using Matrigel-based three-dimensional (3D) culture. In the course of acinar formation, induction of CTEN reactivates focal adhesion kinase (FAK) Y397 phosphorylation and disrupts the acini structure. This study, to our knowledge, is the first report demonstrating that downregulation of CTEN is required for luminal differentiation and acinar formation.

cis-ß-Bromostyrene derivatives from cinnamic acids via a tandem substitutive bromination-decarboxylation sequence.

cis-ß-Bromostyrene derivatives were synthesized stereospecifically from cinnamic acids through ß-lactone intermediates. The synthetic sequence did not require the purification of the ß-lactone intermediates although they were found to be stable and readily purified in most cases.

Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine.

The interaction of various 1,2-dibromides with NEt3 under various conditions (THF and DMF, respectively) at different temperatures was investigated. Our results from these reactions show that substrate dependent dehydrobrominations compete with reductive debrominations. A comprehensive discussion of these competitive pathways is offered.

Reductive debromination of 1,2-dibromides with anisidines.

vic -Dibromides containing the α-bromocarbonyl or α-bromoaromatic moieties were reductively debrominated to furnish alkenes in high yield. o- and m-Anisidines but not p-anisidine were found to be effective debrominating agents. The reductive debrominations were found to be trans-stereospecific.

Convenient synthesis of phosphonohydrazines from arylamines.

Phosphonohydrazines were prepared in good yield from corresponding arylamines by a one-pot reaction through diazotization with an organic nitrite and treatment with a trialkyl phosphite. The trialkyl phosphite is postulated to function as a nucleophile as well as a reducing agent.

One-dimensional CdS/TiO2 nanofiber composites as efficient visible-light-driven photocatalysts for selective organic transformation: synthesis, characterization, and performance.

CdS/TiO2 heterojunction nanofibers have been successfully synthesized through the photodeposition of CdS on 1D TiO2 nanofibers that were prepared via a facile electrospinning method. The as-synthesized samples showed high photocatalytic activities upon selectively oxidizing a series of alcohols into corresponding aldehydes under visible light irradiation. TEM observations revealed that CdS was closely grown on the TiO2 nanofibers. Moreover, it was found that the CdS/TiO2 nanofibers that were photodeposited for 4 h exhibited the highest catalytic activity, with a conversion of 22% and a selectivity of 99%, which were much higher than those of commercial CdS. In addition, we also discuss the photoabsorption performance and the reaction mechanism of the photocatalytic oxidation of alcohols.

Evaluation of benzoic acid derivatives as sirtuin inhibitors.

Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities.

Reactivity in the nucleophilic aromatic substitution reactions of pyridinium ions.

The "element effect" in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving group order, L = F > NO2 > Cl ≈ Br > I, in activated aryl substrates. A different leaving group order is observed in the substitution reactions of ring-substituted N-methylpyridinium compounds with piperidine in methanol: 2-CN ≥ 4-CN > 2-F ∼ 2-Cl ∼ 2-Br ∼ 2-I. The reactions are second-order in [piperidine], the mechanism involving rate determining hydrogen-bond formation between piperidine and the substrate-piperidine addition intermediate followed by deprotonation of this intermediate. Computational results indicate that deprotonation of the H-bonded complex is probably barrier free, and is accompanied by simultaneous loss of the leaving group (E2) for L = Cl, Br, and I, but with subsequent, rapid loss of the leaving group (E1cB-like) for the poorer leaving groups, CN and F. The approximately 50-fold greater reactivity of the 2- and 4-cyano substrates is attributed to the influence of the electron withdrawing cyano group in the deprotonation step. The results provide another example of ß-elimination reactions poised near the E2-E1cB mechanistic borderline.

Convenient synthesis of N1-substituted orotic acid derivatives.

A convenient and efficient method for the synthesis of N1-substituted orotic acid derivatives is reported. The synthetic route utilizes substituted maleimide as synthetic intermediate and takes only four simple steps from readily available starting materials. As a result, orotic acid derivatives with various alkyl and aromatic groups at N1 can be readily synthesized.

Facile and rapid synthesis of pyrochlore W2O6 x H2O nanoplate via a fluorinion-assisted hydrothermal process.

Pyrochlore W2O6 x H2O were successfully prepared via a facile and rapid hydrothermal process in the presence of fluorinion. It is worth noting that our developed method can efficiently overcome the tedious process in the preparation of nanostructured tungstic oxide in the previous reports. The as-prepared samples have been characterized by XRD, SEM and TEM. Results showed the morphologies of the samples were nanoplate and the thickness of the plate was estimated at about several nanometers. TEM image further revealed that the plates were trigonal-like with equal lengths of about 300 nm. Furthermore the selected area electron diffraction (SAED) pattern taken from a single nanoplate indicated that the nanoplates were the single crystals with a preferential growth direction along the [011] direction. The effect of the additive ions on the formation has also been discussed. It was found that the fluorinion played a key role in the formation of W2O6 x H2O nanoplates. It is hoped that our work could provide a new insight into the facile and rapid preparation of metal oxide nanomaterials.