Loss of β‐cell number and function is a hallmark of diabetes. β‐cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily ...expressed in β‐cells. This expression was up‐regulated in β‐cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated β‐cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in β‐cells via its action on the pathway of Ndufs3 and p22phox. Finally, we found that 2‐β‐D‐glucopyranosyloxy1‐hydroxytrideca 5,7,9,11‐tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of β‐cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.
SYNOPSIS
Pancreatic β‐cell failure is associated with diabetes. Pdia4, a protein disulfide isomerase, is identified as a crucial regulator of β‐cell pathogenesis and diabetes.
Pdia4 interacts with Ndufs3 and p22phox and engages them in mitochondrial and cytosolic ROS production in β‐cells.
Pharmacological inhibition of Pdia4 disrupts the interaction of Pdia4 and its downstream partners, decreases ROS production, and ameliorates β‐cell failure and diabetes.
Pancreatic β‐cell failure is associated with diabetes. Pdia4, a protein disulfide isomerase, is identified as a crucial regulator of β‐cell pathogenesis and diabetes.
The survival and foraging of
Shiraki in a microbe-rich environment reflect the adaptation of an extraordinary, sophisticated defense mechanism by the nest-mates. We aimed to explore the host pathogen ...interaction by studying caste-specific volatile chemistry and genes encoding the antioxidant defense of winged imagoes, nymphs, soldiers and workers of Formosan subterranean termites. Qualitative analyses of
Shiraki performed by HS-SPME/GC-MS showed considerable variations in the chemical composition of volatile organic compounds (VOCs) and their proportions among all the castes. Winged imagoes produced the most important compounds such as naphthalene and
hexanoic acid. The antifungal activity of these compounds along with nonanal,
-pentadecane,
tetradecane,
-heptadecane and methyl octanoate against the conidial suspensions of
and
isolates enable us to suggest that the failure of natural fungal infection in the nest is due to the antiseptic environment of the nest, which is mainly controlled by the VOCs of nest-mates. In addition, conidial germination of
and
isolates evaluated on the cuticle of each caste showed significant variations among isolates and different castes. Our results showed that the conidia of
02049 exhibited the highest germination on the cuticle of all the inoculated castes. Moreover, we recorded the lowest germination of the conidia of
200436. Caste-specific germination variations enabled us to report for the first time that the cuticle of winged imagoes was found to be the most resistant cuticle. The analysis of the transcriptome of
Shiraki revealed the identification of 17 genes directly involved in antioxidant defense. Expression patterns of the identified antioxidant genes by quantitative real-time PCR (qPCR) revealed the significantly highest upregulation of
,
,
,
,
,
,
,
,
and
genes among winged imagoes upon infection with the most virulent isolate,
02049. Furthermore, soldiers showed the least expression of genes encoding antioxidant defense. Our findings indicated that the volatile chemistry of nest-mates and genes encoding antioxidant defense greatly contribute to the survival and foraging of Formosan subterranean termites in a microbe-rich habitat.
Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating ...the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role.
(CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis-based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski's rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis-related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD.
Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer's disease (AD).
(UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. ...This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes.
Purpose
Ultrasomics is a radiomics technique that extracts high-throughput quantitative data from ultrasound imaging. The aim of this study was to differentiate malignant from benign focal liver ...lesions (FLLs) using two-dimensional shear wave elastography (2D-SWE)-based ultrasomics.
Methods
A total of 175 FLLs in 169 patients were prospectively analyzed. The study population was divided into a training cohort (
n
= 122) and a validation cohort (
n
= 53). The maxima, minima, mean, and standard deviation of 2D-SWE measurements were expressed in kilopascals (
E
max
,
E
min
,
E
mean
, and
E
SD
). The ultrasonics technique was used to extract the features from the 2D-SWE images. Support vector machine was used to establish two prediction models: the ultrasomics score (ultrasomics features only) and the combined score (SWE measurements and ultrasomics features). The diagnostic performance of the models in differentiating FLLs was analyzed.
Results
A total of 1044 features were extracted and 15 features were selected. The AUC for the combined score, ultrasomics score,
E
max
,
E
mean
,
E
min
and
E
SD
were 0.94, 0.91, 0.92, 0.89, 0.67, and 0.89, respectively. The combined score had the best diagnostic performance. The sensitivity, specificity, PPV, NPV, +LR, LR of the combined score were 92.59%, 87.50%, 94.59%, 82.50%, 7.35%, and 0.09%, respectively. The decision curve analysis results showed that when the threshold probability was > 29%, the combined score showed improved benefits for patients compared to using the ultrasomics score and 2D-SWE measurements.
Conclusion
The results of this study demonstrated that the combined score had good diagnostic accuracy in differentiating malignant from benign FLLs.
The dried and ripe fruits of
and ripe fruits of
Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer's ...disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski's rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.
Previous studies have documented important roles for microRNA-147 (miR-147) in inflammation, radiation-induced injury, cancer, and a range of other diseases. Murine lungs exhibit high levels of ...miRNA, mRNA, and lncRNA expression. However, very little research to date has focused on the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks associated with miR-147, and the regulation of lncRNAs and miRNAs in this setting remains poorly understood.
After establishing a miR-147
model mouse, samples of lung tissue were harvested for RNA-sequencing, and differentially expressed lncRNAs, miRNAs, and mRNAs were identified. The miRNA targets of these lncRNAs and the identified miRNAs were first overlapped to facilitate the prediction of target mRNAs, with analyses then examining the overlap between these targets and mRNAs that were differentially expressed. Then, these target mRNAs were subjected to pathway enrichment analyses. These results were ultimately used to establish a miR-147-related ceRNA network.
Relative to wild-type mice, the lungs of miR-147
mice exhibited 91, 43, and 71 significantly upregulated lncRNAs, miRNAs, and mRNAs, respectively, together with 114, 31, and 156 that were significantly downregulated. The lncRNA-miRNA-mRNA network established based on these results led to the identification of Kcnh6 as a differentially expressed hub gene candidate and enabled the identification of a range of regulatory relationships. KEGG pathway enrichment showed that the mRNA targets of differentially expressed lncRNAs and miRNAs in the mice were associated with tumor-related signaling, endometrial cancer, bladder cancer, and ErbB signaling.
These results suggest that the identified ceRNA network in miR-147
mice shapes tumor-associated signaling activity, with miR-147 potentially regulating various lncRNAs and miRNAs through Kcnh6, ultimately influencing tumorigenesis. Future studies of the lncRNA, miRNA, and mRNA regulatory targets shown to be associated with miR-147 in the present study may ultimately lead to the identification of novel clinically relevant targets through which miR-147 shapes the pathogenesis of cancer and other diseases.
Abstract Objective To assess the efficacy of contrast-enhanced ultrasound (CEUS) in depicting transplant renal artery stenosis (TRAS). Materials and methods Seventy-eight patients (56 men and 22 ...women; aged 36 ± 12.2 years) who were suspected of TRAS due to either Doppler ultrasound (DUS) abnormalities or difficult control of blood pressure and/or persistent deterioration of renal function were enrolled to perform CEUS. The reference standard for the TRAS diagnoses was computed tomography angiography (CTA). The diagnostic performance of DUS and CEUS parameters was assessed by the area under the receiver operating characteristic curve (AUC). Results TRAS was diagnosed in 32 out of 78 cases by CTA. The AUC, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CEUS in predicting TRAS were 0.92, 92.3%, 87.5%, 95.7%, 93.3%, and 91.7%, respectively. CEUS rectified 13 (28.3%) false-positive cases on DUS, which were confirmed by CTA. Compared to DUS parameters, CEUS showed the highest AUC, statistically significant differences of AUC were found ( P = 0.006 − 0.039), except for that of the PSV ratio in the main transplant renal artery to that in interlobar artery (PSV-ratio) (AUC: 0.92 versus 0.86, P = 0.422).However, CEUS showed a significantly higher specificity (95.7% versus 76.1%, P = 0.008) and the same sensitivity compared to PSV-ratio. Conclusions CEUS is superior to DUS in depicting TRAS. Moreover, our results suggest that CEUS might potentially be used as a noninvasive tool to spare many patients from unnecessary CTA.
Aim
A meta‐analysis was carried out to assess the accuracies of shear wave speed imaging (SWSI) in predicting significant fibrosis (stages F2–4) and cirrhosis (stage F4).
Methods
A review was ...performed of relevant studies published until October 2015. A bivariate binomial model was used to combine the sensitivity, specificity, and the area under the summary receiver operating characteristic (AUC), and 95% confidence intervals were derived to indicate the diagnostic accuracy of imaging modalities.
Results
In total, 10 studies with 2182 patients were included in the analysis. The sensitivity, specificity, and AUC (with 95% confidence intervals) of SWSI were: 0.84 (0.81–0.87), 0.83 (0.77–0.88), and 0.88 (0.85–0.90) for significant fibrosis, respectively; and 0.80 (0.66–0.89), 0.93 (0.88–0.96), and 0.95 (0.92–0.96) for cirrhosis, respectively. When SWSI was compared with well‐evaluated transient elastography, the AUCs for the prediction of significant fibrosis were 0.93 and 0.86, respectively. The AUCs for the prediction of cirrhosis were both 0.94.
Conclusion
Shear wave speed imaging is a trustworthy tool for staging hepatic fibrosis, with a high combination of sensitivity and specificity. Compared with transient elastography, SWSI showed better diagnostic performance for the prediction of significant fibrosis.
To explore a new method for color image analysis of ultrasomics and investigate the efficiency in differentiating focal liver lesions (FLLs) by Red, Green, and Blue (RGB) three-channel SWE-based ...ultrasomics model.
One hundred thirty FLLs were randomly divided into training set (n = 65) and validation set (n = 65). The RGB three-channel and direct conversion methods were applied to the same color SWE images. Ultrasomics features were extracted from the preprocessing images establishing two feature data sets. The least absolute shrinkage and selection operator (LASSO) logistic regression model was applied for feature selection and model construction. Two models, named RGB model (based on RGB three-channel conversion) and direct model (based on direct conversion), were used to differentiate FLLs. The diagnosis performance of the two models was evaluated by area under the curve (AUC), calibration curves, decision curves, and net reclassification index (NRI).
In the validation cohort, the AUC of the direct model and RGB model in characterization on FLLs were 0.813 and 0.926, respectively (
= 0.038). Calibration curves and decision curves indicated that the RGB model had better calibration efficiency and provided greater clinical benefits. NRI revealed that the RGB model correctly reclassified 7% of malignant cases and 25% of benign cases compared to the direct model (
= 0.01).
The RGB model generated by RGB three-channel method yielded better diagnostic efficiency than the direct model established by direct conversion method. The RGB three-channel method may be promising on ultrasomics analysis of color images in clinical application.
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