Optimization and evaluation of facial recognition models for Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by special facial gestalt, delayed development, and supravalvular aortic stenosis or/and stenosis of the branches of the pulmonary artery. We aim to develop and optimize accurate models of facial recognition to assist in the diagnosis of WBS, and to evaluate their effectiveness by using both five-fold cross-validation and an external test set. We used a total of 954 images from 135 patients with WBS, 124 patients suffering from other genetic disorders, and 183 healthy children. The training set comprised 852 images of 104 WBS cases, 91 cases of other genetic disorders, and 145 healthy children from September 2017 to December 2021 at the Guangdong Provincial People's Hospital. We constructed six binary classification models of facial recognition for WBS by using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. Transfer learning was used to pre-train the models, and each model was modified with a variable cosine learning rate. Each model was first evaluated by using five-fold cross-validation and then assessed on the external test set. The latter contained 102 images of 31 children suffering from WBS, 33 children with other genetic disorders, and 38 healthy children. To compare the capabilities of these models of recognition with those of human experts in terms of identifying cases of WBS, we recruited two pediatricians, a pediatric cardiologist, and a pediatric geneticist to identify the WBS patients based solely on their facial images. We constructed six models of facial recognition for diagnosing WBS using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. The model based on VGG-19BN achieved the best performance in terms of five-fold cross-validation, with an accuracy of 93.74% ± 3.18%, precision of 94.93% ± 4.53%, specificity of 96.10% ± 4.30%, and F1 score of 91.65% ± 4.28%, while the VGG-16BN model achieved the highest recall value of 91.63% ± 5.96%. The VGG-19BN model also achieved the best performance on the external test set, with an accuracy of 95.10%, precision of 100%, recall of 83.87%, specificity of 93.42%, and F1 score of 91.23%. The best performance by human experts on the external test set yielded values of accuracy, precision, recall, specificity, and F1 scores of 77.45%, 60.53%, 77.42%, 83.10%, and 66.67%, respectively. The F1 score of each human expert was lower than those of the EfficientNet-b3 (84.21%), ResNet-50 (74.51%), VGG-16 (85.71%), VGG-16BN (85.71%), VGG-19 (83.02%), and VGG-19BN (91.23%) models. CONCLUSION: The results showed that facial recognition technology can be used to accurately diagnose patients with WBS. Facial recognition models based on VGG-19BN can play a crucial role in its clinical diagnosis. Their performance can be improved by expanding the size of the training dataset, optimizing the CNN architectures applied, and modifying them with a variable cosine learning rate. WHAT IS KNOWN: • The facial gestalt of WBS, often described as "elfin," includes a broad forehead, periorbital puffiness, a flat nasal bridge, full cheeks, and a small chin. • Recent studies have demonstrated the potential of deep convolutional neural networks for facial recognition as a diagnostic tool for WBS. WHAT IS NEW: • This study develops six models of facial recognition, EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN, to improve WBS diagnosis. • The VGG-19BN model achieved the best performance, with an accuracy of 95.10% and specificity of 93.42%. The facial recognition model based on VGG-19BN can play a crucial role in the clinical diagnosis of WBS.

Umbilical cord blood and peripheral blood-derived regulatory T cells therapy: Progress in type 1 diabetes.

Regulatory T cells (Tregs) are key regulators for the inflammatory response and play a role in maintaining the immune tolerance. Type 1 diabetes (T1D) is a relatively common autoimmune disease that results from the loss of immune tolerance to ß-cell-associated antigens. Preclinical models have demonstrated the safety and efficacy of Tregs given in transplant rejection and autoimmune diseases such as T1D. Adoptive transfer of Tregs has been utilized in clinical trials for over a decade. However, the achievement of the adoptive transfer of Tregs therapy in clinical application remains challenging. In this review, we highlight the characterization of Tregs and compare the differences between umbilical cord blood and adult peripheral blood-derived Tregs. Additionally, we summarize conditional modifications in the expansion of Tregs in clinical trials, especially for the treatment of T1D. Finally, we discuss the existing technical challenges for Tregs in clinical trials for the treatment of T1D.

[Mechanism of pathogenesis of Jingfang Mixture in intervention of chronic spontaneous urticaria based on serum metabolomics].

This study aims to clarify the effect of Jingfang Mixture on the treatment of chronic urticarial and its mechanism, and investigate the regulatory effect of chronic urticaria on the metabolic disorder of endogenous metabolites in the blood. The mice were randomly divided into normal group, model group, and Jingfang Mixture group, and modeling and administration continued for 21 d. The changes in endogenous small molecules in rat serum were determined by ultra-high performance liquid chromatography-electrospray ionization-Q Exactive-Orbitrap-mass spectrometry(UHPLC-ESI-QE-Orbitrap-MS) metabolomics technology. The change trend of endogenous metabolites in rat serum was analyzed to find potential biomarkers. The results showed that Jingfang Mixture regulate 16 biomarkers, mainly including taurine, glutamate, succinic acid, docosahexaenoic acid, and arachidonic acid. Metabolic pathway analysis was carried out by MetaboAnalyst, and P<0.01 was taken as the potential key metabolic pathway. Ten metabolic pathways were closely related to the treatment of chronic urticarial by Jingfang Mixture, mainly involved in the glutamate metabolism, taurine and hypotaurine metabolism, arginine and proline metabolism, arachidonic acid metabolism, tricarboxylic acid cycle, unsaturated fatty acid biosynthesis, glutathione metabolism, phenylalanine metabolism, alanine, aspartic acid, and glutamate metabolism, and butyric acid metabolism. Glutamate metabolism and butyric acid metabolism involved more metabolic pathways than others. Therefore, it was speculated that Jingfang Mixture had a balanced regulating effect on the related metabolic pathways which caused the serum disorder in the rats with urticaria, and tended to regulate the metabolic differential to the normal level in the rats with urticaria. This paper provides references for studying the mechanism of Jingfang Mixture from the perspective of endogenous metabolites and metabolic pathways in vivo. At the same time, the endogenous substances explored in this paper can be used as important biomarkers for the prevention of urticaria.

Influences of different vasopressors on stroke volume variation and pulse pressure variation.

Pulse pressure variation (PPV) and stroke volume variation (SVV) during mechanical ventilation have been shown to be effective parameters to predict preload responsiveness. Although induced hypertension decreases PPV and SVV, the influences of different vasopressors on PPV and SVV are unknown. 94 patients undergoing elective otologic surgery were randomly divided into three groups: Group P (patients were given phenylephrine), Group D (patients were given dopamine), Group E (patients were given ephedrine). When surgery was ongoing and the circulation state was stable, patients were given the vasopressor to increase the systolic arterial pressure (SAP) to the pre-calculated levels: low level, 10 % < ΔSAP ≤ 20 %; medium level, 20 % < ΔSAP ≤ 30 %; high level, 30 % < ΔSAP ≤ 40 %. When invasive arterial pressure reached the target value, PPV, SVV and other parameters were recorded. Dopamine decreased the PPV and SVV more significantly than ephedrine, but less significantly than phenylephrine. The influences of phenylephrine, dopamine and ephedrine on SVV and PPV are different due to their different pharmacological mechanisms.

Integrative proteomics and n-glycoproteomics reveal the synergistic anti-tumor effects of aspirin- and gemcitabine-based chemotherapy on pancreatic cancer cells.

OBJECTIVE AND DESIGN: Pancreatic cancer is a highly malignant tumor that is well known for its poor prognosis. Based on glycosylation, we performed integrated quantitative N-glycoproteomics to investigate the synergistic anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells and explore the potential molecular mechanisms of chemotherapy in pancreatic cancer. METHODS AND RESULTS: Two pancreatic cancer cell lines (PANC-1 and BxPC-3) were treated with gemcitabine, aspirin, and a combination (gemcitabine + aspirin). We found that the addition of aspirin enhanced the inhibitory effect of gemcitabine on the activity of PANC-1 and BxPC-3 cells. Quantitative N-glycoproteome, proteome, phosphorylation, and transcriptome data were obtained from integrated multi-omics analysis to evaluate the anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells. Mfuzz analysis of intact N-glycopeptide profiles revealed two consistent trends associated with the addition of aspirin, which showed a strong relationship between N-glycosylation and the synergistic effect of aspirin. Further analysis demonstrated that the dynamic regulation of sialylation and high-mannose glycoforms on ECM-related proteins (LAMP1, LAMP2, ITGA3, etc.) was a significant factor for the ability of aspirin to promote the anti-tumor activity of gemcitabine and the drug resistance of pancreatic cancer cells. CONCLUSIONS: In-depth analysis of N-glycosylation-related processes and pathways in pancreatic cancer cells can provide new insight for future studies regarding pancreatic cancer therapeutic targets and drug resistance mechanisms.

Discrepancy between arterial oxygen saturation and pulse oximetry measurement in a Chinese pediatric patient cohort.

Background: Increasing evidence suggest a racial bias in pulse oximetry measurement, but this was under investigated in Asian pediatric populations. Methods: Via the Pediatric Intensive Care database, this retrospective study included pediatric patient records of arterial oxygen saturation (SaO2) and oxygen saturation on pulse oximetry (SpO2) measured within 10 min. Discrepancy was examined, and potential predictors of occult hypoxemia (defined as SaO2 <88% with the paired SpO2 ≥92%) as well as its association with outcomes were explored by logistic regression. Results: A total of 390 patients were included with 454 pairs of SaO2-SpO2 readings. The study population consisted of Han Chinese (99.0%) and 43.6% were female. Occult hypoxemia was observed in 20.0% of the patients, with a mean SaO2 of 71.4 ± 15.8%. Potential predictors of occult hypoxemia included female, being first admitted to cardiac ICU, congenital heart disease, increased heart rate, while patients with prior surgery records were less likely to experience occult hypoxemia. Patients with occult hypoxemia had numerically higher in-ICU mortality (16.7% versus 10.9%) and in-hospital mortality (17.9% versus 10.9%), but the associations were not statistically significant. Conclusions: There was a substantial proportion of hypoxemia that was not detected by pulse oximetry in the Chinese pediatric patients, which might be predicted by several characteristics and seemed to associate with mortality.

Targeted protein degradation in hematologic malignancies: latest updates from the 2023 ASH annual meeting.

Protein degraders, emerging as a novel class of therapeutic agents, have gained widespread attention due to their advantages. They have several advantages over traditional small molecule inhibitors, including high target selectivity and ability to target "undruggable" targets and overcome inhibitor drug resistance. Tremendous research and development efforts and massive investment have resulted in rapid advancement of protein degrader drug discovery in recent years. Here, we overview the latest clinical and preclinical updates on protein degraders presented at the 2023 ASH Annual Meeting.

Exosomes derived from cord blood Treg cells promote diabetic wound healing by targeting monocytes.

Chronic nonhealing diabetic wounds are a critical clinical challenge. Regulatory T cells (Tregs) are immunosuppressive modulators affecting wound healing progression by controlling the inflammatory response. The current study attempted to investigate whether the exosomes derived from cord blood (CB) Tregs can accelerate the healing process. Exosomes were isolated from CB-Treg cultures using ultracentrifugation and validated with different specific markers of exosomes. The purified CB-Treg-derived exosomes were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes. The migration-promoting effect of CB-Treg-derived exosomes on fibroblasts and endothelial cells was investigated. We used thermosensitive Pluronic F-127 hydrogel (PF-127) loaded with CB-Treg-derived exosomes in a diabetic wound healing mouse model. CB-Treg-derived exosomes with 30-120 nm diameters revealed exosome-specific markers, such as TSG101, Alix, and CD63. CB-Treg-derived exosomes were mainly bound to the monocytes when co-cultured with PBMCs, and promoted monocyte polarization to the anti-inflammatory phenotype (M2) in vitro. CB-Treg-derived exosomes enhanced the migration of endothelial cells and fibroblasts. Furthermore, CB-Treg-derived exosomes treatment accelerated wound healing by downregulating inflammatory factor levels and upregulating the M2 macrophage ratio in vivo. Our findings indicated that CB-Treg-derived exosomes could be a promising cell-free therapeutic strategy for diabetic wound healing, partly by targeting monocytes.

Multiply restimulated human cord blood-derived Tregs maintain stabilized phenotype and suppressive function and predict their therapeutic effects on autoimmune diabetes.

BACKGROUND: Regulatory T cells (Tregs) are involved in the maintenance of immune homeostasis and immune regulation. Clinical trials on the adoptive transfer of Tregs have been ongoing for > 10 years. However, many unresolved issues remain in the production of readymade Treg products and selection of patients. Hence, this study aimed to develop a method to expand off-the-shelf Tregs derived from umbilical cord blood (UCB-Tregs) in vitro without changing their phenotype and inhibitory function. In addition, the study intended to design an approach to precisely select patients who are more likely to benefit from the adoptive Treg transfer therapy. METHODS: UCB-Tregs were isolated and cultured in a medium containing human recombinant IL-2 and rapamycin and then multiply restimulated with human T-activator CD3/CD28 dynabeads. The phenotype and suppressive capacity of Tregs were assessed on days 18 and 42. The relationship between the suppressive function of UCB-Tregs in vitro and clinical indicators was analyzed, and the ability of the in vitro suppressive capacity to predict the in vivo therapeutic effects was evaluated. RESULTS: UCB-Tregs expanded 123-fold and 5,981-fold at 18 and 42 days, respectively. The suppressive function of UCB-Tregs on the proliferation of immune cells at 42 days was not significantly different compared with that of UCB-Tregs obtained at 18 days. The suppression rate of UCB-Tregs to PBMCs was negatively correlated with the course of diabetes. Moreover, the high-suppression group exhibited a better treatment response than the low-suppression group during the 12-month follow-up period. CONCLUSIONS: Multiply restimulated UCB-Tregs expanded at a large scale without any alterations in their classical phenotypic features and inhibitory functions. The suppressive function of Tregs in vitro was negatively correlated with the disease duration. The present study revealed the possibility of predicting the in vivo therapeutic effects via the in vitro inhibition assay. Thus, these findings provided a method to obtain off-the-shelf Treg products and facilitated the selection of patients who are likely to respond to the treatment, thereby moving toward the goal of precision treatment.

Identification of pyroptosis-related signature and development of a novel prognostic model in diffuse large B-cell lymphoma.

PURPOSE: Emerging evidence suggests that pyroptosis plays an essential role in the development and progression of multiple cancers. However, the role of pyroptosis remains elusive in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression profile data of DLBCL and normal samples of pyroptosis-related genes (PRGs) were analyzed, and the clinical characteristics of DLBCL patients were further investigated. A prognostic model was established using LASSO-Cox regression analysis. The expression of these PRGs was validated by qRT-PCR in DLBCL cell lines. Cell proliferation assay and flow cytometry were utilized to explore the impact of pyroptosis inhibitor (disulfiram, DSF) combined with PD1/PD-L1 inhibitor (BMS1166) on DLBCL cell proliferation. RESULTS: Most PRGs were dysregulated in DLBCL samples and associated with overall survival (OS). Six PRGs were selected to construct a prognostic risk score model. The qRT-PCR analysis revealed that CASP8, CASP9, NLRP1, NLRP6, and TIRAP are downregulated, while SCAF11 was significantly upregulated in DLBCL cell lines. This prognostic model divided DLBCL patients into low-risk and high-risk groups. Patients in the low-risk group exhibited lower mortality and longer OS than those in the high-risk group. The ROC curve and nomogram demonstrated this model's excellent predictive performance. GO and KEGG enrichment indicated that the differentially expressed genes (DEGs) between subgroups were associated with cellular protein modification processes and JAK-STAT signaling pathway regulation. Moreover, the risk score was correlated with the immune profile. Cell proliferation assay and flow cytometry further validated the synergistic anti-tumor effects of DSF and BMS1166 on DLBCL cells. CONCLUSION: In summary, we developed a comprehensive prognostic model based on PRGs characteristics, which accurately predicted the prognosis of DLBCL patients. Pyroptosis-targeting coupled with immunotherapies would be a promising therapeutic strategy for DLBCL.

Evaluation of a Sugarcane (Saccharum spp.) Hybrid F1 Population Phenotypic Diversity and Construction of a Rapid Sucrose Yield Estimation Model for Breeding.

Sugarcane is the major sugar-producing crop worldwide, and hybrid F1 populations are the primary populations used in breeding. Challenged by the sugarcane genome's complexity and the sucrose yield's quantitative nature, phenotypic selection is still the most commonly used approach for high-sucrose yield sugarcane breeding. In this study, a hybrid F1 population containing 135 hybrids was constructed and evaluated for 11 traits (sucrose yield (SY) and its related traits) in a randomized complete-block design during two consecutive growing seasons. The results revealed that all the traits exhibited distinct variation, with the coefficient of variation (CV) ranging from 0.09 to 0.35, the Shannon-Wiener diversity index (H') ranging between 2.64 and 2.98, and the broad-sense heritability ranging from 0.75 to 0.84. Correlation analysis revealed complex correlations between the traits, with 30 trait pairs being significantly correlated. Eight traits, including stalk number (SN), stalk diameter (SD), internode length (IL), stalk height (SH), stalk weight (SW), Brix (B), sucrose content (SC), and yield (Y), were significantly positively correlated with sucrose yield (SY). Cluster analysis based on the 11 traits divided the 135 F1 hybrids into three groups, with 55 hybrids in Group I, 69 hybrids in Group II, and 11 hybrids in Group III. The principal component analysis indicated that the values of the first four major components' vectors were greater than 1 and the cumulative contribution rate reached 80.93%. Based on the main component values of all samples, 24 F1 genotypes had greater values than the high-yielding parent 'ROC22' and were selected for the next breeding stage. A rapid sucrose yield estimation equation was established using four easily measured sucrose yield-related traits through multivariable linear stepwise regression. The model was subsequently confirmed using 26 sugarcane cultivars and 24 F1 hybrids. This study concludes that the sugarcane F1 population holds great genetic diversity in sucrose yield-related traits. The sucrose yield estimation model, ySY=2.01xSN+8.32xSD+0.79xB+3.44xSH-47.64, can aid to breed sugarcane varieties with high sucrose yield.

Simulation of Photosynthetic Quantum Efficiency and Energy Distribution Analysis Reveals Differential Drought Response Strategies in Two (Drought-Resistant and -Susceptible) Sugarcane Cultivars.

Selections of drought-tolerant cultivars and drought-stress diagnosis are important for sugarcane production under seasonal drought, which becomes a crucial factor causing sugarcane yield reduction. The main objective of this study was to investigate the differential drought-response strategies of drought-resistant ('ROC22') and -susceptible ('ROC16') sugarcane cultivars via photosynthetic quantum efficiency (Φ) simulation and analyze photosystem energy distribution. Five experiments were conducted to measure chlorophyll fluorescence parameters under different photothermal and natural drought conditions. The response model of Φ to photosynthetically active radiation (PAR), temperature (T), and the relative water content of the substrate (rSWC) was established for both cultivars. The results showed that the decreasing rate of Φ was higher at lower temperatures than at higher temperatures, with increasing PAR under well-watered conditions. The drought-stress indexes (εD) of both cultivars increased after rSWC decreased to the critical values of 40% and 29% for 'ROC22' and 'ROC16', respectively, indicating that the photosystem of 'ROC22' reacted more quickly than that of 'ROC16' to water deficit. An earlier response and higher capability of nonphotochemical quenching (NPQ) accompanied the slower and slighter increments of the yield for other energy losses (ΦNO) for 'ROC22' (at day5, with a rSWC of 40%) compared with 'ROC16' (at day3, with a rSWC of 56%), indicating that a rapid decrease in water consumption and an increase in energy dissipation involved in delaying the photosystem injury could contribute to drought tolerance for sugarcane. In addition, the rSWC of 'ROC16' was lower than that of 'ROC22' throughout the drought treatment, suggesting that high water consumption might be adverse to drought tolerance of sugarcane. This model could be applied for drought-tolerance assessment or drought-stress diagnosis for sugarcane cultivars.

Metabolic profiling of clonazolam in human liver microsomes and zebrafish models using liquid chromatography quadrupole Orbitrap mass spectrometry.

Clonazolam is a designer benzodiazepine with strong sedative and amnesic effects. As we all know, the detection of metabolites is the key to confirming the use of substances in the field of forensic toxicology. In order to better describe clonazolam metabolism completely, we performed the two different experiments exploiting the unique characteristics of the models used. In this study, in vivo and in vitro samples were analyzed with liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. The results showed that seven Phase I metabolites and one Phase II metabolite were detected in zebrafish model. The remaining Phase I and II metabolites were also found in the incubation solution of pooled human liver microsomes. The main types of metabolic reactions of clonazolam included hydroxylation, dealkylation, nitroreduction, dechlorination, N-Acetylation, and O-glucuronidation. In this paper, the main metabolites and metabolic pathways of clonazolam are clarified in detail in order to further improve the metabolic rule of clonazolam. Based on these results, to better detect and judge the abuse of clonazolam, we suggest that M1, its nitro reduction product, is used as its biomarker. The results of this study provide a theoretical basis for the pharmacokinetics and forensic medicine of clonazolam.

Development of an LC-MS/MS method for the determination of multiple mycotoxins in human urine.

A sensitive liquid chromatography-tandem mass spectrometry method was developed for the determination of 17 mycotoxins in human urine. The method incorporates a two-step liquid-liquid extraction with ethyl acetate:acetonitrile (7:1), which had good extraction recovery. The LOQs of all mycotoxins ranged from 0.1 to 1 ng/mL. Intra-day accuracy ranged from 94 to 106%, and intra-day precision ranged from 1 to 12% for all mycotoxins. Inter-day accuracy and precision were 95-105% and 2-8%, respectively. The method was successfully applied to investigate the urine levels of 17 mycotoxins from 42 volunteers. Deoxynivalenol (DON, 0.97-9.88 ng/mL) was detected in 10 (24%) urine samples and zearalenone (ZEN, 0.13-1.11 ng/mL) in 2 (5%) urine samples.

Pancreatic cancer cells spectral library by DIA-MS and the phenotype analysis of gemcitabine sensitivity.

Data-independent acquisition (DIA)-mass spectrometry (MS)-based proteome strategies are increasingly used for detecting and validating protein biomarkers and therapeutic targets. Here, based on an in-depth proteome analysis of seven pancreatic cancer cell lines, we built a pancreas-specific mass spectrum library containing 10633 protein groups and 184551 peptides. The proteome difference among the seven pancreatic cancer cells was significant, especially for the divergent expression of proteins related to epithelial-mesenchymal transition (EMT). The spectra library was applied to explore the proteome difference of PANC-1 and BxPC-3 cells upon gemcitabine (GEM) treatment, and potential GEM targets were identified. The cytotoxicity test and GEM target analysis found that HPAC, CFPAC-1, and BxPC-3 were sensitive to GEM treatment, whereas PANC-1 and AsPC-1 were resistant. Finally, we found EMT was significant for CFPAC-1, AsPC-1, and PANC-1 cells, whereas BxPC-3 and HPAC cells showed more typical epithelial features. This library provides a valuable resource for in-depth proteomic analysis on pancreatic cancer cell lines, meeting the urgent demands for cell line-dependent protein differences and targeted drug analysis.

Rapid characterization of drugs in a single hair using thermal desorption ionization mass spectrometry.

Hair remains the most common type of physical evidence found in most crime scenes. However, the amount of hair found at a crime scene is limited and analysis of drugs in hair by gas chromatography mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) is laborious and time-consuming. In this study, a rapid and simple method is developed using thermal desorption ionization mass spectrometry (TDI-MS) to analyze drugs directly in a single hair. A single hair is put onto a heated metal ceramic heater (MCH) and then a high voltage direct current and solvent are applied to the single hair. The drugs in the hair are thermally desorbed and ionized, and subsequently transferred to the MS inlet and detected. A typical hair analysis can be completed in a few minutes. This novel technique provides a new orientation for forensic scientists to study drugs in a single hair that is found at a crime scene, on a suspect, or on a victim.

In silico network pharmacology and in vivo analysis of berberine-related mechanisms against type 2 diabetes mellitus and its complications.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine (BBR), extracted from the traditional medicinal plant Coptis chinensis Franch., has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and its complications. AIM OF THE STUDY: To determine the potential pharmacological mechanisms underlying BBR therapeutic effect on T2DM and its complications by in silico network pharmacology and experimental in vivo validation. MATERIALS AND METHODS: A predictive network depicting the relationship between BBR and T2DM was designed based on information collected from several databases, namely STITCH, CHEMBL, PharmMapper, TTD, Drugbank, and PharmGKB. Identified overlapping targets related to both BBR and T2DM were crossed with information on biological processes (BPs) and molecular/signaling pathways using the DAVID platform and Cytoscape software. Three candidate targets identified with the BBR-T2DM network (RXRA, KCNQ1 and NR3C1) were evaluated in the C57BL/6J mouse model of T2DM. The mice were treated with BBR or metformin for 10 weeks. Weight, fasting blood glucose (FBG), oral glucose tolerance, and expression levels of the three targets were evaluated. RESULTS: A total of 31 targets of BBR that were also related to T2DM were identified, of which 14 had already been reported in previous studies. Furthermore, these 31 overlapping targets were enriched in 21 related BPs and 18 pathways involved in T2DM treatment. The identified BP-target-pathway network revealed the underlying mechanisms of BBR antidiabetic activity were mediated by core targets such as RXRA, KCNQ1, and NR3C1. In vivo experiments further confirmed that treatment with BBR significantly reduced weight and FBG and alleviated insulin resistance in T2DM mice. Moreover, BBR treatment promoted RXRA expression, whereas it reduced KCNQ1 and NR3C1 expression in the liver. CONCLUSION: Using network pharmacology and a T2DM mouse model, this study revealed that BBR can effectively prevent T2DM symptoms through vital targets and multiple signaling pathways. Network pharmacology provides an efficient, time-saving approach for therapeutic research and the development of new drugs.

Stabilization of Loess Using Nano-SiO2.

Improving the performance of loess is of significant importance for lowering its collapsibility and water sensitivity to construction requirements and for geohazard mitigation. The present paper studies the changes in mechanical, structural, and mineralogical properties of nano-SiO2-treated loess with different contents and curing days. The mechanical behavior was examined by unconfined compressive strength (UCS) of untreated and treated loess. To better understand the mechanisms of stabilization, particle size distributions, scanning electron microscope (SEM) images, and X-ray diffraction (XRD) analyses were carried out. The results show that the UCS increase with increasing contents and curing days due to nano-SiO2 addition produced coarser particles, denser packing, and smaller pores in treated loess. The changes in the properties can be attributed to the formation of aggregation and agglomeration, with greater particle sizes and more interparticle contact. In addition, the results from mineralogical component analysis further confirm that physical structure modification controls the changes in mechanical and fabric properties, rather than chemical component alteration. Even small nano-SiO2 additions can also provide great improvement when curing days are enough for the treated loess. These findings reveal that nano-SiO2 has the potential to serve as a cost-effective stabilized additive that treats the universal loess.

CTRP3 attenuates hepatic stellate cell activation through transforming growth factor-ß/Smad signaling pathway.

Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of liver fibrosis. C1q/tumor necrosis factor-related protein 3 (CTRP3), a member of CTRPs, was involved in fibrosis. However, little is known about the role of CTRP3 in liver fibrosis. This study aimed to determine its role in liver fibrosis and explore the possible mechanism. Our results demonstrated that CTRP3 was lowly expressed in liver fibrosis tissues and activated HSCs. Overexpression of CTRP3 inhibited the proliferation and migration of HSCs, as well as suppressed the expression of extracellular matrix (ECM) in transforming growth factor-ß1 (TGF-ß1)-stimulated HSC-T6 cells. Furthermore, CTRP3 overexpression greatly inhibited the expression level of phosphorylation of Smad3 in TGF-ß1-stimulated HSC-T6 cells. In conclusion, the present study demonstrated that CTRP3 inhibited the proliferation and migration of TGF-ß1-induced HSC-T6 cells and attenuated liver fibrosis, at least in part, through inhibiting the Smad signaling pathway. These findings suggest that CTRP3 may be a promising therapeutic target for the treatment of liver fibrosis.