Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study.

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 µM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 µM and 0.39 ± 0.05 µM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 µM, 2.04 ± 0.28 µM, and 11.79 ± 0.83 µM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.

MicroRNA-361-5p acts as a biomarker for carotid artery stenosis and promotes vascular smooth muscle cell proliferation and migration.

BACKGROUND: Vascular smooth muscle cells (VSMCs) dysfunction participates in carotid artery stenosis (CAS). The study aimed to examine the expression pattern of miR-361-5p in CAS patients, and explore its role in VSMCs proliferation and migration. METHODS: qRT-PCR was performed for the detection of miR-361-5p in serum samples of 150 CAS cases and 150 healthy people. Multiple logistic regression analysis and receiver operating characteristic (ROC) curve was accomplished to detect diagnostic value via SPSS 21.0 statistical software. Cell function of VSMCs was evaluated. Target association was predicted through bioinformatic analysis and confirmed via luciferase activity. RESULTS: Serum miR-361-5p was enhanced in CAS cases and was positively correlated with CAS degree. Logistic regression analysis determined the independent influence of miR-361-5p in CAS, and ROC curve demonstrated its diagnostic value with AUC of 0.892. miR-361-5p promoted VSMCs proliferation and migration, but the influence was counteracted by TIMP4. CONCLUSIONS: MiR-361-5p is a promising biomarker for CAS, and can be used as a potential target for early diagnosis and treatment of CAS. MiR-361-5p can promote VSMCs proliferation and migration via targeting TIMP4.

The Relationship between Intimate Partner Violence and Online Help-Seeking: A Moderated Mediation Model of Emotion Dysregulation and Perceived Anonymity.

During the COVID-19 pandemic, lockdowns and isolation have limited the availability of face-to-face support services for victims of intimate partner violence (IPV). Despite the growing need for online help in supporting IPV victims, far less is known about the underlying mechanisms between IPV and online help-seeking. We studied the mediating role of emotion dysregulation (ED) and the moderating role of perceived anonymity (PA) on the internet to explain IPV victims' willingness of online help-seeking (WOHS). Through a PROCESS analysis of the questionnaire data (n = 510, 318 female, 192 male, Mage = 22.41 years), the results demonstrate that: (1) ED has been linked with the experience of IPV, and IPV significantly induces ED. (2) When IPV victims realize the symptoms of ED, they have a strong willingness to seek external intervention to support themselves. ED mediates the relationship between IPV and online help-seeking. (3) For youth growing up in the era of social networking sites (SNS), personal privacy protection is an important factor when seeking online help. The anonymity of the internet has a positive effect on victims who experience IPV and ED, and it increases WOHS. This study introduces a new perspective on the psychological mechanism behind IPV victims' help-seeking behaviors, and it suggests that the improvement of anonymity in online support can be an effective strategy for assisting IPV victims.

Public Attention and Sentiment toward Intimate Partner Violence Based on Weibo in China: A Text Mining Approach.

The mobile internet has resulted in intimate partner violence (IPV) events not being viewed as interpersonal and private issues. Such events become public events in the social network environment. IPV has become a public health issue of widespread concern. It is a challenge to obtain systematic and detailed data using questionnaires and interviews in traditional Chinese culture, because of face-saving and the victim's shame factors. However, online comments about specific IPV events on social media provide rich data in understanding the public's attitudes and emotions towards IPV. By applying text mining and sentiment analysis to the field of IPV, this study involved construction of a Chinese IPV sentiment dictionary and a complete research framework. We analyzed the trends of the Chinese public's emotional evolution concerning IPV events from the perspectives of a time series as well as geographic space and social media. The results show that the anonymity of social networks and the guiding role of opinion leaders result in traditional cultural factors such as face-saving and family shame for IPV events being no longer applicable, leading to the spiral of an anti-silence effect. Meanwhile, in the process of public emotional communication, anger often overwhelms reason, and the spiral of silence remains in effect in social media. In addition, there are offensive words used in the IPV event texts that indicate misogyny in emotional, sexual, economic and psychological abuse. Fortunately, mainstream media, as crucial opinion leaders in the social network, can have a positive role in guiding public opinion, improving people's ability to judge the validity of network information, and formulating people's rational behaviour.

Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2.

Dysregulation of circRNAs is reported to exert crucial roles in cancers, including hepatocellular carcinoma (HCC). So far, the function of circRNAs in HCC development remains poorly known. Currently, our data showed that circ_0008305 was highly elevated in HCC cell lines and 30 paired tissue samples of HCC. As evidenced, suppression of circ_0008305 repressed HCC cell growth significantly. Meanwhile, up-regulation of circ_0008305 significantly reduced HCC cell growth. Mechanistically, we displayed that circ_0008305 could bind with miR-186 by using bioinformatics analysis. miR-186 has been reported to be a crucial tumour oncogene in many cancers. In addition, we proved miR-186 was greatly decreased in HCC. The direct correlation between miR-186 and circ_0008305 was confirmed in our work. In addition, up-regulation of miR-186 obviously restrained HCC progression. Increased expression of transmembrane p24 trafficking protein 2 (TMED2) is significantly related to the unfavourable outcomes in cancer patients. At our present work, we proved that TMED2 could act as a direct target of miR-186. Mechanistically, we demonstrated that circ_0008305 up-regulated TMED2 expression by sponging miR-186, which resulted in significantly induced HCC progression in vitro and in vivo. These revealed the significant role of circ_0008305 in HCC progression, which might indicate a new perspective on circRNAs in HCC development.

Green-Labelled Rice versus Conventional Rice: Perception and Emotion of Chinese Consumers Based on Review Mining.

The COVID-19 pandemic increased public health awareness, changing consumers' sensitivity and beliefs about food health. Food anxiety and health scares turn consumers toward safe and healthy foods to strengthen their immunity, which makes green food more popular. However, it remains unclear how to understand the gap between consumer intention to purchase green food and their actual purchasing behaviour. Taking rice as an object of study, comparing differences in consumer perceptions and emotions towards green-labelled rice and conventional rice is beneficial for understanding the components and psychological characteristics of consumer perceptions of green food. Therefore, we used topic modelling and sentiment analysis to explore consumers' focus of attention, attitudinal preferences, and sentiment tendencies based on the review (n = 77,429) from JD.com. The findings revealed that (1) consumers' concerns about green-labelled rice are increasing rapidly, and most have a positive attitude; (2) consumers of green-labelled rice are more concerned about origin, aroma, and taste than conventional rice; (3) consumers of conventional rice are more concerned about the cost-performance ratio, while consumers of green-labelled rice are also price-sensitive; (4) green label mistrust and packaging breakage during logistics are the leading causes of negative emotions among consumers of green-labelled rice. This study provides a comparative analysis of consumer perceptions and emotions between the two types of rice, thus revealing the main influencing factors of the intention-behaviour gap and providing valuable consumer insights for the promotion of green consumption and the sustainable development of the green food industry.

ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling.

Long noncoding RNAs (lncRNAs) are regarded as crucial regulators in tumor progression. Potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1 (KCNK15-AS1) has been confirmed to inhibit the migration and invasion of pancreatic cancer (PC) cells. However, its downstream mechanism and effect on other cellular functions in PC remain unknown. This study probed the function and potential mechanism of KCNK15-AS1 in PC cell growth. RT-qPCR and western blot were employed to measure gene expression in PC cells. ISH was applied to analyze KCNK15-AS1 expression in PC tissues. Functional assays were utilized to evaluate PC cell proliferation, apoptosis, migration and EMT. Mechanical experiments were adopted to detect gene interaction in PC cells. The obtained data indicated that KCNK15-AS1 was down-regulated in PC cells and tissues. Overexpressing KCNK15-AS1 hindered cell proliferation, migration and EMT while facilitated cell apoptosis in PC. Mechanically, alkylation repair homolog protein 5 (ALKBH5) was verified to induce m6A demethylation of KCNK15-AS1 to mediate KCNK15-AS1 up-regulation. KCNK15-AS1 combined with KCNK15 5'UTR to inhibit KCNK15 translation. Moreover, KCNK15-AS1 recruited MDM2 proto-oncogene (MDM2) to promote RE1 silencing transcription factor (REST) ubiquitination, thus transcriptionally upregulating phosphatase and tensin homolog (PTEN) to inactivate AKT pathway. In conclusion, our study first confirmed that KCNK15-AS1 hinders PC cell growth by regulating KCNK15 and PTEN, suggesting KCNK15-AS1 as a potential biomarker of PC.

Analysis of Acanthopanax giraldii Harms Polysaccharide II Composition and Its Immune-Protective Role in a Cyclophosphamide-Induced Immunosuppressive Mice Model.

Acanthopanax giraldii Harms is commonly used in traditional Chinese medicine to treat rheumatism, improve joints, and strengthen muscles and bones. The polysaccharides present in A. giraldii Harms contain major bioactive substances, which have antioxidant, anticancer, and antiviral activities. In this study, the structural characterization of the homogeneous polysaccharide isolated from A. giraldii Harms, known as AHP-II, and its immunomodulatory effects in vivo will be studied. High-performance ion chromatography (HPIC) and high-performance gel permeation chromatography (HPGPC) based analyses revealed that AHP-II was composed of various monosaccharides, which included rhamnose, arabinose, galactose, glucose, mannose, galacturonic acid, and glucuronic acid in molar ratios of 29.5 : 24.6 : 23.8 : 4.4 : 5.7 : 8.8 : 3.1, respectively, and had a collective molecular weight of 80.21 × 103 Da. Fourier-transform infrared (FTIR) spectroscopy indicated the presence of a pyranose ring and ß-type glycosidic linkages in AHP-II. In addition, immunomodulatory effect analyses of AHP-II that used a cyclophosphamide-induced immunosuppressive mouse model demonstrated that its treatment could significantly restore spleen and thymus indices, promote the proliferation of splenic lymphocytes, elevate CD4+ T lymphocyte percentage and CD4+ : CD8+ ratio in the spleen, promote macrophage phagocytosis, and restore cytokines (IL-6, TNF-α, IgM, and IgG) levels. These results suggested that AHP-II could potentially be used as natural immunomodulator and as an alternative treatment to reduce chemotherapy-induced immunosuppression.

Binding of the polysaccharide from Acanthopanax giraldii Harms to toll-like receptor 4 activates macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine, Acanthopanax giraldii Harms, is commonly used to treat arthralgia due to wind, cold and dampness, as well as weakness in the feet and knees. Its other reported effects include eliminating flatulence, strengthening muscles and bones, and delaying aging. The polysaccharides in A. giraldii Harms are the major bioactive substances that confer the herb's antioxidant properties as well as anticancer and antiviral effects. AIMS OF THE STUDY: To elucidate the underlying mechanism and signaling cascade involved in the homogeneous A. giraldii Harms polysaccharide II (AHP-II)-mediated immunomodulation of mice macrophages. MATERIALS AND METHODS: The phagocytosis of neutral red and the production of nitric oxide, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were measured to determine AHP-II-induced macrophage activation. Confocal microscopy and flow cytometry were used to confirm the binding of AHP-II to macrophages. The involvement of Toll-like receptor (TLR) 4 in AHP-II-induced macrophage activation was demonstrated using antibody blocking and macrophages from C3H/HeJ TLR4-mutant mice. Western blotting was used to map AHP-II-induced downstream signaling pathways. RESULTS: AHP-II increased the phagocytosis of macrophages and the release of nitric oxide, IL-6 and TNF-α cytokines. Direct, saturable and reversible binding of AHP-II to macrophages was observed, while it can be inhibited by the anti-TLR4 antibody. In addition, the presence of the anti-TLR4 antibody inhibited AHP-II-induced macrophage IL-6 and TNF-α production in the peritoneal macrophages of C3H/HeJ mice. Moreover, AHP-II-TLR4-stimulated macrophages activate the downstream intracellular ERK and JNK/nuclear factor (NF)-κB signaling pathways. In addition, the AHP-II-mediated regulation of IL-6 and TNF-α production from macrophages was greatly affected by specific ERK, JNK and NF-κB inhibitors. CONCLUSION: Our study elucidated the immunomodulatory mechanism of AHP-II in macrophage activation and identified TLR4 as the main receptor coordinating AHP-II binding. Our findings suggest AHP-II may be used as a novel immunopotentiator for medical purposes.

Effect Of epigallocatechin-3-gallate on the pharmacokinetics of amlodipine in rats.

This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats. The pharmacokinetics of orally administered amlodipine (1 mg/kg) with or without EGCG pretreatment (30 mg/kg/day for 10 days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems. The results indicated that when the rats were pretreated with EGCG, the Cmax of amlodipine increased from 16.32 ± 2.57 to 21.44 ± 3.56 ng/mL (p < 0.05), the Tmax decreased from 5.98 ± 1.25 to 4.01 ± 1.02 h (p < 0.05), and the AUC0-t increased from 258.12 ± 76.25 to 383.34 ± 86.95 µg h L-1 (p < 0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3 ± 5.6 to 52.6 ± 7.9 min (p < 0.05) with the pretreatment of EGCG. It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.

Alterations in resting-state local functional connectivity in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is increasingly conceptualized as a brain connectivity disorder. Recently, abnormalities in remote resting-state functional connectivity (FC) have been well demonstrated in the frontoparietal areas that linked impairments in large-scale intrinsic brain networks with aberrant fronto-striatal interactions. Beyond the remote FC abnormalities in OCD, many studies using regional homogeneity (ReHo) analysis have reported local FC alterations. However, their results were not entirely consistent. METHODS: We conducted a voxel-wise meta-analysis of ReHo studies to identify consistent local FC abnormalities in patients with OCD. A seed-based d mapping approach was used. RESULTS: Eight studies that compared 200 patients with OCD and 187 healthy controls were included. Increased ReHo in the lateral orbitofrontal cortices and dorsomedial prefrontal cortices bilaterally, and decreased ReHo in the fusiform gyri bilaterally were the most consistent and reliable findings in patients with OCD relative to healthy controls. LIMITATIONS: The number of available studies included in the meta-analysis was relatively small. Many potential confounds on changes in ReHo warrant further attention. CONCLUSIONS: These regions are critically implicated in the pathophysiology of OCD. Our findings in local FC alterations are complementary to the abnormalities in remote FC in OCD, contributing to the modeling of brain functional connectomes in OCD.

Aberrant brain regional homogeneity in first-episode drug-naïve patients with major depressive disorder: A voxel-wise meta-analysis.

BACKGROUND: Resting-state functional magnetic resonance imaging studies have reported aberrant brain regional homogeneity (ReHo) in patients with major depressive disorder (MDD). However, the findings across studies were confounded by medication status and different depressive episodes. METHODS: A systematic literature search of the PubMed, Embase, and Web of Science databases was conducted. We conducted a quantitative voxel-wise meta-analysis of ReHo studies, using the Seed-based d Mapping approach, in first-episode drug-naïve patients with MDD. RESULTS: We identified 10 studies with 12 datasets suitable for inclusion, consisting of 402 first-episode drug-naïve patients with MDD and 330 healthy controls. The most consistent and robust findings were that patients with MDD relative to healthy controls exhibited increased ReHo in the left hippocampus and decreased ReHo in the left orbitofrontal cortex. LIMITATIONS: The patient samples included in our meta-analysis were all Chinese, thus limiting the applicability of the present findings to other populations. CONCLUSIONS: ReHo alterations in these brain regions are likely to reflect the core disease-related functional abnormalities, which are implicated in emotional dysregulation and cognitive impairment that are seen in the early stage of MDD. These findings contribute to a better understanding of the neurobiological underpinnings of MDD, and the left hippocampus and orbitofrontal cortex could serve as specific regions of interest for further investigations.

Learning to rank-based gene summary extraction.

BACKGROUND: In recent years, the biomedical literature has been growing rapidly. These articles provide a large amount of information about proteins, genes and their interactions. Reading such a huge amount of literature is a tedious task for researchers to gain knowledge about a gene. As a result, it is significant for biomedical researchers to have a quick understanding of the query concept by integrating its relevant resources. METHODS: In the task of gene summary generation, we regard automatic summary as a ranking problem and apply the method of learning to rank to automatically solve this problem. This paper uses three features as a basis for sentence selection: gene ontology relevance, topic relevance and TextRank. From there, we obtain the feature weight vector using the learning to rank algorithm and predict the scores of candidate summary sentences and obtain top sentences to generate the summary. RESULTS: ROUGE (a toolkit for summarization of automatic evaluation) was used to evaluate the summarization result and the experimental results showed that our method outperforms the baseline techniques. CONCLUSIONS: According to the experimental result, the combination of three features can improve the performance of summary. The application of learning to rank can facilitate the further expansion of features for measuring the significance of sentences.

Preventive effects of rutin on the development of experimental diabetic nephropathy in rats.

AIMS: Diabetic nephropathy (DN) is an important microvascular complication and one of the main causes of end-stage renal disease. In this study, the preventive effect and mechanism of rutin on the development of DN in streptozotocin (STZ)-induced diabetic rats were investigated. MAIN METHODS: After an early DN model was induced by STZ, rats were orally administered rutin at 3 doses for 10 weeks. Fasting blood glucose, creatinine (Cr), blood urea nitrogen (BUN), urine protein, kidney index, antioxidase, advanced glycosylation end products (AGEs), extracellular matrix (ECM) including collagen IV and laminin, connective tissue growth factor (CTGF), phosphorylated Smad 2/3 (p-Smad 2/3) and Smad 7 (p-Smad 7), and transforming growth factor-ß(1) (TGF-ß(1)) were determined by different methods, respectively. The ultrastructural morphology was observed by a transmission electron microscope. KEY FINDINGS: Compared with the DN group, rutin decreased the levels of fasting blood glucose, Cr, BUN, urine protein, the intensity of oxidative stress and p-Smad 7 significantly. The expression of AGEs, collagen IV and laminin, TGF-ß(1), p-Smad 2/3 and CTGF was inhibited by rutin significantly. Moreover, rutin was observed to inhibit proliferation of mesangial cells and decrease thickness of glomerular basement membrane (GBM) by electron microscopy. SIGNIFICANCE: The preventive effect of rutin on the development of DN is closely related to oxidative stress and the TGF-ß(1)/Smad/ECM and TGF-ß(1)/CTGF/ECM signaling pathways. Those results suggest that rutin can prevent the development of experimental DN in rats.

In vitro suppression of quercetin on hypertrophy and extracellular matrix accumulation in rat glomerular mesangial cells cultured by high glucose.

Quercetin's protective effects on the glomerulosclerosis of diabetic nephropathy (DN) in rat mesangial cells were investigated. The cell cycles, type IV collagen and laminin, TGF-ß(1) mRNA, Smad 2/3 and Smad 7, and activities of cell antioxidases were measured. Compared with the high glucose group, quercetin may decrease the cell percentages of G(0)/G(1) phase, Smad 2/3 expression, laminin and type IV collagen, and TGF-ß(1) mRNA level significantly. The antioxidant capacity, the cell percentages of S phase and Smad 7 expression was significantly increased by quercetin. These results suggest that quercetin is a protective agent against glomerulosclerosis in DN.