Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the ...most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3's oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.
The development of high‐efficiency bifunctional electrocatalysts toward the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline surroundings is essential and challenging ...for the large‐scale generation of clean hydrogen. Herein, a novel self‐assembled two‐dimensional (2 D) NiO/CeO2 heterostructure (HS) consisting of NiO and CeO2 nanocrystals is prepared through a facile two‐step approach, and utilized as an enhanced bifunctional electrocatalyst for the HER and OER under alkaline conditions. It is concluded that this 2 D NiO/CeO2 HS, rich in oxygen vacancies, demonstrates attractive electrocatalytic properties for both the HER and OER in 1 m KOH, including low onset overpotential (η1), η10 and Tafel slope, excellent durability, as well as large active surface area. Therefore, the self‐assembled 2 D NiO/CeO2 HS is believed to be an efficient bifunctional electrocatalyst toward the HER and OER.
Bifunctional electrocatalysts: A high‐efficiency bifunctional NiO/CeO2 heterostructure (HS) electrocatalyst is fabricated. The unique self‐assembled NiO/CeO2 HSs consisting of NiO and CeO2 nanocrystals is rich in oxygen vacancies and has a large active surface area. These features contribute to the outstanding HER and OER performance in 1 m KOH. Therefore, these self‐assembled 2 D NiO/CeO2 HSs are expected to find use in numerous renewable energy systems.
Gastrointestinal microbiota may be involved in
associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential ...dysbiosis arising from
infection.
Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-
treatment, relative to 49
negative subjects.
In
positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in
positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between
and
,
,
,
,
were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased
after successful
eradication and more upregulated drug-resistant functional orthologs after failed treatment.
infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful
eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
Previous studies have revealed the involvement of coffee and tea in the development of stroke and dementia. However, little is known about the association between the combination of coffee and tea ...and the risk of stroke, dementia, and poststroke dementia. Therefore, we aimed to investigate the associations of coffee and tea separately and in combination with the risk of developing stroke and dementia.
This prospective cohort study included 365,682 participants (50 to 74 years old) from the UK Biobank. Participants joined the study from 2006 to 2010 and were followed up until 2020. We used Cox proportional hazards models to estimate the associations between coffee/tea consumption and incident stroke and dementia, adjusting for sex, age, ethnicity, qualification, income, body mass index (BMI), physical activity, alcohol status, smoking status, diet pattern, consumption of sugar-sweetened beverages, high-density lipoprotein (HDL), low-density lipoprotein (LDL), history of cancer, history of diabetes, history of cardiovascular arterial disease (CAD), and hypertension. Coffee and tea consumption was assessed at baseline. During a median follow-up of 11.4 years for new onset disease, 5,079 participants developed dementia, and 10,053 participants developed stroke. The associations of coffee and tea with stroke and dementia were nonlinear (P for nonlinear <0.01), and coffee intake of 2 to 3 cups/d or tea intake of 3 to 5 cups/d or their combination intake of 4 to 6 cups/d were linked with the lowest hazard ratio (HR) of incident stroke and dementia. Compared with those who did not drink tea and coffee, drinking 2 to 3 cups of coffee and 2 to 3 cups of tea per day was associated with a 32% (HR 0.68, 95% CI, 0.59 to 0.79; P < 0.001) lower risk of stroke and a 28% (HR, 0.72, 95% CI, 0.59 to 0.89; P = 0.002) lower risk of dementia. Moreover, the combination of coffee and tea consumption was associated with lower risk of ischemic stroke and vascular dementia. Additionally, the combination of tea and coffee was associated with a lower risk of poststroke dementia, with the lowest risk of incident poststroke dementia at a daily consumption level of 3 to 6 cups of coffee and tea (HR, 0.52, 95% CI, 0.32 to 0.83; P = 0.007). The main limitations were that coffee and tea intake was self-reported at baseline and may not reflect long-term consumption patterns, unmeasured confounders in observational studies may result in biased effect estimates, and UK Biobank participants are not representative of the whole United Kingdom population.
We found that drinking coffee and tea separately or in combination were associated with lower risk of stroke and dementia. Intake of coffee alone or in combination with tea was associated with lower risk of poststroke dementia.
Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still ...accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.
Flexible Bi2Te3‐based thermoelectric devices can function as power generators for powering wearable electronics or chip‐sensors for internet‐of‐things. However, the unsatisfied performance of n‐type ...Bi2Te3 flexible thin films significantly limits their wide application. In this study, a novel thermal diffusion method is employed to fabricate n‐type Te‐embedded Bi2Te3 flexible thin films on flexible polyimide substrates, where Te embeddings can be achieved by tuning the thermal diffusion temperature and correspondingly result in an energy filtering effect at the Bi2Te3/Te interfaces. The energy filtering effect can lead to a high Seebeck coefficient ≈160 µV K−1 as well as high carrier mobility of ≈200 cm2 V−1 s−1 at room‐temperature. Consequently, an ultrahigh room‐temperature power factor of 14.65 µW cm−1 K−2 can be observed in the Te‐embedded Bi2Te3 flexible thin films prepared at the diffusion temperature of 623 K. A thermoelectric sensor is also assembled through integrating the n‐type Bi2Te3 flexible thin films with p‐type Sb2Te3 counterparts, which can fast reflect finger‐touch status and demonstrate the applicability of as‐prepared Te‐embedded Bi2Te3 flexible thin films. This study indicates that the thermal diffusion method is an effective way to fabricate high‐performance and applicable flexible Te‐embedded Bi2Te3‐based thin films.
In this study, flexible n‐type Bi2Te3‐based thin‐films are successfully prepared through facile thermal diffusion method and further induce Te/Bi2Te3 heterojunctions and energy filtering effect at the Te/Bi2Te3 interfaces to optimize the thermoelectric performance through tuning the diffusion temperature.
Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli meningitis remains elusive. E. coli penetration of the blood-brain barrier (BBB) ...is the critical step for development of meningitis. Here, we identify Caspr1, a single-pass transmembrane protein, as a host receptor for E. coli virulence factor IbeA to facilitate BBB penetration. Genetic ablation of endothelial Caspr1 and blocking IbeA-Caspr1 interaction effectively prevent E. coli penetration into the brain during meningitis in rodents. IbeA interacts with extracellular domain of Caspr1 to activate focal adhesion kinase signaling causing E. coli internalization into the brain endothelial cells of BBB. E. coli can invade hippocampal neurons causing apoptosis dependent on IbeA-Caspr1 interaction. Our results indicate that E. coli exploits Caspr1 as a host receptor for penetration of BBB resulting in meningitis, and that Caspr1 might be a useful target for prevention or therapy of E. coli meningitis.
Abstract
Drug–target interactions (DTIs) play a crucial role in target-based drug discovery and development. Computational prediction of DTIs can effectively complement experimental wet-lab ...techniques for the identification of DTIs, which are typically time- and resource-consuming. However, the performances of the current DTI prediction approaches suffer from a problem of low precision and high false-positive rate. In this study, we aim to develop a novel DTI prediction method for improving the prediction performance based on a cascade deep forest (CDF) model, named DTI-CDF, with multiple similarity-based features between drugs and the similarity-based features between target proteins extracted from the heterogeneous graph, which contains known DTIs. In the experiments, we built five replicates of 10-fold cross-validation under three different experimental settings of data sets, namely, corresponding DTI values of certain drugs (SD), targets (ST), or drug-target pairs (SP) in the training sets are missed but existed in the test sets. The experimental results demonstrate that our proposed approach DTI-CDF achieves a significantly higher performance than that of the traditional ensemble learning-based methods such as random forest and XGBoost, deep neural network, and the state-of-the-art methods such as DDR. Furthermore, there are 1352 newly predicted DTIs which are proved to be correct by KEGG and DrugBank databases. The data sets and source code are freely available at https://github.com//a96123155/DTI-CDF.
β‐Amino sulfones are commonly found structural motifs in biologically active compounds. Herein, we report a direct photocatalyzed amino‐sulfonylation reaction of alkenes for the efficicient ...production of important compounds by simple hydrolysis without the need for additional oxidants and reductants. In this transformation, the sulfonamides worked as bifunctional reagents, simultaneously generating sulfonyl radicals and N‐centered radicals which were added to alkene in a highly atom‐economical fashion with high regioselectivity and diastereoselectivity. This approach showed high functional group tolerance and compatibility, facilitating the late‐stage modification of some bioactive alkenes and sulfonamide molecules, thereby expanding the biologically relevant chemical space. Scaling up this reaction led to an efficient green synthesis of apremilast, one of the best‐selling pharmceuticals, demonstrating the synthetic utility of the applied method. Moreover, mechanistic investigations suggest that an energy transfer (EnT) process was in operation.
A benign method was developed for the economical and sustainable amino‐sulfonylation of alkenes with high regioselectivity and diastereoselectivity. This approach showed high functional group tolerance and compatibility, facilitating the late‐stage modification of some bioactive alkenes and sulfonamide molecules, thereby expanding the biologically relevant chemical space. Mechanistic investigations suggest that an energy transfer (EnT) process was in operation.
Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ...ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.
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