Binary ruthenium dioxide and nickel oxide ultrafine particles loaded on carbon nanotubes for high-stability oxygen evolution reaction at high current densities.

RuO2 is an efficient electrocatalyst for the oxygen evolution reaction (OER). However, during the OER process, RuO2 is prone to oxidation into Rux+ (x > 4), leading to its dissolution in the electrolyte and resulting in poor stability of RuO2. Here, we report a bicomponent electrocatalyst, NiO and RuO2 co-loaded on carbon nanotubes (RuO2/NiO/CNT). The results demonstrate that the introduction of NiO suppresses the over-oxidation of RuO2 during the OER process, not only inheriting the excellent catalytic performance of RuO2, but also significantly enhancing the stability of the catalyst for OER at high current densities. In contrast to RuO2/CNT, RuO2/NiO/CNT shows no significant change in activity after 150 h of OER at a current density of 100 mA cm-2. Density functional theory (DFT) calculations indicate that NiO transfers a large number of electrons to RuO2, thereby reducing the oxidation state of Ru. In conclusion, this study provides a detailed analysis of the phenomenon where low-valent metal oxides have the ability to enhance the stability of RuO2 catalysts.

Cysteine-Induced Chirality Evolution of Molybdenum Disulfide Nanodots from a Bottom-Up Strategy.

The transfer of chirality from molecules to synthesized nanomaterials has recently attracted significant attention. Although most studies have focused on graphene and plasmonic metal nanostructures, layered transition metal dichalcogenides (TMDs), particularly MoS2, have recently garnered considerable attention due to their semiconducting and electrocatalytic characteristics. Herein, we report a new approach for the synthesis of chiral molybdenum sulfide nanomaterials based on a bottom-up synthesis method in the presence of chiral cysteine enantiomers. In the synthesis process, molybdenum trioxide and sodium hydrosulfide serve as molybdenum and sulfur sources, respectively. In addition, ascorbic acid acts as a reducing agent, resulting in the formation of zero-dimensional MoS2 nanodots. Moreover, the addition of cysteine enantiomers to the growth solutions contributes to the chirality evolution of the MoS2 nanostructures. The chirality is attributed to the cysteine enantiomer-induced preferential folding of the MoS2 planes. The growth mechanism and chiral structure of the nanomaterials are confirmed through a series of characterization techniques. This work combines chirality with the bottom-up synthesis of MoS2 nanodots, thereby expanding the synthetic methods for chiral nanomaterials. This simple synthesis approach provides new insights for the construction of other chiral TMD nanomaterials with emerging structures and properties. More significantly, the as-formed MoS2 nanodots exhibited highly defect-rich structures and chiroptical performance, thereby inspiring a high potential for emerging optical and electronic applications.

Exploring drug repositioning possibilities of kinase inhibitors via molecular simulation.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

Ultrasound-based comparative analysis and nomogram development for predicting triple-negative and non-triple-negative breast cancer: a 4-year institutional study in Quanzhou First Hospital.

OBJECTIVE: The objective of this study was to compare ultrasound features and establish a predictive nomogram for distinguishing between triple-negative breast cancer (TNBC) and non-TNBC. DESIGN: A retrospective cohort study. SETTING: This study was conducted at Quanzhou First Hospital, a grade A tertiary hospital in Quanzhou, China, with the research data set covering the period from September 2019 to August 2023. PARTICIPANTS: The study included a total of 205 female patients with confirmed TNBC and 574 female patients with non-TNBC, who were randomly divided into a training set and a validation set at a ratio of 7:3. MAIN OUTCOME MEASURES: All patients underwent ultrasound examination and received a confirmatory pathological diagnosis. Nodules were classified according to the Breast Imaging-Reporting and Data System standard. Subsequently, the study conducted a comparative analysis of clinical characteristics and ultrasonic features. RESULTS: A statistically significant difference was observed in multiple clinical and ultrasonic features between TNBC and non-TNBC. Specifically, in the logistic regression analysis conducted on the training set, indicators such as posterior echo, lesion size, presence of clinical symptoms, margin characteristics, internal blood flow signals, halo and microcalcification were found to be statistically significant (p<0.05). These significant indicators were then effectively incorporated into a static and dynamic nomogram model, demonstrating high predictive performance in distinguishing TNBC from non-TNBC. CONCLUSION: The results of our study demonstrated that ultrasound features can be valuable in distinguishing between TNBC and non-TNBC. The presence of posterior echo, size, clinical symptoms, margin, internal flow, halo and microcalcification was identified as predictive factors for this differentiation. Microcalcification, hyperechoic halo, internal flow and clinical symptoms emerged as the strongest predictive factors, indicating their potential as reliable indicators for identifying TNBC and non-TNBC.

Efficient turn-on fluorescent probe cooperated by cascade response for disclosing the fluctuation of cysteine in cells.

BACKGROUND: The research on cysteine (Cys) determination is deemed as a hot topic, since it has been reported to be connected with various physiological processes and disease prediction. However, existing Cys-responding probes may expose some defects such as long reaction time, disappointing photostability, and suboptimal sensitivity. Under such a circumstance, our team has proposed an efficient fluorescent probe with novel sensing mechanism to perfectly cope with the above-mentioned drawbacks. RESULTS: A novel cascade reaction-based probe 9-(2,2-dicyanovinyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-yl acrylate (DPQA) has been synthesized for the first time. Undergoing addition-cleavage and cyclization-rearrangement processes, DPQA reacts with Cys to generate an iminocoumarin product with relucent green fluorescence, namely 11-imino-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carbonitrile (IMC-J), and the relative fluorescence quantum yield (Φf) soars from 0.007 to 0.793. Utilizing such a mechanism, DPQA shows a superb turn-on signal (172-fold), low detection limit (4.1 nM), and wide detection range (5-6000 nM) toward Cys detection. Encouraged by the admirable sensing performance of DPQA, bioimaging of endogenous Cys has been attempted in HeLa cells with satisfactory results. Moreover, cell model of H2O2-induced oxidative stress has been established and the Cys fluctuation during this process has been inspected, elucidating how living cells confront with the eruption of reactive oxygen species (ROS) storm. SIGNIFICANCE: The probe DPQA with such an intriguing cascade responding process for Cys detection has been endowed with many merits, such as fast reaction and superior sensitivity, conducive to improving responsiveness and rendering it more suitable for further applications. Thereby, we expect that the DPQA would be an efficient tool for detecting Cys fluctuation in living cells of different physiological processes.

Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.

Targeting the chromatin structural changes of antitumor immunity.

Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.

Limitations and modifications in the clinical application of calcium sulfate.

Calcium sulfate and calcium sulfate-based biomaterials have been widely used in non-load-bearing bone defects for hundreds of years due to their superior biocompatibility, biodegradability, and non-toxicity. However, lower compressive strength and rapid degradation rate are the main limitations in clinical applications. Excessive absorption causes a sharp increase in sulfate ion and calcium ion concentrations around the bone defect site, resulting in delayed wound healing and hypercalcemia. In addition, the space between calcium sulfate and the host bone, resulting from excessively rapid absorption, has adverse effects on bone healing or fusion techniques. This issue has been recognized and addressed. The lack of sufficient mechanical strength makes it challenging to use calcium sulfate and calcium sulfate-based biomaterials in load-bearing areas. To overcome these defects, the introduction of various inorganic additives, such as calcium carbonate, calcium phosphate, and calcium silicate, into calcium sulfate is an effective measure. Inorganic materials with different physical and chemical properties can greatly improve the properties of calcium sulfate composites. For example, the hydrolysis products of calcium carbonate are alkaline substances that can buffer the acidic environment caused by the degradation of calcium sulfate; calcium phosphate has poor degradation, which can effectively avoid the excessive absorption of calcium sulfate; and calcium silicate can promote the compressive strength and stimulate new bone formation. The purpose of this review is to review the poor properties of calcium sulfate and its complications in clinical application and to explore the effect of various inorganic additives on the physicochemical properties and biological properties of calcium sulfate.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Traditional Chinese medicine for gastric cancer: An evidence mapping.

As a complementary and alternative therapy, traditional Chinese medicine (TCM) has been playing a significant role in gastric cancer treatment. Data from individual systematic reviews have not been comprehensively summarized, and the relationship between certain interventions and outcomes are ill-defined. This study aimed to analyze the advantages of TCM interventions for gastric cancer by the method of evidence mapping. We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Chinese Scientific Journals Database, and Wanfang Database for systematic reviews of TCM treating gastric cancer up to December 31, 2023. We used Excel, Endnote 20, and Python software for the analysis of incorporated studies. We assessed the quality of included SRs by AMSTAR-2 and performed evidence mapping including 89 SRs, 1648 RCTs and 122,902 patients, identifying 47 types of interventions and 39 types of outcomes. From a visual overview, we displayed that most SRs reported beneficial effects in improving short- and long-term survival, myelosuppression, and immune function, even though the quality of evidence was generally low. The benefits of Brucea javanica Oil Emulsion Injection, ShenQiFuZheng Injection, XiaoAiPing, Astragalus-Containing TCM and Guben Xiaoji Therapy were found the most solid in corresponding aspects. Our findings suggest that although more rigorous clinical trials and SRs are needed to identify the precise effectiveness, integrating such evidence into clinical care of gastric cancer is expected to be beneficial.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

Factors associated with intervertebral cage subsidence in posterior lumbar fusion.

BACKGROUND: The interbody fusion apparatus is a key component of the operation and plays a key role in the postoperative efficacy. Cage subsidence is one of the common complications after lumbar fusion and internal fixation. Clinical studies on the risk factors of cage subsidence are incomplete and inaccurate, especially paravertebral muscle atrophy and intervertebral bone fusion time. METHODS: Among the patients who underwent PLIF surgery in our hospital from January 2016 to January 2019, 30 patients with cage subsidence and 30 patients without cage subsidence were randomly selected to be included in this study. The differences between the two groups were compared, and the relevant factors of cage subsidence were explored by single factor comparison and multiple logistic regression analysis. RESULTS: Bone mineral density (T) of the subsidence group [(- 1.84 ± 1.81) g/cm2 vs (- 0.87 ± 1.63) g/cm2, P = 0.018] was significantly lower than that of the normal group. There were 4 patients with end plate injury in the subsidence group (P = 0.038). Preoperative end plate Modic changes [I/II/III, (7/2/2) vs (2/5/8), P = 0.043] were significantly different between the two groups. In the subsidence group, preoperative rCSA of psoas major muscle [(1.43 ± 0.40) vs (1.64 ± 0.41), P = 0.043], CSA of paravertebral muscle [(4530.25 ± 776.55) mm2 vs (4964.75 ± 888.48) mm2, P = 0.047], paravertebral muscle rCSA [(3.03 ± 0.72) vs (3.84 ± 0.73), P < 0.001] and paravertebral muscle rFCSA [(2.29 ± 0.60) vs (2.89 ± 0.66), P < 0.001] were significantly lower than those in normal group. In the subsidence group, the vertebral body area [(1547.81 ± 309.89) mm2 vs (1326.48 ± 297.21) mm2, P = 0.004], the height of the immediately corrected vertebral space [(2.86 ± 1.10) mm vs (1.65 ± 1.02) mm, P = 0.020], immediately SL corrective Angle [(5.81 + 4.71)° vs (3.24 + 3.57) °, P = 0.009), postoperative PI-LL [(11.69 + 6.99)° vs (6.66 + 9.62) °, P = 0.029] and intervertebral fusion time [(5.38 ± 1.85) months vs (4.30 ± 1.49) months, P = 0.023] were significantly higher than those in the normal group. Multivariate logistic regression analysis showed that the time of intervertebral fusion (OR = 1.158, P = 0.045), the height of immediate intervertebral space correction (OR = 1.438, P = 0.038), and the Angle of immediate SL correction (OR = 1.101, P = 0.019) were the risk factors for cage subsidence. Bone mineral density (OR = 0.544, P = 0.016) and preoperative paravertebral muscle rFCSA (OR = 0.525, P = 0.048) were protective factors. CONCLUSION: Intervertebral fusion time, correctable height of intervertebral space, excessive Angle of immediate SL correction, bone mineral density and preoperative paravertebral muscle rFCSA are risk factors for cage subsidence after PLIF.

A New Transoral Vestibulum Single Incision Endoscopic-Assisted Thyroidectomy with Gasless.

OBJECTIVE: We developed a novel method for thyroidectomy using a single-incision oral vestibular approach. To assess its advantages and disadvantages, we compared the perioperative parameters of this approach with those of transoral three-incision thyroidectomy and trans-areolar thyroidectomy. METHODS: In a study of 136 papillary thyroid carcinoma patients (2016-2018), precise thyroidectomy and neck dissection were conducted. Among them, 52 chose single-incision oral vestibular approach, 33 chose three-incision variant, and 51 underwent trans-areolar thyroidectomy. Perioperative aspects of the transoral single-incision group were compared with those of transoral three-incision group, and transthoracic group. RESULTS: In the cohort, meticulous tumor level VI lymph node dissection was performed, achieving intended resection extent with one case requiring a switch from transoral to transthoracic approach. No nerve palsy occurred in the transoral group. Thyroidectomy duration varied significantly across groups. Transoral single-incision had a shorter duration than transoral three-incision and longer than transthoracic. Minor differences were observed in blood loss and drainage. Perioperative factors like hematoma, infection, hypocalcemia, et al., remained consistent. Notably, no tumor recurrence was observed in this study. CONCLUSIONS: This new transoral video-assisted neck surgery (TOVANS) method for thyroidectomy without gas insufflation approach did not increase the surgical complexity compared with the transoral vestibular three-incision thyroidectomy and the trans-areolar thyroidectomy. LEVEL OF EVIDENCE: 3 Laryngoscope, 2023.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Anti-PD-1/PD-L1 for nasopharyngeal carcinoma: a comprehensive analysis of registered trials on ClinicalTrials.gov.

Objective: Clinical trials play an important role in the development of healthcare. However, the current status of clinical trials on anti-PD-1/PD-L1 for nasopharyngeal carcinoma remains unclear. Therefore, this study aims to provide a comprehensive analysis of the registered trials related to anti-PD-1/PD-L1 for nasopharyngeal carcinoma on ClinicalTrials.gov. Methods: A search was conducted on the ClinicalTrials.gov database to identify all registered trials related to anti-PD-1/PD-L1 for nasopharyngeal carcinoma up to 26 February 2023. The characteristics of the trials were examined, and the studied drugs, disease conditions, as well as details of trials with available results were analyzed. Publication status was assessed by a PubMed search using the ClinicalTrials.gov NCT number. Results: A total of 112 interventional clinical trials registered between 2015 and 2023 were included. Of the trials, 90 were carried out in Asia, 72 were in phase 2, and 31 trials had either companies or universities as sponsors/collaborators. The sample sizes across the trials varied greatly, with a median of 71.5 participants per trial. The majority of trials were recruiting participants, with only 6 had posted results. PD-1 inhibitors were preferred over PD-L1, and Toripalimab emerged as the most extensively studied drug. About one-third (33.9%) of the studies looked into recurrent/metastatic nasopharyngeal cancer. Conclusion: This study provides an overview of all registered trials of anti-PD-1/PD-L1 for NPC. It is needed to improve the completeness, outcome selection, randomization and masking of trials and to be transparent and timely in reporting of results.

An intelligent "chemical tongue" for high-order monitoring ATP-related physiological phosphates and ATP hydrolysis through diverse transduction principles.

For discriminating diverse analytes and monitoring a specific chemical reaction, the emerging multi-channel "chemical nose/tongue" is challenging multi-material "chemical nose/tongue". The former contributes greatly to integrating different transduction principles from a single sensing material, avoiding the need for complex design, high cost, and tedious operation involved with the latter. Therefore, this high-order sensing puts a particular emphasis on the effects of encapsulation. Herein, the plasmonic gold nanoparticles (Au NPs) are encapsulated as a core into the fluorescent guanine monophosphate-Tb3+ infinite coordination polymer nanoparticles (GMP-Tb ICPs) to obtain a core-shell nanocomposite named Au NPs@GMP-Tb ICPs. Hence, a dual-channel "chemical tongue" based on Au NPs@GMP-Tb ICPs is present to realize high-order sensing of adenosine triphosphate (ATP)-related physiological phosphates and the monitoring of ATP hydrolysis. Considering the affinity of Tb3+ towards P-O bonds, four inorganic phosphates and three nucleotide phosphates with different phosphate group numbers and steric hindrance effect directly regulate two stimulus responses (fluorescence intensity and UV-vis absorbance) of Au NPs@GMP-Tb ICPs. Robust statistical methods, such as linear discriminant analysis and hierarchical cluster analysis, are used to recognize each phosphate by the developed sensor array either in the aqueous solution or in complex media such as serum, together with efficiently monitored ATP hydrolysis at different intervals. These findings and blind test clarify that the designed "chemical tongue" guarantees interference resistance and strengthens analytical capacity, together with offering valuable insight into "lab-on-a-nanoparticle" development for monitoring specific chemical reactions.

Modulating adsorption energy on nickel nitride-supported ruthenium nanoparticles through in-situ electrochemical activation for urea-assisted alkaline hydrogen production.

The rational design of electrocatalysts with exceptional performance and durability for hydrogen production in alkaline medium is a formidable challenge. In this study, we have developed in-situ activated ruthenium nanoparticles dispersed on Ni3N nanosheets, forming a bifunctional electrocatalyst for hydrogen evolution and urea oxidation. The results of experimental analysis and theoretical calculations reveal that the enhanced hydrogen evolution reaction (HER) performance of O-Ru-Ni3N stems primarily from the optimized hydrogen adsorption and hydroxyl adsorption on Ru sites. The O-Ru-Ni3N on nickel foam (NF) electrode exhibits excellent HER performance, requiring only 29 mV to reach 10 mA cm-2 in an alkaline medium. Notably, when this O-Ru-Ni3N/NF catalyst is employed for both HER and urea oxidation reaction (UOR) to create an integrated H2 production system, a current density of 50 mA cm-2 can be generated at the cell voltage of 1.41 V. This report introduces an energy-efficient catalyst for hydrogen production and proposes a viable strategy for anodic activation in energy chemistry.

Challenges for the development of mutant isocitrate dehydrogenases 1 inhibitors to treat glioma.

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.

Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway.

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.

Diagonal Interactions between Glutamate and Arginine Analogs with Varying Side-Chain Lengths in a ß-Hairpin.

Cross-strand interactions are important for the stability of ß-sheet structures. Accordingly, cross-strand diagonal interactions between glutamate and arginine analogs with varying side-chain lengths were studied in a series of ß-hairpin peptides. The peptides were analyzed by homonuclear two-dimensional nuclear magnetic resonance methods. The fraction folded population and folding free energy of the peptides were derived from the chemical shift data. The fraction folded population trends could be rationalized using the strand propensity of the constituting residues, which was not the case for the peptides with lysine analogs, highlighting the difference between the arginine analogs and lysine analogs. Double-mutant cycle analysis was used to derive the diagonal ion-pairing interaction energetics. The most stabilizing diagonal cross-strand interaction was between the shortest residues (i.e., Asp2-Agp9), most likely due to the least side-chain conformational penalty for ion-pair formation. The diagonal interaction energetics in this study involving the arginine analogs appears to be consistent with and extend beyond our understanding of diagonal ion-pairing interactions involving lysine analogs. The results should be useful for designing ß-strand-containing molecules to affect biological processes such as amyloid formation and protein-protein interactions.