Acute interval running induces greater excess post-exercise oxygen consumption and lipid oxidation than isocaloric continuous running in men with obesity.

Studies seem to show that high-intensity interval training (HIIT) is a more time-efficient protocol for weight loss, compared with moderate-intensity continuous training (MICT). Our aim was to compare the acute effects of energy expenditure (EE) matched HIIT vs. MICT on excess post-exercise oxygen consumption (EPOC) and substrate metabolism in male college students with obesity. Twenty-one untrained male college students (age, 22 ± 3 years; body fat, 28.4 ± 4.5%) completed two acute interventions (~ 300 kcal) on a treadmill in a randomized order: (1) HIIT: 3 min bouts at 90% of maximal oxygen uptake (VO2max) with 2 min of recovery at 25% of VO2max; (2) MICT: 60% of VO2max continuous training. EPOC and substrate metabolism were measured by indirect calorimetry during and 30 min after exercise. Results showed that EPOC was higher after HIIT (66.20 ± 14.36 kcal) compared to MICT (53.91 ± 12.63 kcal, p = 0.045), especially in the first 10 min after exercise (HIIT: 45.91 ± 9.64 kcal and MICT: 34.39 ± 7.22 kcal, p = 0.041). Lipid oxidation rate was higher after HIIT (1.01 ± 0.43 mg/kg/min) compared to MICT (0.76 ± 0.46 mg/kg/min, p = 0.003). Moreover, the percentage of energy from lipid was higher after HIIT (37.94 ± 14.21%) compared to MICT (30.09 ± 13.54%, p = 0.020). We conclude that HIIT results in greater total EE and EPOC, as well as higher percentage of energy from lipid during EPOC than EE matched MICT in male college students with obesity.

Bioinspired Nanozymes as Nanodecoys for Urinary Tract Infection Treatment.

Urinary tract infections (UTIs), common bacterial infections in communities and medical facilities, are mainly mediated by FimH. The glycan sites of the uromodulin protein play a crucial role in protecting against UTIs by interacting with FimH. A bioinspired approach using glycan-FimH interactions may effectively reduce bacteria through an antiadhesive mechanism, thereby curbing bacterial resistance. However, typical antiadhesive therapy alone fails to address the excessive reactive oxygen species and inflammatory response during UTIs. To bridge this gap, antioxidant nanozymes with antiadhesive ability were developed as nanodecoys to counter bacteria and inflammation. Specifically, ultrasmall dextran-coated ceria (DEC) was engineered to address UTIs, with dextran blocking FimH adhesion and ceria exhibiting anti-inflammatory properties. DECs, metabolizable by the kidneys, reduced bacterial content in the urinary tract, mitigating inflammation and tissue damage. In murine models, DECs successfully treated acute UTIs, repeated infections, and catheter-related UTIs. This dual approach not only highlights the potential of nanozymes for UTIs but also suggests applicability to other FimH-induced infections in the lungs and bowels, marking a significant advancement in nanozyme-based clinical approaches.

Lycorine inhibits migration and proliferation of hepatocellular carcinoma cells by reducing transketonase expression.

Background: Previous studies have showed that lycorine can restrain the development of multiple tumor types, containing hepatocellular carcinoma (HCC), but the underlying mechanisms remain unknown. Methods: We assessed the impact of lycorine on hepatocellular cancer cell proliferation, migration, colony formation, cell cycle, and apoptosis. The possible inhibitory effect of lycorine on the activity of HCC cells was analyzed by RNA-seq, and transketolase (TKT) expression in HCC and nontumorous tissues was detected using RT-PCR. The expression of TKT protein in HCC and tumor adjacent non-cancerous tissues was detected by immunohistochemistry. We evaluated the association of expression of TKT in HCC tissues with prognosis, and investigated the inhibitory effect of lycorine on tumor growth in vivo. Results: Lycorine significantly inhibited the proliferation, invasion, migration, colony formation, cell cycle of HCC cells, but had no obvious impact on apoptosis. Twenty-eight genes were found to be down-regulated in HuH7 and HepG2 cells after lycorine treatment, and the difference of TKT gene expression was significantly. The expression of TKT protein was significantly higher in HCC than in non-tumorous tissues. The expression of TKT was correlated with tumor size, Edmondson grade, AFP, and overall survival. Survival analysis suggested that high expression of TKT was associated with a poor survival. The average tumor volume and weight were significantly reduced in the lycorine injection group, but the body weights of the mice did not change significantly. Conclusion: Lycorine can restrict the migration and proliferation of HCC cells by down-regulating TKT expression, and it may be a potential meaningful drug for the prevention and treatment of HCC.

Hyaluronic acid/dextran-based polymeric micelles co-delivering ursolic acid and doxorubicin to mitochondria for potentiating chemotherapy in MDR cancer.

Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA: 9.06 %). After hyaluronic acid (HA)-mediated endocytosis, the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles. Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc.; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.

Hydrous ruthenium oxide triggers template-free and spontaneous growth of metal nanostructures.

Intrinsically conductive ruthenium oxide is an excellent material for energy storage and conversion. Herein, we present hydrous RuO2 (H-RuO2) as a potent reducing agent to achieve spontaneous growth of multiple noble metals at room temperature. Self-assembled gold and platinum, comprising small-sized nanoparticles, are generated on the surface of H-RuO2 without the need for additional templates. Structural analysis reveals that the disordered structure and the presence of oxygen vacancies trigger interfacial redox reactions between H-RuO2 and oxidative metal salts. The resulting integrated nanostructures, consisting of a metal oxide and different metals (H-RuO2@metal), are subsequently used to treat inflammatory bowel diseases. In addition to biomedical applications, our developed synthetic strategy, using reactive oxides to spontaneously generate multicomponent nanostructures, also holds great significance for other catalysis-based applications.

Nanozyme-Enhanced Probiotic Spores Regulate the Intestinal Microenvironment for Targeted Acute Gastroenteritis Therapy.

Antibiotic therapeutics to combat intestinal pathogen infections often exacerbate microbiota dysbiosis and impair mucosal barrier functions. Probiotics are promising strategies, because they inhibit pathogen colonization and improve intestinal microbiota imbalance. Nevertheless, their limited targeting ability and susceptibility to oxidative stress have hindered their therapeutic potential. To tackle these challenges, Ces3 is synthesized by in situ growth of CeO2 nanozymes with positive charges on probiotic spores, facilitating electrostatic interactions with negatively charged pathogens and possessing a high reactive oxygen species (ROS) scavenging activity. Importantly, Ces3 can resist the harsh environment of the gastrointestinal tract. In mice with S. Typhimurium-infected acute gastroenteritis, Ces3 shows potent anti-S. Typhimurium activity, thereby alleviating the dissemination of S. Typhimurium into other organs. Additionally, owing to its O2 deprivation capacity, Ces3 promotes the proliferation of anaerobic probiotics, reshaping a healthy intestinal microbiota. This work demonstrates the promise of combining antibacterial, anti-inflammatory, and O2 content regulation properties for acute gastroenteritis therapy.

Light-Induced Variation of Lithium Coordination Environment in g-C3N4 Nanosheet for Highly Efficient Oxygen Reduction Reactions.

The structure and electronic state of the active center in a single-atom catalyst undergo noticeable changes during a dynamic catalytic process. The metal atom active center is not well demonstrated in a dynamic manner. This study demonstrated that Li metal atoms, serving as active centers, can migrate on a C3N4 monolayer or between C3N4 monolayers when exposed to light irradiation. This migration alters the local coordination environment of Li in the C3N4 nanosheets, leading to a significant enhancement in photocatalytic activity. The photocatalytic H2O2 process could be maintained for 35 h with a 920 mmol/g record-high yield, corresponding to a 0.4% H2O2 concentration, which is far greater than the value (0.1%) of practical application for wastewater treatment. Density functional theory calculations indicated that dynamic Li-coordinated structures contributed to the superhigh photocatalytic activity.

Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study.

A mutation to serine of a conserved threonine (T634S) in the hERG K+ channel S6 pore region has been identified as a variant of uncertain significance, showing a loss-of-function effect. However, its potential consequences for ventricular excitation and arrhythmogenesis have not been reported. This study evaluated possible functional effects of the T634S-hERG mutation on ventricular excitation and arrhythmogenesis by using multi-scale computer models of the human ventricle. A Markov chain model of the rapid delayed rectifier potassium current (IKr) was reconstructed for wild-type and T634S-hERG mutant conditions and incorporated into the ten Tusscher et al. models of human ventricles at cell and tissue (1D, 2D and 3D) levels. Possible functional impacts of the T634S-hERG mutation were evaluated by its effects on action potential durations (APDs) and their rate-dependence (APDr) at the cell level; and on the QT interval of pseudo-ECGs, tissue vulnerability to unidirectional conduction block (VW), spiral wave dynamics and repolarization dispersion at the tissue level. It was found that the T634S-hERG mutation prolonged cellular APDs, steepened APDr, prolonged the QT interval, increased VW, destablized re-entry and augmented repolarization dispersion across the ventricle. Collectively, these results imply potential pro-arrhythmic effects of the T634S-hERG mutation, consistent with LQT2.

Effect of knee osteoarthritis on the postoperative outcome of proximal femoral nail anti-rotation in the treatment of intertrochanteric fractures in the elderly: a retrospective analysis.

BACKGROUND: The proximal femoral nail anti-rotation (PFNA) is a commonly used internal fixation system for intertrochanteric fractures (IFs) in older adults. Knee osteoarthritis (KOA) is a degenerative lower extremity disease that occurs most frequently in the elderly. Some patients have already had KOA before the IFs. However, whether KOA impacts the postoperative outcome of IFs has not been reported. OBJECTIVE: This study aimed to investigate the effect of KOA on the fracture side on the outcome after PFNA for IFs in the elderly. METHODS: Between January 2016 and November 2021, 297 elderly patients treated with PFNA for IFs were enrolled in this study. They were divided into two groups according to the American Rheumatism Association KOA clinical and radiographic criteria: the control group and the KOA group. Intraoperative bleeding, operative time, length of hospital stay, postoperative time out of bed, fracture healing time, postoperative complications, postoperative Harris hip function score, and Barthel ability to daily living Score were compared between the two groups. Follow-up was routinely scheduled at 1, 3, 6, and 12 months postoperatively. RESULTS: Based on the exclusion criteria, 254 patients who met the requirements were left to be included in this study, including the control group (n = 133) and the KOA group (n = 121). Patients were followed up for a mean of 17.5 months (12-24 months). There was no significant difference between the two groups in preoperative demographic data, intraoperative blood loss, operation time, and length of stay in the hospital. The control group was statistically significant compared to the KOA group in terms of postoperative time out of bed (17.8 ± 4.0 days vs. 19.1 ± 5.8 days), fracture healing time (13.7 ± 2.2 weeks vs. 14.6 ± 3.7 weeks), and postoperative complications (12.8 vs. 23.1%). The Harris hip function score and Barthel ability to daily living score were higher in the control group than in the KOA group at 1, 3, 6, and 12 months postoperatively (the control group: 63.8 ± 10.9, 71.8 ± 10.3, 81.5 ± 8.7, and 91.6 ± 6.3 vs. The KOA group 61.0 ± 10.4, 68.6 ± 9.1, 79.0 ± 9.2, and 88.5 ± 5.9). CONCLUSIONS: In elderly patients with IFs combined with KOA of the fracture side treated with PFNA internal fixation, KOA increases the incidence of postoperative complications of the fracture, prolongs postoperative time out of bed and fracture healing, and reduces postoperative hip function and ability to daily living. Therefore, treating KOA on the fractured side needs to be considered when treating IFs in the elderly.

A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders.

Digestive disorders are a significant contributor to the global burden of disease and seriously affect human quality of life. Research has already confirmed the presence of pleiotropic genetic loci among digestive disorders, and studies have explored shared genetic factors among pan-cancers, including various malignant digestive disorders. However, most cross-phenotype studies within the digestive tract system have been limited to a few traits, with no systematic coverage of common benign and malignant digestive disorders. Here, we analyzed data from the UK Biobank to investigate 21 digestive disorders, exploring the genetic correlations and causal relationships between diseases, as well as the common genetic factors and potential biological pathways driving these relationships. Our findings confirmed the extensive genetic correlation and causal relationship between digestive disorders, providing important insights into the genetic etiology, causality, disease prevention, and clinical treatment of diseases.

Identification of Core Symptom Cluster in Patients With Digestive Cancer: A Network Analysis.

BACKGROUND: A lack of identified core symptom clusters in digestive cancer patients hinders achieving precision symptom intervention. There are few studies on identifying digestive cancer symptom clusters based on network analysis. OBJECTIVES: The aims of this study were to construct the symptom network of digestive cancer patients and identify the core symptom cluster. METHODS: A cross-sectional study was conducted among 202 digestive cancer patients. The Chinese version of the MD Anderson Symptom Inventory for gastrointestinal cancer scale was used to assess the symptoms by convenience sampling. R software was used to construct a symptom network and identify core symptom clusters. Edge weight and centrality difference tests were used to test the accuracy of core symptom cluster identification. RESULTS: The most common symptoms were distress, poor appetite, and sadness. The most serious symptoms were poor appetite, disturbed sleep, and fatigue. The core symptom cluster of the psychoemotional symptom group was distress, sadness, and numbness. The centrality index showed that the top 3 in strength were distress (Rs = 1.11), fatigue (Rs = 1.09), and sadness (Rs = 1.04). The edge weight difference test showed that the psychoemotional symptom group had high stability. CONCLUSIONS: The psychoemotional symptoms of digestive cancer patients should be given priority for intervention. Network analysis must be extended to the symptom research of cancer patients as soon as possible to provide a scientific basis for symptom management. IMPLICATIONS FOR PRACTICE: Nurses must perform comprehensive psychological and emotional assessments, initiate referrals for psychoemotional symptom management and psychological services, and administer pharmacologic and nonpharmacologic interventions to improve appetite loss in digestive cancer patients.

Inhibition of the hERG Potassium Channel by a Methanesulphonate-Free E-4031 Analogue.

hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (IKr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, "E-4031-17", to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (IhERG) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT IhERG was inhibited by a half-maximal inhibitory concentration (IC50) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced IhERG inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of IhERG.

Nanozyme-Cosmetic Contact Lenses for Ocular Surface Disease Prevention.

Efficiently balancing excess reactive oxygen species (ROS) caused by various factors on the ocular surface is a promising strategy for preventing the development of ocular surface diseases (OSDs). Nevertheless, the conventional topical administration of antioxidants is limited in efficacy due to poor absorption, rapid metabolism, and irreversible depletion, which impede their performance. To address this issue, contact lenses embedded with antioxidant nanozymes that can continuously scavenge ROS, thereby providing an excellent preventive effect against OSDs are developed. Specifically, Prussian blue family nanozymes are chosen based on their multiple antioxidant enzyme-like activities and excellent biocompatibility. The diverse range of colors made them promising candidates for the development of cosmetic contact lenses (CCLs) as a substitute for conventional pigments. The efficacy of nanozyme-CCLs is demonstrated in rabbits and rats exposed to a high risk of developing OSDs. These OSDs' prevention nanozyme-CCLs can pave the way for CCLs toward powerful wearable biomedical devices and provide novel strategies for the rational utilization of nanomaterials in clinical practice.

Dynamic Analysis and Optimal Control of Fractional Order African Swine Fever Models with Media Coverage.

African swine fever is a highly contagious virus that causes pig disease. Its onset process is short, but the mortality rate is as high as 100%. There are still no effective drugs that have been developed to treat African swine fever, and prevention and control measures are currently the best means to avoid infection in pig herds. In this paper, two fractional order mathematical models with media coverage are constructed to describe the transmission of African swine fever. The first model is a basic model with media coverage, and no control measures are considered. For this model, the reproduction number is obtained by using the next generation matrix method. Then, the sufficient conditions for the existence and stability of two equilibriums are obtained. Based on the first model, the second model is established incorporating two control measures. By using Pontryagin's maximal principle, the optimal control solution is derived. After that, some numerical simulations are performed for the two models to verify the theoretical results. Both the qualitative analysis and numerical results indicate that timely media coverage combined with disinfection control measures is crucial to preventing the spread of disease.

Integrated Cascade Nanozymes with Antisenescence Activities for Atherosclerosis Therapy.

Senescent cells are the critical drivers of atherosclerosis formation and maturation. Mitigating senescent cells holds promise for the treatment of atherosclerosis. In an atherosclerotic plaque microenvironment, senescent cells interact with reactive oxygen species (ROS), promoting the disease development. Here, we hypothesize that a cascade nanozyme with antisenescence and antioxidant activities can serve as an effective therapeutic for atherosclerosis. An integrated cascade nanozyme with superoxide dismutase- and glutathione peroxidase-like activities, named MSe1 , is developed in this work. The obtained cascade nanozyme can attenuate human umbilical vein endothelial cell (HUVEC) senescence by protecting DNA from damage. It significantly weakens inflammation in macrophages and HUVECs by eliminating overproduced intracellular ROS. Additionally, the MSe1 nanozyme effectively inhibits foam cell formation in macrophages and HUVECs by decreasing the internalization of oxidized low-density lipoprotein. After intravenous administration, the MSe1 nanozyme significantly inhibits the formation of atherosclerosis in apolipoprotein E-deficient (ApoE-/- ) mice by reducing oxidative stress and inflammation and then decreases the infiltration of inflammatory cells and senescent cells in atherosclerotic plaques. This study not only provides a cascade nanozyme but also suggests that the combination of antisenescence and antioxidative stress holds considerable promise for treating atherosclerosis.

A deep learning method for the automated assessment of paradoxical pulsation after myocardial infarction using multicenter cardiac MRI data.

OBJECTIVE: The current study aimed to explore a deep convolutional neural network (DCNN) model that integrates multidimensional CMR data to accurately identify LV paradoxical pulsation after reperfusion by primary percutaneous coronary intervention with isolated anterior infarction. METHODS: A total of 401 participants (311 patients and 90 age-matched volunteers) were recruited for this prospective study. The two-dimensional UNet segmentation model of the LV and classification model for identifying paradoxical pulsation were established using the DCNN model. Features of 2- and 3-chamber images were extracted with 2-dimensional (2D) and 3D ResNets with masks generated by a segmentation model. Next, the accuracy of the segmentation model was evaluated using the Dice score and classification model by receiver operating characteristic (ROC) curve and confusion matrix. The areas under the ROC curve (AUCs) of the physicians in training and DCNN models were compared using the DeLong method. RESULTS: The DCNN model showed that the AUCs for the detection of paradoxical pulsation were 0.97, 0.91, and 0.83 in the training, internal, and external testing cohorts, respectively (p < 0.001). The 2.5-dimensional model established using the end-systolic and end-diastolic images combined with 2-chamber and 3-chamber images was more efficient than the 3D model. The discrimination performance of the DCNN model was better than that of physicians in training (p < 0.05). CONCLUSIONS: Compared to the model trained by 2-chamber or 3-chamber images alone or 3D multiview, our 2.5D multiview model can combine the information of 2-chamber and 3-chamber more efficiently and obtain the highest diagnostic sensitivity. CLINICAL RELEVANCE STATEMENT: A deep convolutional neural network model that integrates 2-chamber and 3-chamber CMR images can identify LV paradoxical pulsation which correlates with LV thrombosis, heart failure, ventricular tachycardia after reperfusion by primary percutaneous coronary intervention with isolated anterior infarction. KEY POINTS: • The epicardial segmentation model was established using the 2D UNet based on end-diastole 2- and 3-chamber cine images. • The DCNN model proposed in this study had better performance for discriminating LV paradoxical pulsation accurately and objectively using CMR cine images after anterior AMI compared to the diagnosis of physicians in training. • The 2.5-dimensional multiview model combined the information of 2- and 3-chamber efficiently and obtained the highest diagnostic sensitivity.

GATA zinc finger protein p66ß promotes breast cancer cell migration by acting as a co-activator of Snail.

The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66ß to transactivate genes in breast cancer cells. Biologically, depletion of p66ß reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66ß and cooperatively induces gene transcription. Notably, a group of genes induced by Snail harbor conserved G-rich cis-elements (5'-GGGAGG-3', designated as G-box) in their proximal promoter regions. Snail directly binds to G-box via its zinc fingers and transactivates the G-box-containing promoters. p66ß enhances Snail binding affinity to G-box, whereas depletion of p66ß results in a decreased binding affinity of Snail to the endogenous promoters and concomitantly reduces the transcription of Snail-induced genes. Taken together, these data demonstrated that p66ß is critical for Snail-mediated cell migration by acting as a co-activator of Snail to induce genes containing G-box elements in the promoters.

D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity.

D-1553 is a small molecule inhibitor selectively targeting KRASG12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRASG12C mutation were determined by thermal shift assay and KRASG12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRASG12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRASG12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRASG12C mutation. Compared to the KRAS WT and KRASG12D cell lines, D-1553 selectively inhibited cell viability in multiple KRASG12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRASG12C mutation.

A probiotic nanozyme hydrogel regulates vaginal microenvironment for Candida vaginitis therapy.

Molecular therapeutics are limited for Candida vaginitis because they damage normal cells and tissues of vagina, aggravating the imbalance of vaginal microbiota and increasing the recurrence. To tackle this limitation, through the combination of peroxidase-like rGO@FeS2 nanozymes [reduced graphene oxide (rGO)] with Lactobacillus-produced lactic acid and H2O2, a responsive hyaluronic acid (HA) hydrogel rGO@FeS2/Lactobacillus@HA (FeLab) is developed. FeLab has simultaneous anti-Candida albicans and vaginal microbiota-modulating activities. In particular, the hydroxyl radical produced from rGO@FeS2 nanozymes and Lactobacillus kills C. albicans isolated from clinical specimens without affecting Lactobacillus. In mice with Candida vaginitis, FeLab has obvious anti-C. albicans activity but hardly damages vaginal mucosa cells, which is beneficial to vaginal mucosa repair. Moreover, a higher proportion of Firmicutes (especially Lactobacillus) and a decrease in Proteobacteria reshape a healthy vaginal microbiota to reduce the recurrence. These results provide a combined therapeutic of nanozymes and probiotics with translational promise for Candida vaginitis therapy.

Air-Derived Inhibitor of Nanozymes.

Nanozymes are functional nanomaterials with enzyme-mimicking activities, which have found wide applications in various fields. Investigation on nanozyme inhibitors not only helps to apply nanozymes in a controlled manner but also deepens our insight into the catalysis mechanism. Herein, we report an inorganic ion inhibitor, HCO3-, which can significantly inhibit the alkaline phosphatase-mimicking activities of Ce6 cluster-based metal-organic framework (Ce-MOF) nanozymes. The inhibition of adsorption of the negatively charged fluorescence sodium on Ce6 clusters in Ce-MOF nanoparticles (NPs) by HCO3- proves that HCO3- ions occupy and deactivate Ce6 clusters (i.e., catalytic active sites), leading to the activity inhibition of Ce-MOF nanozymes. Tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl) buffer is widely employed as the alkaline reaction medium. HCO3- ions can be formed in Tris-HCl buffer through adsorption of CO2 in the air during storage in a sealed tube, which significantly inhibits the activity of Ce-MOF nanozymes. To our knowledge, this study is the first to demonstrate an air-derived inhibitor of nanozymes.