Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Bioinspired and Bioderived Aqueous Electrocatalysis.

The development of efficient and sustainable electrochemical systems able to provide clean-energy fuels and chemicals is one of the main current challenges of materials science and engineering. Over the last decades, significant advances have been made in the development of robust electrocatalysts for different reactions, with fundamental insights from both computational and experimental work. Some of the most promising systems in the literature are based on expensive and scarce platinum-group metals; however, natural enzymes show the highest per-site catalytic activities, while their active sites are based exclusively on earth-abundant metals. Additionally, natural biomass provides a valuable feedstock for producing advanced carbonaceous materials with porous hierarchical structures. Utilizing resources and design inspiration from nature can help create more sustainable and cost-effective strategies for manufacturing cost-effective, sustainable, and robust electrochemical materials and devices. This review spans from materials to device engineering; we initially discuss the design of carbon-based materials with bioinspired features (such as enzyme active sites), the utilization of biomass resources to construct tailored carbon materials, and their activity in aqueous electrocatalysis for water splitting, oxygen reduction, and CO2 reduction. We then delve in the applicability of bioinspired features in electrochemical devices, such as the engineering of bioinspired mass transport and electrode interfaces. Finally, we address remaining challenges, such as the stability of bioinspired active sites or the activity of metal-free carbon materials, and discuss new potential research directions that can open the gates to the implementation of bioinspired sustainable materials in electrochemical devices.

Epigenetic Activation of Cytochrome P450 1A2 Sensitizes Hepatocellular Carcinoma Cells to Sorafenib.

Cytochrome P450 1A2 (CYP1A2) is a known tumor suppressor in hepatocellular carcinoma (HCC), but its expression is repressed in HCC and the underlying mechanism is unclear. In this study, we investigated the epigenetic mechanisms of CYP1A2 repression and potential therapeutic implications. In HCC tumor tissues, the methylation rates of CYP1A2 CpG island (CGI) and DNA methyltransferase (DNMT) 3A protein levels were significantly higher, and there was a clear negative correlation between DNMT3A and CYP1A2 protein expression. Knockdown of DNMT3A by siRNA significantly increased CYP1A2 expression in HCC cells. Additionally, treating HCC cells with decitabine (DAC) resulted in a dose-dependent upregulation of CYP1A2 expression by reducing the methylation level of CYP1A2 CGI. Furthermore, we observed a decreased enrichment of H3K27Ac in the promoter region of CYP1A2 in HCC tissues. Treatment with the trichostatin A (TSA) restored CYP1A2 expression in HCC cells by increasing H3K27Ac levels in the CYP1A2 promoter region. Importantly, combination treatment of sorafenib with DAC or TSA resulted in a leftward shift of the dose-response curve, lower IC50 values, and reduced colony numbers in HCC cells. Our findings suggest that hypermethylation of the CGI at the promoter, mediated by the high expression of DNMT3A, and hypoacetylation of H3K27 in the CYP1A2 promoter region, leads to CYP1A2 repression in HCC. Epigenetic drugs DAC and TSA increase HCC cell sensitivity to sorafenib by restoring CYP1A2 expression. Our study provides new insights into the epigenetic regulation of CYP1A2 in HCC and highlights the potential of epigenetic drugs as a therapeutic approach for HCC. SIGNIFICANCE STATEMENT: This study marks the first exploration of the epigenetic mechanisms underlying cytochrome P450 (CYP) 1A2 suppression in hepatocellular carcinoma (HCC). Our findings reveal that heightened DNA methyltransferase expression induces hypermethylation of the CpG island at the promoter, coupled with diminished H3K27Ac levels, resulting in the repression of CYP1A2 in HCC. The use of epigenetic drugs such as decitabine and trichostatin A emerges as a novel therapeutic avenue, demonstrating their potential to restore CYP1A2 expression and enhance sorafenib sensitivity in HCC cells.

Pyridine Functionalized Carbon Nanotubes: Unveiling the Role of External Pyridinic Nitrogen Sites for Oxygen Reduction Reaction.

Pyridinic nitrogen has been recognized as the primary active site in nitrogen-doped carbon electrocatalysts for the oxygen reduction reaction (ORR), which is a critical process in many renewable energy devices. However, the preparation of nitrogen-doped carbon catalysts comprised of exclusively pyridinic nitrogen remains challenging, as well as understanding the precise ORR mechanisms on the catalyst. Herein, a novel process is developed using pyridyne reactive intermediates to functionalize carbon nanotubes (CNTs) exclusively with pyridine rings for ORR electrocatalysis. The relationship between the structure and ORR performance of the prepared materials is studied in combination with density functional theory calculations to probe the ORR mechanism on the catalyst. Pyridinic nitrogen can contribute to a more efficient 4-electron reaction pathway, while high level of pyridyne functionalization result in negative structural effects, such as poor electrical conductivity, reduced surface area, and small pore diameters, that suppressed the ORR performance. This study provides insights into pyridine-doped CNTs-functionalized for the first time via pyridyne intermediates-as applied in the ORR and is expected to serve as valuable inspiration in designing high-performance electrocatalysts for energy applications.

CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt/Dvl2/ß-catenin signaling.

OBJECTIVE: Knowledge of the role of CYP2E1 in hepatocarcinogenesis is largely based on epidemiological and animal studies, with a primary focus on the role of CYP2E1 in metabolic activation of procarcinogens. Few studies have directly assessed the effects of CYP2E1 on HCC malignant phenotypes. METHODS: The expression of CYP2E1 in HCC tissues was determined by qRT-PCR, western blotting and immunohistochemistry. Overexpression of CYP2E1 in HCC cell was achieved by lentivirus transfection. The function of CYP2E1 were detected by CCK-8, wound healing, transwell assays, xenograft models and pulmonary metastasis model. TOP/FOPFlash reporter assay, western blotting, functional rescue experiments, Co-immunoprecipitation and reactive oxygen species detection were conducted to reveal the underlying mechanism of the tumor suppressive role of CYP2E1. RESULTS: CYP2E1 expression is down-regulated in HCC tissues, and this downregulation was associated with large tumor diameter, vascular invasion, poor differentiation, and shortened patient survival time. Ectopic expression of CYP2E1 inhibits the proliferation, invasion and migration and epithelial-to-mesenchymal transition of HCC cells in vitro, and inhibits tumor formation and lung metastasis in nude mice. Mechanistic investigations show that CYP2E1 overexpression significantly inhibited Wnt/ß-catenin signaling activity and decreased Dvl2 expression in HCC cells. An increase in Dvl2 expression restored the malignant phenotype of HCC cells. Notably, CYP2E1 promoted the ubiquitin-mediated degradation of Dvl2 by strengthening the interaction between Dvl2 and the E3 ubiquitin ligase KLHL12 in CYP2E1-stable HCC cells. CYP2E1-induced ROS accumulation was a critical upstream event in the Wnt/ß-Catenin pathway in CYP2E1-overexpressing HCC cells. CONCLUSIONS: These results provide novel insight into the role of CYP2E1 in HCC and the tumor suppressor role of CYP2E1 can be attributed to its ability to manipulate Wnt/Dvl2/ß-catenin pathway via inducing ROS accumulation, which provides a potential target for the prevention and treatment of HCC.

Unveiling of dietary and gut-microbiota derived B vitamins: Metabolism patterns and their synergistic functions in gut-brain homeostasis.

Nutrition-gut cross-talk holds a vital position in sustaining intestinal function, and micronutrient metabolism has emerged as the foremost metabolic pathway to preserve gut homeostasis. Among micronutrients, B vitamins have evolved prior to DNA/RNA and are known for their vital roles for major evolutionary transitions in extant organisms. Despite their universal requirement and critical role, not all the three domains of life are endowed with a natural ability for de novo B vitamins synthesis. The human gut microbiome constitutes prototrophs and auxotroph which are entirely dependent on dietary intake and gut microbial production of B vitamins. The syntrophic metabolism involving cross-feeding of B vitamins and community-wide exchange between commensal bacteria elicit important changes in the diversity and composition of the human gut microbiome. Hereto, we discuss the B-vitamins sharing among prototrophic and auxotrophic gut bacteria, their absorption in small intestine and transport in distal gut, functional role in relation to the gut homeostasis and symptoms linked to their deficiency. We also briefly explore their potential involvement as psychobiotics in brain energetic metabolism (kynurenines/tryptophan pathway) for neurological functions and highlight their deficiency related malfunctioning.

Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.

The Charge Transfer Band as a Key to Study the Site Selection Preference of Eu3+ in Inorganic Crystals.

On account of the strong oxidizing property of the europium(III) ion, its charge transfer band (CTB) can be easily formed in many inorganic compounds. In this work, the Eu3+ ions were singly doped into the K3LuSi2O7 compound with a hexagonal structure, and two kinds of Eu3+-O2- CTBs were detected by monitoring at specific wavelengths. The qualitative analysis of Eu3+ ion site occupation was illuminated by combining Eu3+-O2- CTBs with the corresponding cell volume. Furthermore, the two kinds of Eu3+ sites are eventually assigned to the K(2) and Lu sites, which means that Eu3+ ions selectively occupy the site with a low coordination number, according to the calculated CT energy by the dielectric theory of complex crystals and the magnitude of CT energy in the excitation spectra. Meanwhile, at high temperatures, the CTB does not show the traditional thermal quenching like f-f transitions but demonstrates thermal enhancement; thus, by using this opposite variation in excitation spectra, a noninvasive optical thermometer is presented, and this opposite variation tendency is thought to be the difference of thermal stability of disparate excited energy states. When new luminescent phosphors are designed with interesting spectral properties, this work will give us an alternative approach to determine the site occupation preference of Eu3+, especially when there are more than two different sites in the compound.

A life cycle assessment of hard carbon anodes for sodium-ion batteries.

Waste management is one of the biggest environmental challenges worldwide. Biomass-derived hard carbons, which can be applied to rechargeable batteries, can contribute to mitigating environmental changes by enabling the use of renewable energy. This study has carried out a comparative environmental assessment of sustainable hard carbons, produced from System A (hydrothermal carbonization (HTC) followed by pyrolysis) and System B (direct pyrolysis) with different carbon yields, as anodes in sodium-ion batteries (SIBs). We have also analysed different scenarios to save energy in our processes and compared the biomass-derived hard carbons with commercial graphite used in lithium-ion batteries. The life cycle assessment results show that the two systems display significant savings in terms of their global warming potential impact (A1: -30%; B1: -21%), followed by human toxicity potential, photochemical oxidants creation potential, acidification potential and eutrophication potential (both over -90%). Possessing the best electrochemical performance for SIBs among our prepared hard carbons, the HTC-based method is more stable in both environmental and electrochemical aspects than the direct pyrolysis method. Such results help a comprehensive understanding of sustainable hard carbons used in SIBs and show an environmental potential to the practical technologies. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)'.

Riboflavin-overproducing lactobacilli for the enrichment of fermented soymilk: insights into improved nutritional and functional attributes.

The influence of riboflavin (B2)-overproducing lactobacilli on the antioxidant status, isoflavone conversion, off-flavor reduction, amino acid profile, and viscosity of B2-bio-enriched fermented soymilk was investigated. Results showed that B2 in fermented soymilk was notably increased from 0.2 to 3.8 µg/mL for Lactobacillus fermentum UFG169 and to 1.9 µg/mL for Lactobacillus plantarum UFG10. The apparent viscosity significantly changed with rising acidity and agglutination of protein. The off-flavor volatile substances (hexanal and nonanal) were significantly reduced in fermented soymilk. Furthermore, a large amount of glucoside form isoflavones was deglycosylated into bioactive aglycones after 4 h up to 32 h. B2 content and isoflavones significantly improved the antioxidant status of soymilk. Partial least squares regression analysis correlated the strain activity and fermentation time with the improved nutritional and functional soymilk qualities. This study demonstrated the strategy for strain development for B2-bio-enriched fermentation to extend the health-promoting benefits of soymilk and soy-related foods. KEY POINTS: • B2-enriched fermentation enhanced the nutrition and functional status of soymilk. • Fermentation time significantly affected the apparent viscosity of fermented soymilk. • Off-flavor volatile substances were significantly reduced or even diminished. • Increased B2and bioactive isoflavones contributed to improved antioxidant potential.

A Comprehensive Survey on Local Differential Privacy toward Data Statistics and Analysis.

Collecting and analyzing massive data generated from smart devices have become increasingly pervasive in crowdsensing, which are the building blocks for data-driven decision-making. However, extensive statistics and analysis of such data will seriously threaten the privacy of participating users. Local differential privacy (LDP) was proposed as an excellent and prevalent privacy model with distributed architecture, which can provide strong privacy guarantees for each user while collecting and analyzing data. LDP ensures that each user's data is locally perturbed first in the client-side and then sent to the server-side, thereby protecting data from privacy leaks on both the client-side and server-side. This survey presents a comprehensive and systematic overview of LDP with respect to privacy models, research tasks, enabling mechanisms, and various applications. Specifically, we first provide a theoretical summarization of LDP, including the LDP model, the variants of LDP, and the basic framework of LDP algorithms. Then, we investigate and compare the diverse LDP mechanisms for various data statistics and analysis tasks from the perspectives of frequency estimation, mean estimation, and machine learning. Furthermore, we also summarize practical LDP-based application scenarios. Finally, we outline several future research directions under LDP.

Securing Cooperative Spectrum Sensing Against Collusive SSDF Attack using XOR Distance Analysis in Cognitive Radio Networks.

Cooperative spectrum sensing (CSS) is considered as a powerful approach to improve the utilization of scarce spectrum resources. However, if CSS assumes that all secondary users (SU) are honest, it may offer opportunities for attackers to conduct a spectrum sensing data falsification (SSDF) attack. To suppress such a threat, recent efforts have been made to develop trust mechanisms. Currently, some attackers can collude with each other to form a collusive clique, and thus not only increase the power of SSDF attack but also avoid the detection of a trust mechanism. Noting the duality of sensing data, we propose a defense scheme called XDA from the perspective of XOR distance analysis to suppress a collusive SSDF attack. In the XDA scheme, the XOR distance calculation in line with the type of "0" and "1" historical sensing data is used to measure the similarity between any two SUs. Noting that collusive SSDF attackers hold high trust value and the minimum XOR distance, the algorithm to detect collusive SSDF attackers is designed. Meanwhile, the XDA scheme can perfect the trust mechanism to correct collusive SSDF attackers' trust value. Simulation results show that the XDA scheme can enhance the accuracy of trust evaluation, and thus successfully reduce the power of collusive SSDF attack against CSS.

Encoding and retrieval of artificial visuoauditory memory traces in the auditory cortex requires the entorhinal cortex.

Damage to the medial temporal lobe impairs the encoding of new memories and the retrieval of memories acquired immediately before the damage in human. In this study, we demonstrated that artificial visuoauditory memory traces can be established in the rat auditory cortex and that their encoding and retrieval depend on the entorhinal cortex of the medial temporal lobe in the rat. We trained rats to associate a visual stimulus with electrical stimulation of the auditory cortex using a classical conditioning protocol. After conditioning, we examined the associative memory traces electrophysiologically (i.e., visual stimulus-evoked responses of auditory cortical neurons) and behaviorally (i.e., visual stimulus-induced freezing and visual stimulus-guided reward retrieval). The establishment of a visuoauditory memory trace in the auditory cortex, which was detectable by electrophysiological recordings, was achieved over 20-30 conditioning trials and was blocked by unilateral, temporary inactivation of the entorhinal cortex. Retrieval of a previously established visuoauditory memory was also affected by unilateral entorhinal cortex inactivation. These findings suggest that the entorhinal cortex is necessary for the encoding and involved in the retrieval of artificial visuoauditory memory in the auditory cortex, at least during the early stages of memory consolidation.

Clinical Efficacy of Hexue Tongbi Formula on Oxaliplatin-Induced Peripheral Neuropathy: A Randomized Controlled Study.

AIM: The aim of this study was to analyse the effiacy of HeXue Tongbi Formula in the treatment of oxaliplatin-induced perpheral neuropathy. METHOD: An open randomized, non-blind, controlled study was conducted at the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from September 2019 to December 2020. A total of 78 maligant tumor patients receiving oxaliplatin-containing chemotherapy were recruited, with half of them receiving HeXue Tongbi Formula for 4 cycles of 21 days. The study assessed the incidence and severity of perpheral neuropathy and the safety of HeXue Tongbi Formula. RESULT: After 4 cycles of treatment, the incidence of perpheral neuropathy in the treatment group was significantly lower than that in the control group (30.77% versus 84.62%, P < .05). The severity of perpheral neuropathy in the treatment group increased sligthly and stabilized from the third cycle, whlie it gradually increased in the control group. yhere were no severe adverse reactions to HeXue Tongbi Formula. CONCLUSION: HeXue Tongbi Formula demonstrated good preventive and therapeutic effects on oxaliplatin-induced perpheral neuropathy. TRIAL REGISTRATION: This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2000032996).

Cholecystokinin facilitates motor skill learning by modulating neuroplasticity in the motor cortex.

Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout of Cck gene (Cck-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation upon high-frequency stimulation in the motor cortex of Cck-/- mice, indicating a possible association between motor learning deficiency and neuroplasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signaling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivation of the CCK neurons in the rhinal cortex that project to the motor cortex bilaterally using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of Cck-/- mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, may surpport motor skill learning by modulating neuroplasticity in the motor cortex.

Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning.

Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists' diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted.

Anticancer and Biological Effects of Some Natural Compounds and Theoretical Investigation of them Against RdRP of SARS-COV-2: In Silico and In Vitro Studies.

In this study, Skullcapflavone I and Skullcapflavone II molecules showed good inhibitory activities against α-glucosidase and sorbitol dehydrogenase enzymes with IC50 values of 102.66 ± 8.43 and 95.04 ± 11.52 nM for α-glucosidase and 38.42 ± 3.82 and 28.81 ± 3.26 µM for sorbitol dehydrogenase. The chemical activities of Skullcapflavone I and Skullcapflavone II against α-glucosidase and sorbitol dehydrogenase were assessed by conducting the molecular docking study. The anticancer activities of the compounds were examined against SW-626, SK-OV-3, OVCAR3, and Caov-3 cell lines. The chemical activities of Skullcapflavone I and Skullcapflavone II against some of the expressed surface receptor proteins (estrogen receptor, EGFR, androgen receptor, and GnRH receptor) in the mentioned cell lines were investigated using in silico calculations. Moreover, the activity of the compounds against RNA polymerase of SARS-COVE-2 was also assessed using the molecular modeling study. These compounds created strong contacts with the enzymes and receptors. The considerable binding affinity of the compounds to the enzymes and proteins showed their ability as inhibitors. Furthermore, even at modest dosages, these substances markedly reduced the viability of ovarian cancer cells. Additionally, the viability of ovarian cancer cells was significantly decreased by a 300 µM dosage of all compounds. Antiovarian cancer results of Skullcapflavone I on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 63.14, 1.55, 19.42, and 52.04 µM, respectively. Also, cytotoxicity results of Skullcapflavone II on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 5.18, 21.44, 33.87, and 72.66 µM, respectively.

Dihydroartemisinin Affects STAT3/DDA1 Signaling Pathway and Reverses Breast Cancer Resistance to Cisplatin.

Dihydroartemisinin (DHA) has anticancer effects on multiple tumors, including those associated with breast cancer. This study aimed to investigate the mechanism causing DHA-reversing cisplatin (DDP) resistance in breast cancer. Relative mRNA and protein levels were tested using a qRT-PCR and western blot assay. Cell proliferation, viability, and apoptosis were evaluated using colony formation, MTT, and flow cytometry assays, respectively. Interaction of STAT3 and DDA1 was measured via a dual-luciferase reporter assay. The results showed that DDA1 and p-STAT3 levels were dramatically elevated in DDP-resistant cells. DHA treatment repressed proliferation and induced apoptosis of DDP-resistant cells by suppressing STAT3 phosphorylation; the inhibition ability was positively proportional to the DHA concentration. DDA1 knockdown inhibited cyclin expression, promoted G0/G1 phase arrest, restrained cell proliferation, and induced apoptosis of DDP-resistant cells. Furthermore, knockdown of STAT3 restrained proliferation and induced apoptosis and G0/G1 cell cycle arrest of DDP-resistant cells by targeting DDA1. DHA could restrain tumor proliferation of breast cancer via enhancing drug sensitivity of DDP-resistant cells through the STAT3/DDA1 signaling pathway.

LC-MS based metabolomics analysis of okara fermented by Bacillus subtilis DC-15: Insights into nutritional and functional profile.

Recent studies emphasize the improved nutritional and functional status of fermented okara; however, little is known about the metabolite change during fermentation and how it alters metabolic pathways. A metabolomics approach based on untargeted LC-MS reveals metabolic changes in okara fermented by Bacillus subtilis DC-15. We identified 761 differential metabolites, with the highest abundances found in amino acids, dipeptides, fatty acids, small molecule sugars, and vitamins. Moreover, these identified metabolites were mapped to their respective biosynthesis pathways in order to gain a better understanding of the biochemical reactions triggered by fermentation. Based on Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, 485 metabolites were enriched to metabolism-related pathways. They include 37 carbohydrate metabolites, 79 amino acid metabolites, and 22 lipid metabolites. As a result of okara fermentation, we observed a gradual enrichment of metabolites and stabilization of the compounds.