A red cell membrane-camouflaged nanoreactor for enhanced starvation/chemodynamic/ion interference therapy for breast cancer.

In this study, a multifunctional Cu-doped CaO2 nanoreactor loaded with GOx and camouflaged with a folic acid-modified cell membranewas developed for breast cancer treatment. The as-developed composite nanoreactor showed a synergistic effect on calcium overload to damage mitochondria, thus killing tumor cells to achieve ion interference therapy (IIT). The loaded GOx could deplete glucose to "starve" tumor cells. The H2O2 released by CaO2 decomposition and enzyme catalytic reactions from GOx could not only be highly toxic in the tumor microenvironment but also enhance the efficiency of chemodynamic therapy (CDT) with Cu2+. The red blood cell membranes modified by folic acid achieved a combination of active targeting and passive targeting, thereby enhancing the targeting ability of the as-prepared multifunctional composite nanoreactor and prolonging its retention time at the tumor sites for more than 48 h.

Metabolic mediators: microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy.

The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.

In vitro and in vivo evidence of the antineoplastic activity of quercetin against endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.

Quercetin (QUE) is a natural flavonoid with well-known anticancer capabilities, although its effect on viral-induced cancers is less studied. Kaposi's sarcoma (KS) is a viral cancer caused by the human herpesvirus-8, which, during its lytic phase, expresses a constitutively activated viral G protein-coupled receptor (vGPCR) able to induce oncogenic modifications that lead to tumor development. The aim of this work was to investigate the potential effect of QUE on in vitro and in vivo models of Kaposi's sarcoma, developed by transforming endothelial cells with the vGPCR of Kaposi's sarcoma-associated herpesvirus. Initially, the antiproliferative effect of QUE was determined in endothelial cells stably expressing the vGPCR (vGPCR cells), with an IC50 of 30 µM. Additionally, QUE provoked a decrease in vGPCR cell viability, interfered with the cell cycle progression, and induced apoptosis, as revealed by annexin V/PI analysis and caspase-3 activity. The presence of apoptotic bodies and disorganized actin filaments was observed by SEM and phalloidin staining. Furthermore, tumors from vGPCR cells were induced in nude mice, which were treated with QUE (50 or 100 mg/kg/d) resulting in retarded tumor progression and reduced tumor weight. Notably, neither kidney nor liver damage was observed, as indicated by biochemical parameters in serum. In conclusion, this study suggests for the first time that QUE exhibits antineoplastic activity in both in vitro and in vivo models of KS, marking a starting point for further investigations and protocols for therapeutic purpose.

Traditional Chinese herbal medicine: harnessing dendritic cells for anti-tumor benefits.

Chinese Herbal Medicine (CHM) is being more and more used in cancer treatment because of its ability to regulate the immune system. Chinese Herbal Medicine has several advantages over other treatment options, including being multi-component, multi-target, and having fewer side effects. Dendritic cells (DCs) are specialized antigen presenting cells that play a vital part in connecting the innate and adaptive immune systems. They are also important in immunotherapy. Recent evidence suggests that Chinese Herbal Medicine and its components can positively impact the immune response by targeting key functions of dendritic cells. In this review, we have summarized the influences of Chinese Herbal Medicine on the immunobiological feature of dendritic cells, emphasized an anti-tumor effect of CHM-treated DCs, and also pointed out deficiencies in the regulation of DC function by Chinese Herbal Medicine and outlined future research directions.

Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors.

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 µM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

A patent review of lactate dehydrogenase inhibitors (2014-present).

INTRODUCTION: Lactate dehydrogenase (LDH) is a key enzyme in glycolysis responsible for the conversion of pyruvate into lactate and vice versa. Lactate plays a crucial role in tumor progression and metastasis; therefore, reducing lactate production by inhibiting LDH is considered an optimal strategy to tackle cancer. Additionally, dysregulation of LDH activity is correlated with other pathologies, such as cardiovascular and neurodegenerative diseases as well as primary hyperoxaluria, fibrosis and cryptosporidiosis. Hence, LDH inhibitors could serve as potential therapeutics for treating these pathological conditions. AREAS COVERED: This review covers patents published since 2014 up to the present in the Espacenet database, concerning LDH inhibitors and their potential therapeutic applications. EXPERT OPINION: Over the past 10 years, different compounds have been identified as LDH inhibitors. Some of them are derived from the chemical optimization of already known LDH inhibitors (e.g. pyrazolyl derivatives, quinoline 3-sulfonamides), while others belong to newly identified chemical classes of LDH inhibitors. LDH inhibition has proven to be a promising therapeutic strategy not only for preventing human pathologies, but also for treating animal diseases. The published patents from both academia and the pharmaceutical industry highlight the persistent high interest of the scientific community in developing efficient LDH inhibitors.

[Oscillation-static cycle cultivation enhances the synthesis of triterpenes and mycelium activity in Ganoderma lucidum].

Ganoderma lucidum is a precious fungus with both edible and medicinal values and has a long history of medical use. Triterpenes as the main active components endow G. lucidum with anti-tumor, antioxidant, and other pharmacological activities. The present study endeavors to establish a proficient liquid-state fermentation technology for the enhanced production of triterpenes. In view of the limitations inherent in conventional submerged fermentation and oscillation-static two-stage cultivation, this study established an oscillation-static cycle cultivation process and optimized the cultivation conditions by building an artificial neural network model based on genetic algorithms. The cultivation conditions for the high-yield production of triterpenes were optimized as follows: 2.8 days of oscillation, 7.3 days of static cultivation, 0.2 day of oscillation, and 0.3 day of static cultivation. Under these conditions, the content of triterpenes reached 20.82 mg/g. The yield of triterpenes reached 129.09 mg/L, showing a remarkable increase of 324.78% compared with that of the Z10J0 method. Moreover, the established method shortened the cultivation cycle by 10.6 days. The mycelia cultivated under this regimen exhibited commendable anti-tumor and antioxidant activities. This study not only presents an economical liquid-state fermentation approach but also streamlines the fermentation flow, reduces fermentation duration, and effectively ameliorates drawbacks associated with conventional cultivation methods. In addition, this study gives valuable insights into the scaled application of liquid-state fermentation in the high-yield production of triterpenes, which showcases broad prospects.

Induction of Non-Canonical Ferroptosis by Targeting Clusters Suppresses Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. There is a pressing need to develop novel treatment strategies due to the poor targeting effect of current therapeutics. Here, a gold cluster coated with optimized GBM-targeting peptide is engineered, namely NA. NA can efficiently target GBM both in vitro and in vivo. Interestingly, the uptake of NA significantly sensitizes GBM cells to ferroptosis, a form of programmed cell death that can bypass the tumor resistance to apoptosis. This effect is exerted through regulating the HO-1-dependent iron ion metabolism, which is the non-canonical pathway of ferroptosis. The combined treatment of a ferroptosis inducer and NA profoundly inhibited tumor growth in both the GBM spheroid model and a syngeneic mouse model with enhanced ferroptosis levels and excellent biosafety. Importantly, the infiltration of tumoricidal lymphocytes is also significantly increased within tumor. Therefore, NA presents a potential novel nanomaterial-based strategy for GBM treatment.

Dentatacid A: An Unprecedented 2, 3-Seco-arbor-2, 3-dioic Triterpenoid from the Invasive Plant Euphorbia dentata, with Cytotoxicity Effect on Colon Cancer.

Euphorbia dentata Michx. is an invasive plant species in China, known for its toxicity and potential to reduce crop yields, posing numerous threats. To gain a deeper understanding of this invasive plant, phytochemical methods were employed to isolate 13 terpenoids (1-11, 19, 20) and 7 sterols (12-18) from the ethanol extract of E. dentata, identifying one new compound and 19 known compounds. Within spectroscopic methods such as NMR, HR-ESI-MS, and ECD, the structures and absolute configurations of these compounds were established. Among them, dentatacid A (11) possesses an unprecedented 2, 3-seco-arbor-2, 3-dioic skeleton within the potential biosynthetic pathway proposed. Dentatacid A also exhibited excellent anti-proliferative activity against the HT-29 (human colorectal adenocarcinoma) cell line, with an IC50 value of 2.64 ± 0.78 µM, which was further confirmed through network pharmacology and molecular docking. This study significantly expands the chemical diversity of E. dentata and offers new insights into the resource utilization and management of this invasive plant from the perspective of natural product discovery.

Chemical Constituents, Anti-Tumor Mechanisms, and Clinical Application: A Comprehensive Review on Scutellaria barbata.

With the increasing global incidence and mortality rates of cancer, the development of novel anti-tumor drugs has become particularly urgent. Scutellaria barbata D. Don, a perennial herb belonging to the genus Scutellaria in the family Lamiaceae, has aroused extensive attention for its medicinal value in recent years. This article presents an exhaustive review of the flavonoid, diterpene, and other chemical constituents harbored within Scutellaria barbata, delving into the intricate mechanisms by which these compounds orchestrate their anti-tumor effects via diverse biological pathways. Remarkably, these compounds distinguish themselves through their capability to regulate cellular signaling, inhibit cancer cell proliferation, trigger apoptosis, disrupt angiogenesis, and bolster immune responses. These anti-tumor effects are achieved through strategic modulation of pivotal signaling cascades, particularly the PI3K/Akt/mTOR, MAPK, and NFκB pathways. In addition, this article also summarizes the clinical applications of Scutellaria barbata in tumor treatment, especially its potential in alleviating the side effects of radiotherapy and chemotherapy and improving patients' quality of life. In conclusion, this review comprehensively summarizes and analyzes the chemical constituents, anti-tumor mechanisms, and clinical applications of Scutellaria barbata, with the aim of systematically reviewing the existing research results and exploring potential future research directions.

An improved approach to generate IL-15+/+/TGFßR2-/- iPSC-derived natural killer cells using TALEN.

We present a TALEN-based workflow to generate and maintain dual-edited (IL-15+/+/TGFßR2-/-) iPSCs that produce enhanced iPSC-derived natural killer (iNK) cells for cancer immunotherapy. It involves using a cell lineage promoter for knocking in (KI) gene(s) to minimize the potential effects of expression of any exogenous genes on iPSCs. As a proof-of-principle, we KI IL-15 under the endogenous B2M promoter and show that it results in high expression of the sIL-15 in iNK cells but minimal expression in iPSCs. Furthermore, given that it is known that knockout (KO) of TGFßR2 in immune cells can enhance resistance to the suppressive TGF-ß signaling in the tumor microenvironment, we develop a customized medium containing Nodal that can maintain the pluripotency of iPSCs with TGFßR2 KO, enabling banking of these iPSC clones. Ultimately, we show that the dual-edited IL-15+/+/TGFßR2-/- iPSCs can be efficiently differentiated into NK cells that show enhanced autonomous growth and are resistant to the suppressive TGF-ß signaling.

Comparative real-world outcomes between ustekinumab, infliximab, and adalimumab in bio-naïve and bio-experienced Crohn's disease patients: a retrospective multicenter study.

BACKGROUND: Numerous studies have compared the efficacy of ustekinumab (UST) and anti-TNF agents [infliximab (IFX) or adalimumab(ADA)] in moderate to severe Crohn's disease (CD) patients. This study aims to compare the efficacy of UST, IFX, and ADA while differentiating between bio-naïve and bio-experienced patients, which is an underexplored aspect, particularly in Asia. METHODS: We conducted a retrospective multi-center study from 2012 to 2023, categorizing patients into bio-naïve and bio-experienced groups. We evaluated clinical remission rates after induction therapy and clinical outcomes, including CD-related hospitalization, intestinal resection, and drug discontinuation during maintenance therapy. RESULTS: Among the 214 bio-naïve CD patients, 60 received UST, 108 received IFX, and 46 received ADA. After 1:1 propensity score matching between UST and anti-TNF agents groups, 59 patients were analyzed in each group (45 in the IFX group and 14 in the ADA group). We found no significant differences in clinical remission rates (P = 0.071), CD-related hospitalization (P = 0.800), intestinal resection (P = 0.390), or drug discontinuation (P = 0.052) between the UST, IFX, and ADA groups in bio-naïve CD patients. In bio-experienced CD patients, with 35 in the UST group and 13 in the anti-TNF agents group, the UST group showed a lower risk of drug discontinuation (P = 0.004) than the anti-TNF agents group. CONCLUSIONS: This study suggests that UST, IFX, and ADA are equally effective in bio-naïve CD patients, while in bio-experienced patients, mostly with previous exposure to anti-TNF agents, UST may offer superior drug durability.

Comparison of structural characteristics and anti-tumor activity of two alkali extracted peach gum arabinogalactan.

Two polysaccharides, PGP-90 and PGP-100 (molecular weights of 7.59 × 102 kDa and 10.48 × 102 kDa, respectively), were isolated from Peach gum using alkaline electrolyte water as an extraction solution. Structural characterization showed that PGP-90 and PGP-100 are AG-II arabinogalactans with ß-D-(1 â†’ 6)-Galp as the main chain and 1 â†’ 3 Araf and 1 â†’ 5 Araf branched chains at O-3 and O-4 positions. Animal experiments showed that PGP-90 and PGP-100 significantly improved immune function, enhance the proliferative capacity of lymphocytes and phagocytosis of peritoneal macrophages, and regulated the ratio of lymphocyte subpopulations in S180 tumor-bearing mice. Meanwhile, PGP-90 and PGP-100 promoted the secretion of cytokines (TNF-α, IFN-γ, and IL-2) by activated macrophages and blocked apoptosis at the G1 phase, resulting in tumor suppression rates of 40.80 % and 46.30 % (100 mg/kg), respectively, with PGP-100 demonstrating stronger in vivo anti-tumor activity. The above experimental results indicate that Peach gum polysaccharides have the potential to be functional anti-tumor agents.

The possible anti-tumor actions and mechanisms of active metabolites from Cortex Fraxini.

Cortex Fraxini is a traditional Chinese herb that is widely available, inexpensive, and has low toxicity. Modern pharmacological studies have demonstrated that the active metabolites in Cortex Fraxini, including esculin, esculetin, and fraxetin, exert anti-tumor activities by regulating genes and proteins involved in cancer cell proliferation, apoptosis, invasion, and migration. Additionally, these metabolites play a pivotal role in the regulation of several tumor-associated signaling pathways, including the PI3K/Akt, MAPK/ERK, JAK/STAT3, and Wnt/ß-catenin pathways. Due to their pro-apoptotic and anti-proliferative properties in vitro and in vivo, Cortex Fraxini and its active metabolites may be considered as potential candidates for the treatment of tumor. The aim of this review is to highlight the anti-tumor biological activities and underlying mechanisms of action of the active metabolites of Cortex Fraxini, with a view to providing a reference for their further development and application in the treatment of tumors.

Anti-liver tumor ingredient exploration and validation of Elephantopus tomentosus Linn. by combining in silico and in vitro experiments.

Elephantopus tomentosus (ET) Linn. was reported to be an anti-tumor plant. However, the chemical composition of ET and its anti-tumor compounds and potential mechanisms still unclear. In this paper, UPLC-Q-TOF-MS/MS was firstly used to identified the ingredients in ET and UPLC was used to determine the main compounds of ET. Network pharmacology was applied to predict the potential mechanisms of anti-liver cancer. Anti-tumor nuclear activate compounds and targets of ET were obtained and the anti-liver cancer effect was validated on HepG2. Finally, Molecule docking, RT-qPCR, and western blotting were used for verification of the relationship between nuclear activate compounds and nuclear targets and the potential anti-cancer mechanisms. The result showed that 42 compounds were identified in ET, which consisted of sesquiterpene lactones, flavonoids, and phenylpropanoid compounds. Scabertopin (ST), chlorogenic acid, Isochlorogenic acid B, Isochlorogenic acid A and Isochlorogenic acid C were identified as main compounds and were determined as 0.426%, 0.457%, 0.159%, 0.701%, and 0.103% respectively. 24 compounds showed high pharmacokinetics and good drug-likeness. 520 overlapping targets of the ET compounds and liver cancer were collected. The targets were used for KEGG and GO analysis. GO enrichment analysis suggested that the targets of 24 active compound closed related to promote apoptosis, inhibit proliferation, and regulate oxidative levels. KEGG enrichment analysis suggested that pathway in cancer was enriched most and p38 MAPK/p53 signaling pathway, which closely related to promoting apoptosis and inhibiting proliferation. Compounds-targets analysis based on the parameter of Betweenness, Closeness, Information, Eigenvector, Degree, and component content indicated that ST was the nucleus anti-tumor active compound of ET. HepG2 was first used to validated the anti-tumor effect of ST and the result showed that ST significantly inhibited HepG2 proliferation with a low IC50 less than 5 µM. Nucleus active compound targets, including TP53, CASP3, BCL2, EGFR, TNF-a, IL-1ß, and IL-6 were enriched based on degree value of PPI analysis. Molecule docking suggested that ST showed a good combination to TGFBR1 with the combination energy less than - 5 kcal/mol. RT-qPCR result also suggested that ST significantly medicated the mRNA expression level of TP53, CASP3, BCL2, EGFR, TNF-a, IL-1ß, and IL-6. Protein expression of p-p38/p38 and p-p53/p53 notable increased by ST treatment. In conclude, combining with UPLC-Q-TOF-MS/MS qualitative analysis, UPLC quantitative analysis, network pharmacology analysis, molecule docking, and in vitro experiments on HepG2, we suggest that ST is an anti-tumor ingredient of ET, which may target to TGFBR1 and promote apoptosis and inhibited proliferation of HepG2 by activating p38 MAPK/p53 signaling pathway. ST can be regarded as a quality marker of ET.

Isolation of Novel Compounds from Lepidium sativum Seeds and Evaluation of Their Potential Anti-tumor Activity.

Four undescribed compounds including a pair of enantiomers of a dihydroarylnaphthalene lignan [(±)-1], an arylnaphthalene lignan (2), and an indoleacetic acid ester (3), together with four known compounds (4－7), were isolated from the seeds of Lepidium sativum. Their structures were identified by HRMS and NMR spectroscopic data, and the absolute configuration of these compounds were assigned by ECD data in combination with quantum chemical calculations. Compound (-)-1 had weak inhibitory activity against HeLa cell line with an IC50 value of 60.23 ± 3.51 µM, and compound (+)-1 presented moderate inhibitory effect against HeLa cell line with an IC50 value of 19.99 ± 1.00 µM (IC50 value of the positive control was 0.40 ±0.02 µM).

Peroxidase-Mimetic Iron Silicate Nanosheets Coordinated with Indocyanine Green for Enhanced Anti-Tumor Therapy.

The versatile element composition and multifunctional properties of biodegradable silicates have attracted significant attention in cancer therapeutics. However, their application as nanozymes is often limited by suboptimal catalytic efficiency and insufficient intratumoral retention. In this study, the hydrothermal synthesis of iron silicate (FeSi) nanosheets are reported exhibiting exceptional peroxidase (POD)-like activity (136.7 U mg-1), outperforming most reported iron-based nanozymes. Density functional theory calculations revealed that the introduction of Si into the catalyst enhances H2O2 adsorption and dissociation of Fe sites, leading to superior POD performance. Furthermore, the FeSi nanosheets are modified with Indocyanine Green (ICG) to facilitate targeted aggregation-potentiated therapy. The integration of ICG improved tumor penetration and retention of the FeSi nanosheets, significantly increasing their reactive oxygen species production and bolstering therapeutic efficacy.

Advances in Immunomodulatory Mesoporous Silica Nanoparticles for Inflammatory and Cancer Therapies.

In recent decades, immunotherapy has been considered a promising treatment approach. The modulatable enhancement or attenuation of the body's immune response can effectively suppress tumors. However, challenges persist in clinical applications due to the lack of precision in antigen presentation to immune cells, immune escape mechanisms, and immunotherapy-mediated side effects. As a potential delivery system for drugs and immunomodulators, mesoporous silica has attracted extensive attention recently. Mesoporous silica nanoparticles (MSNs) possess high porosity, a large specific surface area, excellent biocompatibility, and facile surface modifiability, making them suitable as multifunctional carriers in immunotherapy. This article summarizes the latest advancements in the application of MSNs as carriers in cancer immunotherapy, aiming to stimulate further exploration of the immunomodulatory mechanisms and the development of immunotherapeutics based on MSNs.