The use of potentially interacting supplement-drug pairs in adults with type 2 diabetes: A large population-based cohort study in the UK Biobank.

AIMS: To examine the patterns of use of potentially interacting supplement-drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement-drug pairs on downstream outcomes. METHODS: Potentially interacting supplement-drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. RESULTS: 26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement-drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement-drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10-1.44, P < 0.001). CONCLUSIONS: Real-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement-drug interactions in clinical settings.

Development of a zinc chloride-based chemo-mechanical system for potential minimally invasive dental caries removal system.

Background/purpose: The chemo-mechanical caries-removal technique is known to offer advantages of selective dentin caries treatment while leaving healthy dental tissues intact. However, current sodium hypochlorite based reagents usually excessively damage dentin collagen. Therefore, the purpose of this study was to develop a novel chemo-mechanical caries-removal system to preserve the collagen network for subsequent prosthetic restorations. Materials and methods: The calfskin-derived collagen was chosen as a model system to investigate the dissolution behavior of collagen under different operating conditions of chemical-ultrasonic treatment systems. The molecular weight, triple-helix structure, the morphology, and functional group of collagen after treatment were investigated. Results: Various concentrations of sodium hypochlorite or zinc chloride together with ultrasonic machinery were chosen to investigate. The outcomes of circular dichroism (CD) spectra demonstrated stability of the triple-helix structure after treatment of a zinc chloride solution. In addition, two apparent bands at molecular weights (MWs) of 130 and 121 kDa evidenced the stability of collagen network. The positive 222 nm and 195 nm negative CD absorption band indicated the existence of a triple-helix structure for type I collagen. The preservation of the morphology and functional group of the collagen network on the etched dentin surface were investigated by in vitro dentin decalcification model. Conclusion: Unlike NaOCl, the 5 wt% zinc chloride solution combined with ultra-sonication showed dissolution rather than denature as well as degradation of the dentin collagen network. Additional in vivo evaluations are needed to verify its usefulness in clinical applications.

Enhanced burn wound healing by controlled-release 3D ADMSC-derived exosome-loaded hyaluronan hydrogel.

Adipose mesenchymal stem cell (ADMSC)-derived exosomes (ADMSC-Exos) have shown great potential in regenerative medicine and been evidenced benefiting wound repair such as burns. However, the low yield, easy loss after direct coating, and no suitable loading system to improve their availability and efficacy hinder their clinical application for wound healing. And few studies focused on the comparison of biological functions between exosomes derived from different culture techniques, especially in exosome-releasing hydrogel system. Therefore, we designed a high-performance exosome controllable releasing hydrogel system for burn wound healing, namely loading 3D-printed microfiber culture-derived exosomes in a highly biocompatible hyaluronic acid (HA). In this project, we compared the biological functions in vitro and in a burn model among exosomes derived from the conventional two-dimensional (2D) plate culture (2D-Exos), microcarrier culture (2.5D-Exos), and 3D-printed microfiber culture (3D-Exos). Results showed that compared with 2D-Exos and 2.5D-Exos, 3D-Exos promoted HACATs and HUVECs cell proliferation and migration more significantly. Additionally, 3D-Exos had stronger angiogenesis-promoting effects in tube formation of (HUVECs) cells. Moreover, we found HA-loaded 3D-Exos showed better burn wound healing promotion compared to 2D-Exos and 2.5D-Exos, including accelerated burn wound healing rate and better collagen remodeling. The study findings reveal that the HA-loaded, controllable-release 3D-Exos repair system distinctly augments therapeutic efficacy in terms of wound healing, while concurrently introducing a facile application approach. This system markedly bolsters the exosomal loading efficiency, provides a robust protective milieu, and potentiates the inherent biological functionalities of the exosomes. Our findings provide a rationale for more efficient utilization of high-quality and high-yield 3D exosomes in the future, and a novel strategy for healing severe burns.

Calcified chondroid mesenchymal neoplasm: report of a case involving the temporomandibular joint region and review of the literature.

The calcified chondroid mesenchymal neoplasm (CCMN) represents a recently recognized tumor type with only 50 well-documented cases in the English-language literature. Herein we report an additional case of CCMN presenting as a large mass in the temporomandibular joint region of a 41-year-old female. A review of previously reported cases and the current case of CCMN shows the following features: 1) average age 52 years (range 14-87 years) and an approximately even sex distribution; 2) most frequently involved sites: distal extremities (including foot, hand, wrist, forearm) (n=41) and temporomandibular joint/temporal/parotid region (n=9); 3) multilobular soft tissue tumor with chondroid to cartilaginous matrix, often grungy or lace-like calcifications, and variable cytologic atypia; 4) frequently detected FN1 rearrangement (n=15), including FN1 fusion with FGFR2 (n=7) or other receptor tyrosine kinases; 5) 2 reported local recurrences (after incomplete excision); 6) no reports of malignant biologic behavior.

Regulating Reactive Oxygen Species over M-N-C Single-Atom Catalysts for Potential-Resolved Electrochemiluminescence.

The development of potential-resolved electrochemiluminescence (ECL) systems with dual emitting signals holds great promise for accurate and reliable determination in complex samples. However, the practical application of such systems is hindered by the inevitable mutual interaction and mismatch between different luminophores or coreactants. In this work, for the first time, by precisely tuning the oxygen reduction performance of M-N-C single-atom catalysts (SACs), we present a dual potential-resolved luminol ECL system employing endogenous dissolved O2 as a coreactant. Using advanced in situ monitoring and theoretical calculations, we elucidate the intricate mechanism involving the selective and efficient activation of dissolved O2 through central metal species modulation. This modulation leads to the controlled generation of hydroxyl radical (·OH) and superoxide radical (O2·-), which subsequently trigger cathodic and anodic luminol ECL emission, respectively. The well-designed Cu-N-C SACs, with their moderate oxophilicity, enable the simultaneous generation of ·OH and O2·-, thereby facilitating dual potential-resolved ECL. As a proof of concept, we employed the principal component analysis statistical method to differentiate antibiotics based on the output of the dual-potential ECL signals. This work establishes a new avenue for constructing a potential-resolved ECL platform based on a single luminophore and coreactant through precise regulation of active intermediates.

Functional analysis and validation of oncodrive gene AP3S1 in ovarian cancer through filtering of mutation data from whole-exome sequencing.

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most aggressive and prevalent subtype of ovarian cancer and accounts for a significant portion of ovarian cancer-related deaths worldwide. Despite advancements in cancer treatment, the overall survival rate for HGSOC patients remains low, thus highlighting the urgent need for a deeper understanding of the molecular mechanisms driving tumorigenesis and for identifying potential therapeutic targets. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying somatic mutations and alterations across the entire exome, thus providing valuable insights into the genetic drivers and molecular pathways underlying cancer development and progression. METHODS: Via the analysis of whole-exome sequencing results of tumor samples from 90 ovarian cancer patients, we compared the mutational landscape of ovarian cancer patients with that of TCGA patients to identify similarities and differences. The sequencing data were subjected to bioinformatics analysis to explore tumor driver genes and their functional roles. Furthermore, we conducted basic medical experiments to validate the results obtained from the bioinformatics analysis. RESULTS: Whole-exome sequencing revealed the mutational profile of HGSOC, including BRCA1, BRCA2 and TP53 mutations. AP3S1 emerged as the most weighted tumor driver gene. Further analysis of AP3S1 mutations and expression demonstrated their associations with patient survival and the tumor immune response. AP3S1 knockdown experiments in ovarian cancer cells demonstrated its regulatory role in tumor cell migration and invasion through the TGF-ß/SMAD pathway. CONCLUSION: This comprehensive analysis of somatic mutations in HGSOC provides insight into potential therapeutic targets and molecular pathways for targeted interventions. AP3S1 was identified as being a key player in tumor immunity and prognosis, thus providing new perspectives for personalized treatment strategies. The findings of this study contribute to the understanding of HGSOC pathogenesis and provide a foundation for improved outcomes in patients with this aggressive disease.

A Non-Disposable Electrochemical Sensor Based on Laser-Synthesized Pd/LIG Nanocomposite-Modified Screen-Printed Electrodes for the Detection of H2O2.

There have been many studies on the significant correlation between the hydrogen peroxide content of different tissues or cells in the human body and the risk of disease, so the preparation of biosensors for detecting hydrogen peroxide concentration has been a hot topic for researchers. In this paper, palladium nanoparticles (PdNPs) and laser-induced graphene (LIG) were prepared by liquid-phase pulsed laser ablation and laser-induced technology, respectively. The complexes were prepared by stirring and used for the modification of screen-printed electrodes to develop a non-enzymatic hydrogen peroxide biosensor that is low cost and mass preparable. The PdNPs prepared with anhydrous ethanol as a solvent have a uniform particle size distribution. The LIG prepared by laser direct writing has good electrical conductivity, and its loose porous structure provides more adsorption sites. The electrochemical properties of the modified electrode were characterized by cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy. Compared with bare screen-printed electrodes, the modified electrodes are more sensitive for the detection of hydrogen peroxide. The sensor has a linear response range of 5 µM-0.9 mM and 0.9 mM-5 mM. The limit of detection is 0.37 µM. The above conclusions indicate that the hydrogen peroxide electrochemical biosensor prepared in this paper has great advantages and potential in electrochemical catalysis.

Comparison of Alternative Protein Hydrogels for Delivering Myricetin: Interaction Mechanism and Stability Evaluation.

Food protein carriers from different sources might have distinct stabilizing and enhancing effects on the same small molecule. To elucidate the molecular mechanism, five different sourced proteins including soy protein isolates (SPIs), whey protein isolates (WPIs), edible dock protein (EDP), Tenebrio molitor protein (TMP), and yeast protein (YP) were used to prepare protein hydrogels for delivering myricetin (Myr). The results suggested that the loading capacity order of Myr in different protein hydrogels was EDP (11.5%) > WPI (9.3%) > TMP (8.9%) > YP (8.0%) > SPI (7.6%), which was consistent with the sequence of binding affinity between Myr and different proteins. Among five protein hydrogels, EDP had an optimum loading ability since it possessed the highest hydrophobic amino acid content (45.52%) and thus provided a broad hydrophobic cavity for loading Myr. In addition, these protein-Myr composite hydrogels displayed the core-shell structure, wherein hydrogen bonding and hydrophobic interaction were the primary binding forces between proteins and Myr. Moreover, the thermal stability, storage stability, and sustained-release properties of Myr were significantly enhanced via these protein delivery systems. These findings can provide scientific guidance for deeper utilization of food alternative protein sources.

Comparison of orbital fibroblasts from Graves' ophthalmopathy and healthy control.

Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved in orbital inflammation, tissue remodeling, and fibrosis. This study offers a primary exploration of cell behavior and characteristics on OFs from GO (GO-OFs), and compared to OFs from healthy control (HC-OFs). Results reveal that GO-OFs exhibit delayed migration from tissue fragments, while no significant difference in cell proliferation is observed between GO-OFs and HC-OFs. Aberrant expression pattern of surface proteins Thy-1, TSHR, and IGF-1R suggests shared autoantigens and pathways between GO and GD, contributing to inflammation and fibrosis. Investigations into cytokine responses unveil elevated secretion of hyaluronic acid (HA) and prostaglandin E2 (PGE2) in GO-OFs, emphasizing their role in tissue remodeling. These findings deepen our understanding of OFs in GO pathogenesis, offering potential therapeutic avenues.

NCAPD3 is a prognostic biomarker and is correlated with immune infiltrates in glioma.

Non-SMC Condensin II Complex Subunit D3 (NCAPD3) has been linked with the genesis and progression of multiple human cancers. Nevertheless, the scientific value and molecular process of NCAPD3 in glioma remain unclear. We explored the level of NCAPD3 expression in pan-cancer by multiple online databases. And we focused on the level and prognostic value of NCAPD3 expression in glioma by immunohistochemistry (IHC) and survival analysis. Meanwhile, we verified the relationship between NCAPD3, biological function and immune infiltration in glioma by Linkedomics and SangerBox databases. The expression of NCAPD3 was increased in a variety of cancers, including glioma. Its high expression was strongly related to WHO grade (P=0.002) and programmed cell death ligand 1 (PD-L1) expression of glioma (P=0.001). Patients with a high level of NCAPD3 expression had a lower overall survival (OS) in glioma than patients with a low level of NCAPD3 expression. Multivariate statistical analyses showed NCAPD3 expression (P=0.040), WHO grade (P<0.001), 1p/19q codeletion (P<0.001), recurrence (P<0.001), age (P=0.023), and chemotherapy status (P=0.001) were meaningful independent prognostic factors in patients with glioma. Furthermore, bioinformatics analysis proved that NCAPD3 has been linked to immune infiltration in glioma. High level of NCAPD3 expression may serve as a promising prognostic biomarker and correlate with dendritic cell infiltration, representing a potential immunotherapy target in glioma.

Long non-coding RNA MALAT1 in hematological malignancies and its clinical applications.

ABSTRACT: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a well-established oncogenic long non-coding RNA, the higher expression of which is strongly correlated with cancer events such as tumorigenesis, progression, metastasis, drug resistance, and treatment outcome in solid cancers. Recently, a series of studies has highlighted its potential role in hematological malignancies in terms of these events. Similar to solid cancers, MALAT1 can regulate various target genes via sponging and epigenetic mechanisms, but the miRNAs sponged by MALAT1 differ from those identified in solid cancers. In this review, we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies, including regulation of cell proliferation, metastasis, stress response, and glycolysis. Clinically, MALAT1 expression is related to poor treatment outcome and drug resistance, therefore exhibiting potential prognostic value in multiple myeloma, lymphoma, and leukemia. Finally, we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.

Neonatal Filaggrin Genetic Screening and Counseling to Prevent Atopic Dermatitis in High-Risk Infants.

Background: Mutations in filaggrin (FLG), the gene that codes for the skin barrier protein, have been shown to be associated with atopic dermatitis (AD). Objective: The objectives of this study were to determine the effects of genetic counseling and parental education on infants at a high risk of AD. Methods: We enrolled 7521 newborns in Taiwan from January 1, 2016, to March 30, 2020, and all of them received genetic testing encompassing 20 known FLG mutations. The genetic counseling and AD prevention and care team consisted of pediatricians, dermatologists, social workers, and genetic counselors. The counseling was arranged for at least 30 minutes within 45 days after delivery. Results: A total of 2963 high-risk infants (39.4%) were identified. Homozygous c.1432C>T was the most commonly identified mutation. A total of 418 neonates' parents were stratified into counseling and noncounseling groups, where the effect of parental education was evaluated. The genetically stratified parental education program was effective in preventing AD development by 63.3% in high-risk infants before 12 months of life (P < 0.0001). Conclusion: Genetic stratification and parental education are effective in preventing the development of AD in high-risk infants before 12 months of life.

Diagnostic utility and sensitivities of matrix Gla protein (MGP), TRPS1 and GATA3 in breast cancer: focusing on metastatic breast cancer, invasive breast carcinoma with special features, and salivary gland-type tumours.

Matrix Gla protein (MGP) and trichorhinophalangeal syndrome type 1 (TRPS1) have recently emerged as novel breast-specific immunohistochemical (IHC) markers, particularly for triple-negative breast cancer (TNBC) and metaplastic carcinoma. The present study aimed to validate and compare the expression of MGP, TRPS1 and GATA binding protein 3 (GATA3) in metastatic breast carcinoma (MBC), invasive breast carcinoma (IBC) with special features, including special types of invasive breast carcinoma (IBC-STs) and invasive breast carcinoma of no special type with unique features, and mammary and non-mammary salivary gland-type tumours (SGTs). Among all enrolled cases, MGP, TRPS1 and GATA3 had comparable high positivity for ER/PR-positive (p=0.148) and HER2-positive (p=0.310) breast carcinoma (BC), while GATA3 positivity was significantly lower in TNBC (p<0.001). Similarly, the positive rates of MGP and TRPS1 in MBCs (99.4%), were higher than in GATA3 (90.9%, p<0.001). Among the IBC-STs, 98.4% of invasive lobular carcinomas (ILCs) were positive for all three markers. Among neuroendocrine tumours (NTs), all cases were positive for TRPS1 and GATA3, while MGP positivity was relatively low (81.8%, p=0.313). In the neuroendocrine carcinoma (NC) subgroup, all cases were positive for GATA3 and MGP, while one case was negative for TRPS1. All carcinomas with apocrine differentiation (APOs) were positive for GATA3 and MGP, while only 60% of the cases demonstrated moderate staining for TRPS1. Among mammary SGTs, MGP demonstrated the highest positivity (100%), followed by TRPS1 (96.0%) and GATA3 (72.0%). Positive staining for these markers was also frequently observed in non-mammary SGTs. Our findings further validate the high sensitivity of MGP and TRPS1 in MBCs, IBC-STs, and breast SGTs. However, none of these markers are capable of distinguishing between mammary and non-mammary SGTs.

ADAMTS13 deficiency exacerbates neuroinflammation by targeting matrix metalloproteinase-9 in ischemic brain injury.

Our design aimed to explore the potential involvement of matrix metalloproteinase-9 (MMP-9) in the inflammatory response associated with acute ischemic stroke (AIS). We also aimed to preliminarily examine the potential impact of a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 (ADAMTS13) on MMP-9 in AIS. We conducted oxygen-glucose deprivation models of microglia cells and mice models of AIS with middle cerebral artery occlusion (MCAO). We assessed the expression pattern of MMP-9 with western blotting (WB) and real-time quantitative PCR both in vivo and in vitro. MMP-9 downregulation was achieved by using ACE inhibitors such as trandolapril. For the MCAO model, we used ADAMTS13-deficient mice. We then evaluated the related neurological function scores, cerebral edema and infarct volume. The levels of inflammation-related proteins, such as COX2 and iNOS, were assessed using WB, and the expression of inflammatory cytokines was measured via enzyme-linked immuno sorbent assay in vivo. Our findings indicated that MMP-9 was up-regulated while ADAMTS13 was down-regulated in the MCAO model. Knockdown of MMP-9 reduced both inflammation and ischemic brain injury. ADAMTS13 prevented brain damage, improved neurological function and decreased the inflammation response in mice AIS models. Additionally, ADAMTS13 alleviated MMP-9-induced neuroinflammation in vivo. It showed that ADAMTS13 deficiency exacerbated ischemic brain injury through an MMP-9-dependent inflammatory mechanism. Therefore, the ADAMTS13-MMP-9 axis could have therapeutic potential for the treatment of AIS.

Identification of odorant-binding proteins and functional analysis of antenna-specific BhorOBP28 in Batocera horsfieldi (Hope).

BACKGROUND: The important wood-boring pest Batocera horsfieldi has evolved a sensitive olfactory system to locate host plants. Odorant-binding proteins (OBPs) are thought to play key roles in olfactory recognition. Therefore, exploring the physiological function of OBPs could facilitate a better understanding of insect chemical communications. RESULTS: In this research, 36 BhorOBPs genes were identified via transcriptome sequencing of adults' antennae from B. horsfieldi, and most BhorOBPs were predominantly expressed in chemosensory body parts. Through fluorescence competitive binding and fluorescence quenching assays, the antenna-specific BhorOBP28 was investigated and displayed strong binding affinities forming stable complexes with five volatiles, including (+)-α-Pinene, (+)-Limonene, ß-Pinene, (-)-Limonene, and (+)-Longifolene, which could also elicit conformation changes when they were interacting with BhorOBP28. Batocera horsfieldi females exhibited a preference for (-)-Limonene, and a repellent response to (+)-Longifolene. Feeding dsOBP19 produced by a bacteria-expressed system with a newly constructed vector could lead to the knockdown of BhorOBP28, and could further impair B. horsfieldi attraction to (-)-Limonene and repellent activity of (+)-Longifolene. The analysis of site-directed mutagenesis revealed that Leu7, Leu72, and Phe121 play a vital role in selectively binding properties of BhorOBP28. CONCLUSION: By modeling the molecular mechanism of olfactory recognition, these results demonstrate that BhorOBP28 is involved in the chemoreception of B. horsfieldi. The bacterial-expressed dsRNA delivery system gains new insights into potential population management strategies. Through the olfactory process concluded that discovering novel behavioral regulation and environmentally friendly control options for B. horsfieldi in the future. © 2024 Society of Chemical Industry.

Remodeling brain pathological microenvironment to lessen cerebral ischemia injury by multifunctional injectable hydrogels.

Ischemia stroke is one of the leading causes of death and disability worldwide. Owing to the limited delivery efficiency to the brain caused by the blood-brain barrier (BBB) and off-target effects of systemic treatment, it is crucial to develop an in situ drug delivery system to improve the therapeutic effect in ischemic stroke. Briefly, we report a multifunctional in situ hydrogel delivery system for the co-delivery of reactive oxygen species (ROS)-responsive nanoparticles loaded with atorvastatin calcium (DSPE-se-se-PEG@AC NPs) and ß-nerve growth factor (NGF), which is expected to remodel pathological microenvironment for improving cerebral ischemia injury. The in vitro results exhibited the multifunctional hydrogel scavenged oxygen-glucose deprivation (OGD)-induced free radical, rescued the mitochondrial function, and maintained the survival and function of neurons, hence reducing neuronal apoptosis and neuroinflammation, consequently relieving ischemia injury in hippocampal neurons cell line (HT22). In the rat ischemia stroke model, the hydrogel significantly minified cerebral infarction by regulating inflammatory response, saving apoptotic neurons, and promoting angiogenesis and neurogenesis. Besides, the hydrogel distinctly improved the rats' neurological deficits after cerebral ischemia injury over the long-term observation. In conclusion, the in-situ hydrogel platform has demonstrated promising therapeutic effects in both in vitro and in vivo studies, indicating its potential as a new and effective therapy.

The crosstalk between exosomes and ferroptosis: a review.

Exosomes are a subtype of extracellular vesicles composed of bioactive molecules, including nucleic acids, proteins, and lipids. Exosomes are generated by the fusion of intracellular multivesicular bodies (MVBs) with the cell membrane and subsequently released into the extracellular space to participate in intercellular communication and diverse biological processes within target cells. As a crucial mediator, exosomes have been implicated in regulating ferroptosis-an iron-dependent programmed cell death characterized by lipid peroxide accumulation induced by reactive oxygen species. The involvement of exosomes in iron, lipid, and amino acid metabolism contributes to their regulatory role in specific mechanisms underlying how exosomes modulate ferroptosis, which remains incompletely understood, and some related studies are still preliminary. Therefore, targeting the regulation of ferroptosis by exosomes holds promise for future clinical treatment strategies across various diseases. This review aims to provide insights into the pathophysiology and mechanisms governing the interaction between exosomes and ferroptosis and their implications in disease development and treatment to serve as a reference for further research.

Esculin induces endoplasmic reticulum stress and drives apoptosis and ferroptosis in colorectal cancer via PERK regulating eIF2α/CHOP and Nrf2/HO-1 cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Cortex fraxini (also known as Qinpi), the bark of Fraxinus rhynchophylla Hance and Fraxinus stylosa Lingelsh, constitutes a crucial component in several traditional Chinese formulas (e.g., Baitouweng Tang, Jinxiao Formula, etc.) and has demonstrated efficacy in alleviating intestinal carbuncle and managing diarrhea. Cortex fraxini has demonstrated commendable anticancer activity in the realm of Chinese ethnopharmacology; nevertheless, the underlying mechanisms against colorectal cancer (CRC) remain elusive. AIM OF THE STUDY: Esculin, an essential bioactive compound derived from cortex fraxini, has recently garnered attention for its ability to impede viability and induce apoptosis in cancer cells. This investigation aims to assess the therapeutic potential of esculin in treating CRC and elucidate the underlying mechanisms. MATERIALS AND METHODS: The impact of esculin on CRC cell viability was assessed using CCK-8 assay, Annexin V/PI staining, and Western blotting. Various cell death inhibitors, along with DCFH-DA, ELISA, biochemical analysis, and Western blotting, were employed to delineate the modes through which esculin induces HCT116 cells death. Inhibitors and siRNA knockdown were utilized to analyze the signaling pathways influenced by esculin. Additionally, an azomethane/dextran sulfate sodium (AOM/DSS)-induced in vivo CRC mouse model was employed to validate esculin's potential in inhibiting tumorigenesis and to elucidate its underlying mechanisms. RESULTS: Esculin significantly suppressed the viability of various CRC cell lines, particularly HCT116 cells. Investigation with diverse cell death inhibitors revealed that esculin-induced cell death was associated with both apoptosis and ferroptosis. Furthermore, esculin treatment triggered cellular lipid peroxidation, as evidenced by elevated levels of malondialdehyde (MDA) and decreased levels of glutathione (GSH), indicative of its propensity to induce ferroptosis in HCT116 cells. Enhanced protein levels of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and p-eIF2α suggested that esculin induced cellular endoplasmic reticulum (ER) stress, subsequently activating the Nrf2/ARE signaling pathway and initiating the transcriptional expression of heme oxygenase (HO)-1. Esculin-induced excessive expression of HO-1 could potentially lead to iron overload in HCT116 cells. Knockdown of Ho-1 significantly attenuated esculin-induced ferroptosis, underscoring HO-1 as a critical mediator of esculin-induced ferroptosis in HCT116 cells. Furthermore, utilizing an AOM/DSS-induced colorectal cancer mouse model, we validated that esculin potentially inhibits the onset and progression of colon cancer by inducing apoptosis and ferroptosis in vivo. CONCLUSIONS: These findings provide comprehensive insights into the dual induction of apoptosis and ferroptosis in HCT116 cells by esculin. The activation of the PERK signaling pathway, along with modulation of downstream eIF2α/CHOP and Nrf2/HO-1 cascades, underscores the mechanistic basis supporting the clinical application of esculin on CRC treatment.