The new era of lung cancer therapy: Combining immunotherapy with ferroptosis.

Ferroptosis is an unconventional programmed cell death mode caused by phospholipid peroxidation dependent on iron. Emerging immunotherapies (especially immune checkpoint inhibitors) have the potential to enhance lung cancer patients' long-term survival. Although immunotherapy has yielded significant positive applications in some patients, there are still many mechanisms that can cause lung cancer cells to evade immunity, thus leading to the failure of targeted therapies. Immune-tolerant cancer cells are insensitive to conventional death pathways such as apoptosis and necrosis, whereas mesenchymal and metastasis-prone cancer cells are particularly vulnerable to ferroptosis, which plays a vital role in mediating immune tolerance resistance by tumors and immune cells. As a result, triggering lung cancer cell ferroptosis holds significant therapeutic potential for drug-resistant malignancies. Here, we summarize the mechanisms underlying the suppression of ferroptosis in lung cancer, highlight its function in the lung cancer immune microenvironment, and propose possible therapeutic strategies.

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP.

BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice. METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or ß-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging. RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP). CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Screening and identification of potential hypoglycemic and hypolipidemic compounds from aqueous extract of Scutellaria baicalensis Georgi root combing affinity ultrafiltration with multiple drug targets and in silico analysis.

INTRODUCTION: Scutellaria baicalensis Georgi, a traditional Chinese medicine, is widely applied to treat various diseases among people, especially in East Asia. However, the specific active compounds in S. baicalensis aqueous extracts (SBAEs) responsible for the hypoglycemic and hypolipidemic properties as well as their potential mechanisms of action remain unclear. OBJECTIVES: This work aimed to explore the potential hypoglycemic and hypolipidemic compounds from SBAE and their potential mechanisms of action. METHODOLOGY: The in vitro inhibitory tests against lipase and α-glucosidase, and the effects of SBAE on glucose consumption and total triglyceride content in HepG2 cells were first performed to evaluate the hypoglycemic and hypolipidemic effects. Then, affinity ultrafiltration liquid chromatography-mass spectrometry (LC-MS) screening strategy with five drug targets, including α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B), lipase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) was developed to screen out the potential active constituents from SBAE, and some representative active compounds were further validated. RESULTS: SBAE displayed noteworthy hypoglycemic and hypolipidemic properties, and 4, 10, 4, 8, and 8 potential bioactive components against α-amylase, α-glucosidase, PTP1B, HMGCR, and lipase were initially screened out, respectively. The interaction network was thus constructed between the potential bioactive compounds screened out and their corresponding drug targets. Among them, baicalein, wogonin, and wogonoside were revealed to possess remarkable hypoglycemic and hypolipidemic effects. CONCLUSION: The potential hypolipidemic and hypoglycemic bioactive compounds in SBAE and their mode of action were initially explored through ligand-target interactions by combining affinity ultrafiltration LC-MS strategy with five drug targets.

Bazi Bushen mitigates epigenetic aging and extends healthspan in naturally aging mice.

Bazi Bushen (BZBS), a traditional Chinese medicine, has been proven effective in the treatment of age-related disease in mouse models. However, whether its therapeutic effects are due to antiaging mechanism has not yet been explored. In the present study, we investigated the antiaging effects of BZBS in naturally aging mice by using behavioral tests, liver DNA methylome sequencing, methylation age estimation, and frailty index assessment. The methylome analysis revealed a decrease of mCpG levels in the aged mouse liver. BZBS treatment tended to restore age-associated methylation decline and prune the methylation pattern toward that of young mice. More importantly, BZBS significantly rejuvenated methylation age of the aged mice, which was computed by an upgraded DNA methylation clock. These results were consistent with enhanced memory and muscular endurance, as well as decreased frailty score and liver pathological changes. KEGG analysis together with aging-related database screening identified methylation-targeted pathways upon BZBS treatment, including oxidative stress, DNA repair, MAPK signaling, and inflammation. Upregulation of key effectors and their downstream effects on elevating Sod2 expression and diminishing DNA damage were further investigated. Finally, in vitro experiments with senescent HUVECs proved a direct effect of BZBS extracts on the regulation of methylation enzymes during cellular aging. In summary, our work has revealed for the first time the antiaging effects of BZBS by slowing the methylation aging. These results suggest that BZBS might have great potential to extend healthspan and also explored the mechanism of BZBS action in the treatment of age-related diseases.

Phosphorus availability and planting patterns regulate soil microbial effects on plant performance in a semiarid steppe.

BACKGROUND AND AIMS: Growing evidence has suggested that plant responses to model soil microorganisms are context dependent; however, few studies have investigated the effects of whole soil microbial communities on plant performance in different abiotic and biotic conditions. To address this, we examined how soil phosphorus (P) availability and different planting patterns regulate soil microbial effects on the growth of two native plant species in a semiarid steppe. METHODS: We carried out a glasshouse experiment to explore the effects of the whole indigenous soil microbiota on the growth and performance of Leymus chinensis and Cleistogenes squarrosa using soil sterilization with different soil P availabilities and planting patterns (monoculture and mixture). Transcriptome sequencing (RNA-seq) was used to explain the potential molecular mechanisms of the soil microbial effects on C. squarrosa. KEY RESULTS: The soil sterilization treatment significantly increased the biomass of L. chinensis and C. squarrosa in both monoculture and mixture conditions, which indicated that the soil microbiota had negative growth effects on both plants. The addition of P neutralized the negative microbial effects for both L. chinensis and C. squarrosa, whereas the mixture treatment amplified the negative microbial effects on L. chinensis but alleviated them on C. squarrosa. Transcriptomic analysis from C. squarrosa roots underscored that the negative soil microbial effects were induced by the upregulation of defence genes. The P addition treatment resulted in significant decreases in the number of differentially expressed genes attributable to the soil microbiota, and some defence genes were downregulated. CONCLUSIONS: Our results underline that indigenous soil microbiota have negative effects on the growth of two dominant plant species from a semiarid steppe, but their effects are highly dependent on the soil P availability and planting patterns. They also indicate that defence genes might play a key role in controlling plant growth responses to the soil microbiota.

Extraordinary microcarriers derived from spores and pollens.

Spores and pollens refer to the reproductive cells of seed plants and asexually reproducing sporophytes, exhibiting a natural core-shell structure and exquisite surface morphology. They possess extraordinary dimensional homogeneity, porosity, amphiphilicity and adhesion. Their sporopollenin exine layer endows them with chemically stable, UV resistant, and biocompatible properties, which can also be facilely functionalized due to sufficient groups on the surface. The unique characteristics of spores and pollens have facilitated a wide range of applications in drug carriers, biological imaging, food science, microrobotics, environmental purification, flexible electronics, cell scaffolds, 3D printing materials and biological detection. This review showcases the common structural composition and physicochemical properties of spores and pollens, describes the extraction and processing methods, and summarizes the recent research on their applications in various fields. Following these sections, this review analyzes the existing challenges in spores and pollen research and provides a future outlook.

Association of Folic Acid Supplementation in Early Pregnancy with Risk of Gestational Diabetes Mellitus: A Longitudinal Study.

BACKGROUND: Gestational diabetes mellitus (GDM) may lead to many adverse effects on women and their offspring. METHOD: 24,429 pregnant women were enrolled during early pregnancy from January 2018 to December 2021. The self-reported intake of folic acid supplements was assessed via a questionnaire. Oral glucose tolerance tests were used for the diagnosis of GDM. The association between intake or not, dose, and duration of folic acid and GDM risk was assessed. RESULTS: 6396 (26.18%) women were diagnosed with GDM. In the univariate models, folic acid was found to be correlated with total GDM risk (OR = 0.82, 95% CI: 0.70~0.95, p = 0.009). After adjusting for potential confounders, the association with total GDM risk was not significant, but the association of folic acid with 2-h PBG diagnosed GDM risk was consistently significant (OR = 0.75, 95% CI: 0.63~0.90, p = 0.002). No significant association between the dose and duration of folic acid supplementation and GDM risk was observed in the analyses. CONCLUSION: Folic acid supplementation might be a protective factor for the risk of GDM caused by the high level of postprandial blood glucose, but the dose or duration-related association between folic acid supplementation and GDM risk is not clear.

Analysis of Early Warning Diagnostic Indexes and Influencing Factors of Anxiety and Depression in Patients with Arrhythmia.

Objective: Arrhythmia patients complicated with psychological problems are very common in clinics. The imbalance of autonomic nervous regulation of the heart caused by anxiety and depression will further promote the occurrence and development of arrhythmia. For nonorganic heart disease, ß receptor blockers combined with antianxiety drugs have a good effect. Therefore, it is necessary to analyze the influencing factors of anxiety and depression in patients with arrhythmias. Methods: We included 150 patients with arrhythmia and divided them into observation groups (80 patients with anxiety and depression) and control groups (70 patients without anxiety and depression). All patients were monitored by Holter, and the detection of arrhythmia was compared between the two groups. We took the general situation and quality of life of the investigated patients as independent variables and the anxiety and depression status of the patients as dependent variables. Results: The detection rates of atrioventricular premature beats, ventricular premature beats, atrial fibrillation, short bursts of atrial tachycardia, and atrioventricular block in the observation group were all higher than those in the control group by dynamic electrocardiogram. Multivariate logistic stepwise regression analysis showed that age, years of education, obsessive-compulsive score, somatization score and alcohol consumption were the main influencing factors for anxiety and depression. Conclusions: The detection rate of arrhythmia in patients with anxiety/depression status was higher than in those without abnormal psychophylaxis. We should need to pay close attention to the risk factors of age, education years, obsessive-compulsive score, somatization score, and alcohol consumption, so as to prevent and timely detect anxiety and depression symptoms in patients with arrhythmias.

The Mediating Effects of Coping Style on the Effects of Breath Count Mindfulness Training on Depressive Symptoms among International Students in China.

Mindfulness training has gained popularity in the scientific field and has been proposed as an efficient way for emotional regulation. Mindfulness-based cognitive therapy (MBCT) is designed especially for depressive people in reducing risk of depression relapse and is recommended in national guidelines as a treatment choice for relapse prevention in recurrent depression. The aim of the current study was to investigate the effects of mindfulness training on depressive symptoms of international students and probe into the mediating role of mindfulness in stressful events and depression. In addition, we introduced a new kind of mindfulness training, the breathing exercise-based mindfulness training, which is based on the integration of Buddhism and Daoism. Self-report questionnaires assessing the coping style, abnormal depressive behavior, and stressful live events were completed in 260 international students in China (mean age = 21.4 years). The results showed that (1) many international students showed depression symptoms, (2) stressful life events play a completely mediating role in the initiation of depression and anxiety, and (3) mindfulness training for 8 weeks significantly reduced the depressive symptoms, and it was also related to a positive coping style. This study has certain theoretical significance in exploring the mechanism of the occurrence and development of depression among international students and provides useful tools for this special group of international students. In addition, the international students can also learn Chinese culture through the training. These findings indicate that mindfulness training and positive coping style are interrelated with treating depressive symptoms for international students.

Interactions of indole alkaloids with myoglobin: A mass spectrometry based spectrometric and computational method.

RATIONALE: Interactions of drug molecules and proteins play important roles in physiological and pathological processes in vivo. It is of significance to establish a reliable strategy for studying protein-drug ligand interactions and would be helpful for the design and screening of new drugs in pharmacological research. METHODS: The interactions between four indole alkaloids (IAs) extracted from Ophiorrhiza japonica (O. japonica) and myoglobin (Mb) protein were investigated using a multi-spectrometric and computational method of native electrospray ionization mass spectrometry (native ESI-MS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), circular dichroism (CD) and molecular docking (MD). RESULTS: The IA-bound Mb complexes were analyzed using native ESI-MS, with the obtained protein-to-ligand stoichiometry at 1:1, 1:2 and 1:3. Binding constants were measured according to the interpretation of MS spectra. MD complemented MS measurements, probing the binding sites and modes of the four IAs to Mb. Analyses involving CD and HDX-MS demonstrated that exposure to IAs could affect the conformation of Mb by decreasing the α-helix content and made Mb more susceptible to HDX at the backbone. CONCLUSIONS: A new MS-based integrated analysis method has been developed to successfully study the interactions of Mb and IAs extracted from O. japonica. The experimental and calculation results have good consistency, revealing all of the four IA molecules could bind to Mb to form 1:1, 1:2 and 1:3 Mb-IA complexes. The order of binding ability of these IAs to Mb was ophiorrhine B > compound C > ophiorrhine A > compound D. CD and HDX-MS results indicated that binding with IAs destabilizes Mb. HDX-MS analysis suggests that Mb becomes more susceptible to HDX, indicating that binding with IAs destabilizes the structure of Mb. In addition, the interaction with IAs affected the overall structure of Mb, ascribed to the decrease of α-helix content and less folding of the backbone.

pH Responsiveness of Hexosomes and Cubosomes for Combined Delivery of Brucea javanica Oil and Doxorubicin.

We report pH-responsive liquid crystalline lipid nanoparticles, which are dual-loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH = 7.4) to cubic (pH = 6.8) to emulsified microemulsion (pH = 5.3) phase transition with a therapeutic application in cancer inhibition. BJO is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an antitumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need for safe delivery carriers. Here, pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein-oleic acid-BJO-DOX) systems are determined by synchrotron small-angle X-ray scattering and the Langmuir film balance technique. The nanocarrier assemblies display good physical stability in the studied pH range and adequate particle sizes and ζ-potentials. Their interaction with model lipid membrane interfaces is enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO-DOX dual-loaded pH-switchable liquid crystalline nanoparticles are performed on the human breast cancer Michigan Cancer Foundation-7 (MCF-7) cell line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines exhibit enhanced antitumor efficacy. The performed preliminary studies suggest a potential reversal of the resistance of the MCF-7/DOX cells to DOX. These results highlight the necessity for further understanding the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, and emulsified microemulsion inner organizations for therapeutic outcomes.

Mitochondria-Targeted Polydopamine Nanocomposite with AIE Photosensitizer for Image-Guided Photodynamic and Photothermal Tumor Ablation.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are two kinds of treatment for tumors. Herein, a new aggregation-induced emission (AIE)gen (MeO-TPE-indo, MTi) is synthesized with a D-π-A conjugated structure. MTi, which has an electron donor and an acceptor on a tetraphenylethene (TPE) conjugated skeleton, can induce the effective generation of reactive oxygen species (ROS) for PDT. With the guide of the indolium group, MTi can target and image mitochondrion selectively. In order to get good dispersion in water and long-time retention in tumors, MTi is modified on the surface of polydopamine nanoparticles (PDA NPs) to form the nanocomposite (PDA-MeO-TPE-indo, PMTi) by π-π and hydrogen interactions. PMTi is a nanoscale composite for imaging-guided PDT and PTT in tumor treatment, which is constructed with AIEgens and PDA for the first time. The organic functional molecules are combined with nanomaterials for building a multifunctional diagnosis and treatment platform by utilizing the advantages of both sides.

Self-assembled stable sponge-type nanocarries for Brucea javanica oil delivery.

Sponge-type nanocarriers (spongosomes) are produced upon dispersion of a liquid crystalline sponge phase formed by self-assembly of an amphiphilic lipid in excess aqueous phase. The inner organization of the spongosomes is built-up by randomly ordered bicontinuous lipid membranes and their surfaces are stabilized by alginate chains providing stealth properties and colloidal stability. The present study elaborates spongosomes for improved encapsulation of Brucea javanica oil (BJO), a traditional Chinese medicine that may strongly inhibit proliferation and metastasis of various cancers. The inner structural organization and the morphology characteristics of BJO-loaded nanocarriers at varying quantities of BJO were determined by cryogenic transmission electron microscopy (Cryo-TEM), small angle X-ray scattering (SAXS) and dynamic light scattering (DLS). Additionally, the drug loading and drug release profiles for BJO-loaded spongosome systems also were determined. We found that the sponge-type liquid crystalline lipid membrane organization provides encapsulation efficiency rate of BJO as high as 90%. In vitro cytotoxicity and apoptosis study of BJO spongosome nanoparticles with A549 cells demonstrated enhanced anti-tumor efficiency. These results suggest potential clinical applications of the obtained safe spongosome formulations.

Sedative and anticonvulsant activities of styrax after oral and intranasal administration in mice.

CONTEXT: Styrax, resin of Liquidambar orientalis Mill. (N.O. Hamamelaceae), belongs to resuscitation-inducing aromatic herbs in traditional Chinese medicine and functions in inducing resuscitation and restoring conscientiousness. OBJECTIVE: The possible sedative and anticonvulsant activities of styrax on CNS were investigated. The onsets of action of two different routes (oral and intranasal administration) were compared. MATERIALS AND METHODS: Styrax was tested for sedative, hypnotic, and anticonvulsant effects using locomotor activity evaluation, pentobarbital-induced sleeping time, and pentylenetetrazol (PTZ)-induced convulsion, respectively. RESULTS: After oral administration (25, 50, 100 mg/kg), styrax prolonged the sodium pentobarbital-induced sleeping time. In comparison with oral administration, intranasal administration (12.5, 25, 50 mg/kg) prolonged the sleeping time at lower dosage. Moreover, styrax (100 and 200 mg/kg) promoted a significant protection against PTZ-induced seizures and mortality 30 min after oral administration. In contrast, 5 min after intranasal administration, styrax promoted significant protection at lower dosages (25 and 50 mg/kg). These data show that styrax had faster onset of action (5 vs. 30 min) and better anticonvulsant efficacy (25, 50 vs. 100, 200 mg/kg) by intranasal route in comparison with that by intragastric route. Styrax decreased the spontaneous locomotor movements at 100 mg/kg during 5-60 min interval after oral administration. DISCUSSION AND CONCLUSION: Styrax has sedative and anticonvulsant activities. Furthermore, styrax has faster onset of action as well as more potent efficacy after intranasal administration at lower dosage than by intragastric route. This result illustrates that intranasal administration may act as a promising alternative to conventional routes of administration.