Mind-body exercise for patients with stable COPD on lung function and exercise capacity: a systematic review and meta-analysis of RCTs.

Chronic Obstructive Pulmonary Disease (COPD) is a global health concern. Mind-body exercises like Tai Chi and Yoga are suggested as non-pharmacological interventions for COPD management. This meta-analysis evaluates mind-body exercises' impact on lung function and exercise capacity in stable COPD patients, aiming to assess their effectiveness in rehabilitation. A systematic search across various databases identified relevant randomized controlled trials until April 2024. Primary outcomes included lung function tests (FEV1, FVC, FEV1/FVC, FEV1%) and Six-Minute Walk Test (6MWT) results. The Standardized Mean Difference (SMD) measured intervention effects. Fifteen studies with 1047 participants were analyzed. Mind-body exercises significantly improved FEV1 (SMD = 0.87), FEV1/FVC (SMD = 0.19), FEV1% (SMD = 0.43), and 6MWT (SMD = 1.21) compared to standard care. Sensitivity and subgroup analyses confirmed result stability despite some heterogeneity.In conclusion, Mind-body exercises enhance lung function and exercise capacity in stable COPD patients. Integrating them into comprehensive rehabilitation programs is advisable. Further research should explore the specific impacts of different exercise types and intensities.

Enhancing lower limb and core muscle activation with blood flow restriction training: a randomized crossover study on high-intensity squat exercises.

Objective: The primary objective of this study was to assess the impact of high-intensity deep squat training integrated with various blood flow restriction (BFR) modalities on the activation of lower limb and core muscles. Methods: A randomized, self-controlled crossover experimental design was employed with 12 participants. The exercise protocol consisted of squat training at 75% of one-repetition maximum (1RM), performed in 3 sets of 8 repetitions with a 2-min inter-set rest period. This was conducted under four distinct BFR conditions: continuous low BFR (T1), intermittent medium BFR (T2), intermittent high BFR (T3), and a non-restricted control (C). Surface electromyography (EMG) was utilized to collect EMG signals from the target muscles during the BFR and squat training sessions. The root mean square (RMS) amplitude standard values were calculated for each squat set to quantify muscle activation levels, with these values expressed as a percentage of the maximum voluntary contraction (%MVC). Rating of Perceived Exertion was evaluated after each squat set, and leg circumference measurements were taken. Results: 1) During the first two sets of deep squats, the %MVC of the vastus lateralis and vastus medialis in all compression groups was significantly higher than that in the control group (p < 0.05). Furthermore, in the first set, the %MVC of the vastus lateralis in Group T3 was significantly higher than in Group T2 (p < 0.05). In the third set, the %MVC of the vastus medialis in Groups T1 and T3 was significantly lower than in the first two sets (p < 0.05). 2) Group T1 showed an increased activation of the biceps femoris and semitendinosus muscles in the second and third sets, with %MVC values significantly greater than in the first set (p < 0.05). Group T2 only showed an increase in biceps femoris activation in the third set (p < 0.05). Group T3 significantly increased the activation of the biceps femoris and semitendinosus muscles only in the first set (p < 0.05). 3) No significant differences were observed in the changes of rectus abdominis %MVC among the groups (p > 0.05). In the first set, Group T3's erector spinae %MVC was significantly higher than the control group's; in the second set, it was significantly higher than both Group T2 and the control group's (p < 0.05). 4) After training, a significant increase in thigh circumference was observed in all groups compared to before training (p < 0.05). 5) For RPE values, Group T2's post-squat values were significantly higher than the control group's after all three sets (p < 0.05). Group T1's RPE values were also significantly higher than the control group's after the third set (p < 0.05). Groups T1, T2, and C all had significantly higher RPE values in the second and third sets compared to the first set (p < 0.05). Conclusion: All BFR modalities significantly enhanced the activation level of the anterior thigh muscles, with the continuous low BFR mode demonstrating a more stable effect. No significant differences were found in the activation level of the rectus abdominis among the groups. However, the intermittent high BFR mode was the most effective in increasing the activation level of the erector spinae muscles. While BFR did not further augment leg circumference changes, it did elevate subjective fatigue levels. The RPE was lowest during squatting under the intermittent high BFR condition.

A Bimetallic Nanomodulator to Reverse Immunosuppression via Sonodynamic-Ferroptosis and Lactate Metabolism Modulation.

Triple-negative breast cancer (TNBC) responds poorly to immunotherapy due to insufficient immunogenicity and highly immunosuppressive tumor microenvironment (TME). Herein, an intelligent calcium/cobalt-based nanomodulator (Ca,Co)CO3-LND-TCPP@F127-TA (abbreviated as CCLT@FT) is developed to act as a sonodynamic-ferroptosis inducer and metabolic immunoadjuvant to enhance anti-tumor immunotherapy. More details, simultaneous reactive oxygen species (ROS) generation and glutathione (GSH) depletion can be achieved due to the existence of Co2+/Co3+ redox couple in CCLT@FT. Meanwhile, mitochondrial Ca2+ overload and tetrakis(4-carboxyphenyl) porphyrin (TCPP)-mediated sonodynamic therapy (SDT) further amplify the oxidative stress and promote ferroptosis in tumor cells. More impressively, CCLT@FT can modulate lactate metabolism by doping with cobalt and loading with lonidamine (LND, an inhibitor of MCT4), thereby reversing the high-lactate immunosuppressive TME. Furthermore, the combination with immune checkpoint blockade (ICB) therapy is found to achieve superior anti-tumor immunity, which in turn promotes ferroptosis of tumor cells by downregulating SLC7A11 protein, ultimately creating a "cycle" therapy. Overall, this work demonstrates a novel strategy for enhancing anti-tumor immunotherapy based on a closed-loop enhancement therapeutic route between CCLT@FT inducing ferroptosis/lactate metabolism modulation and ICB therapy, providing an alternative and important reference for effective immunotherapy of TNBC.

A "Ferroptosis-Amplifier" Hydrogel for Eliminating Refractory Cancer Stem Cells Post-lumpectomy.

The unique "Iron Addiction" feature of cancer stem cells (CSCs) with tumorigenicity and plasticity generally contributes to the tumor recurrence and metastasis after a lumpectomy. Herein, a novel "Ferroptosis Amplification" strategy is developed based on integrating gallic acid-modified FeOOH (GFP) and gallocyanine into Pluronic F-127 (F127) and carboxylated chitosan (CC)-based hydrogel for CSCs eradication. This "Ferroptosis Amplifier" hydrogel is thermally sensitive and achieves rapid gelation at the postsurgical wound in a breast tumor model. Specifically, gallocyanine, as the Dickkopf-1 (DKK1) inhibitor, can decrease the expression of SLC7A11 and GPX4 and synergistically induce ferroptosis of CSCs with GFP. Encouragingly, it is found that this combination suppresses the migratory and invasive capability of cancer cells via the downregulation of matrix metalloproteinase 7 (MMP7). The in vivo results further confirm that this "Ferroptosis Amplification" strategy is efficient in preventing tumor relapse and lung metastasis, manifesting an effective and promising postsurgical treatment for breast cancer.

PanIN or IPMN? Redefining Lesion Size in 3 Dimensions.

Pancreatic ductal adenocarcinoma (PDAC) develops from 2 known precursor lesions: a majority (∼85%) develops from pancreatic intraepithelial neoplasia (PanIN), and a minority develops from intraductal papillary mucinous neoplasms (IPMNs). Clinical classification of PanIN and IPMN relies on a combination of low-resolution, 3-dimensional (D) imaging (computed tomography, CT), and high-resolution, 2D imaging (histology). The definitions of PanIN and IPMN currently rely heavily on size. IPMNs are defined as macroscopic: generally >1.0 cm and visible in CT, and PanINs are defined as microscopic: generally <0.5 cm and not identifiable in CT. As 2D evaluation fails to take into account 3D structures, we hypothesized that this classification would fail in evaluation of high-resolution, 3D images. To characterize the size and prevalence of PanINs in 3D, 47 thick slabs of pancreas were harvested from grossly normal areas of pancreatic resections, excluding samples from individuals with a diagnosis of an IPMN. All patients but one underwent preoperative CT scans. Through construction of cellular resolution 3D maps, we identified >1400 ductal precursor lesions that met the 2D histologic size criteria of PanINs. We show that, when 3D space is considered, 25 of these lesions can be digitally sectioned to meet the 2D histologic size criterion of IPMN. Re-evaluation of the preoperative CT images of individuals found to possess these large precursor lesions showed that nearly half are visible on imaging. These findings demonstrate that the clinical classification of PanIN and IPMN fails in evaluation of high-resolution, 3D images, emphasizing the need for re-evaluation of classification guidelines that place significant weight on 2D assessment of 3D structures.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Low-level ambient ozone exposure associated with neutrophil extracellular traps and pro-atherothrombotic biomarkers in healthy adults.

BACKGROUND AND AIMS: Uncertainty of the causality determinations for ambient ozone (O3) on cardiovascular events is heightened by the limited understanding of the mechanisms involved in humans. We aimed to examine the pro-atherothrombotic impacts of O3 exposure and to explore the potential mediating roles of dysfunctional neutrophils, focusing on neutrophil extracellular traps (NETs). METHODS: A longitudinal panel study of 152 healthy adults was conducted in the cool to cold months with relatively low levels of O3 between September 2019 and January 2020 in Beijing, China. Four repeated measurements of indicators reflecting atherothrombotic balance and NETs were performed for each participant. RESULTS: Daily average exposure levels of ambient O3 were 16.6 µg/m3 throughout the study period. Per interquartile range increase in average concentrations of O3 exposure at prior up to 7 days, we observed elevations of 200.1-276.3% in D-dimer, 27.2-36.8% in thrombin-antithrombin complex, 10.8-60.3% in plasminogen activator inhibitor 1, 13.9-21.8% in soluble P-selectin, 16.5-45.1% in matrix metalloproteinase-8, and 2.4-12.4% in lipoprotein-associated phospholipase A2. These pro-atherothrombotic changes were accompanied by endothelial activation, lung injury, and immune inflammation. O3 exposure was also positively associated with circulating NETs indicators, including citrullinated histone H3, neutrophil elastase, myeloperoxidase, and double-stranded DNA. Mediation analyses indicated that NETs could mediate O3-associated pro-atherothrombotic responses. The observational associations remained significant and robust after controlling for other pollutants, and were generally greater in participants with low levels of physical activity. CONCLUSIONS: Ambient O3 exposure was associated with significant increases in NETs and pro-atherothrombotic potential, even at exposure levels well below current air quality guidelines of the World Health Organization.

Short-Term Effects of Primary and Secondary Particulate Matter on Ceramide Metabolism, Pro-Inflammatory Response, and Blood Coagulation.

Evidence of the precise biological pathway responsible for acute cardiovascular events triggered by particulate matter (PM) exposure from anthropogenic emissions is sparse. We investigated the associations of biomarkers relevant to the pathophysiology of atherothrombosis (ceramide metabolism, pro-inflammatory response, and blood coagulation) with primary and secondary components in particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5). A total of 152 healthy participants were followed with four repeated clinical visits between September 2019 and January 2020 in Beijing. Exposure to ambient inorganic aerosols (sulfate, nitrate, ammonium, and chloride), as well as organic aerosols (OA) in PM2.5, was measured by a real-time aerosol chemical speciation monitor, and sources of OA were performed by positive matrix factorization. We found significant increases of 101.9-397.9% in ceramide indicators associated with interquartile-range increases in inorganic aerosols and OA prior to 72 h of exposure. Higher levels of organic and inorganic aerosols in PM2.5 were associated with increases of 3.1-6.0% in normal T cells regulated upon activation and expressed and secreted relevant to the pro-inflammatory response; increases of 276.9-541.5% were observed in D-dimers relevant to coagulation. Detrimental effects were further observed following OA exposure from fossil fuel combustion. Mediation analyses indicated that ceramide metabolism could mediate the associations of PM2.5 components with pro-inflammatory responses. Our findings expand upon the current understanding of potential pathophysiological pathways of cardiovascular events posed by ambient particulates and highlight the importance of reducing primary and secondary PM from anthropogenic combustions.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

Effects of fertilizer application on the growth of Stranvaesia davidiana D. seedlings.

Wild plants represent a potential source of urban landscape trees. Stranvaesia davidiana Dcne. is a member of the Stranvaesia Lindl. Genus, which belongs to family Rosaceae Juss. It has great ornamental value. It can contribute to urban color foliage and fruit species. However, the most effective fertilizer application strategy required for its cultivation is unknown. Therefore, we conducted an orthogonal experiment to investigate the fertilizer type and level (pure nitrogen) using ten experimental groups, including an untreated control group. Pot experiments were used to determine the growth indices of seedlings, including plant height, basal diameter, and chlorophyll content post-fertilizer treatment. This study explored the most appropriate fertiler application model for the growth of S. davidiana seedlings. The results revealed that enhanced seedling growth depended on the type and amount of fertilizer used, and their interaction. Fertilizer application increased the plant height by 2.67 cm to 12.26 cm, basal diameter by 0.39 cm to 0.75 cm, and chlorophyll content by 5.66 to 19.86. Among the different types of fertilizer, organic fertilizer increased the plant height by 0.42 cm to 9.59 cm and basal diameter by 0.01 cm to 0.05 cm, compared with the control group. Organic fertilizer had the maximum effect on seedling growth, especially at medium levels. The total growth of basal diameter and chlorophyll content was 1.58 ± 0.04 cm and 39.53 ± 2.37, respectively. Basal diameter is the most critical index in seedling reproduction . The study results suggest that the application of 4.06 g of organic fertilizer per plant was the most effective, and served as a basis for further field trials.

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation and fibrosis are currently under clinical investigation. Nevertheless, the long-term ineffectiveness and remarkable adverse effects are well documented, and new concepts are required to tackle with the root causes of NASH progression. We critically assess the recently validated drug targets that regulate the systemic metabolism to ameliorate NASH. Thermogenesis promoted by mitochondrial uncouplers restores systemic energy expenditure. Furthermore, regulation of mitochondrial proteases and proteins that are pivotal for intracellular metabolic homeostasis normalize mitochondrial function. Secreted proteins also improve systemic metabolism, and NASH is ameliorated by agonizing receptors of secreted proteins with small molecules. We analyze the drug design, the advantages and shortcomings of these novel drug candidates. Meanwhile, the structural modification of current NASH therapeutics significantly increased their selectivity, efficacy and safety. Furthermore, the arising CRISPR-Cas9 screen strategy on liver organoids has enabled the identification of new genes that mediate lipid metabolism, which may serve as promising drug targets. In summary, this article discusses the in-depth novel mechanisms and the multidisciplinary approaches, and they provide new horizons to treat NASH.

Vanin1 (VNN1) in chronic diseases: Future directions for targeted therapy.

Vanin1 (VNN1) is an exogenous enzyme with pantetheinase activity that mainly exerts physiological functions through enzyme catalysis products, including pantothenic acid and cysteamine. In recent years, the crosstalk between VNN1 and metabolism and oxidative stress has attracted much attention. As a result of the ability of VNN1 to affect multiple metabolic pathways and oxidative stress to exacerbate or alleviate pathological processes, it has become a key component of disease progression. This review discusses the functions of VNN1 in glucolipid metabolism, cysteamine metabolism, and glutathione metabolism to provide perspectives on VNN1-targeted therapy for chronic diseases.

Ca & Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening.

Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment (TME), triple-negative breast cancer (TNBC) has been poorly responsive to immunotherapy so far. Herein, a Ca & Mn dual-ion hybrid nanostimulator (CMS) is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening, which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently. On one hand, glutathione (GSH) depletion and reactive oxygen species (ROS) generation can be achieved due to the mixed valence state of Mn in CMS. On the other hand, as an exotic Ca2+ supplier, CMS causes mitochondrial Ca2+ overload, which further amplifies the oxidative stress. Significantly, tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxidation (LPO). More impressively, CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway, which promotes polarization of tumor-associated macrophages (TAMs) and activation of dendritic cells (DCs) for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes (CTLs) into tumor tissues. Taken together, this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity, offering a new perspective for effective tumor immunotherapy of TNBC.

Direct degradation and stabilization of proteins: New horizons in treatment of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is featured with excessive hepatic lipid accumulation and its global prevalence is soaring. Nonalcoholic steatohepatitis (NASH), the severe systemic inflammatory subtype of NAFLD, is tightly associated with metabolic comorbidities, and the hepatocytes manifest severe inflammation and ballooning. Currently the therapeutic options for treating NASH are limited. Potent small molecules specifically intervene with the signaling pathways that promote pathogenesis of NASH. Nevertheless they have obvious adverse effects and show long-term ineffectiveness in clinical trials. It poses the fundamental question to efficiently and safely inhibit the pathogenic processes. Targeted protein degradation (TPD) belongs to the direct degradation strategies and is a burgeoning strategy. It utilizes the small molecules to bind to the target proteins and recruit the endogenous proteasome, lysosome and autophagosome-mediated degradation machineries. They effectively and specifically degrade the target proteins. It has exhibited promising therapeutic effects in treatment of cancer, neurodegenerative diseases and other diseases in a catalytic manner at low doses. We critically discuss the principles of multiple direct degradation strategies, especially PROTAC and ATTEC. We extensively analyze their emerging application in degradation of excessive pathogenic proteins and lipid droplets, which promote the progression of NASH. Moreover, we discuss the opposite strategy that utilizes the small molecules to recruit deubiquinases to stabilize the NASH/MASH-suppressing proteins. Their advantages, limitations, as well as the solutions to address the limitations have been analyzed. In summary, the innovative direct degradation strategies provide new insights into design of next-generation therapeutics to combat NASH with optimal safety paradigm and efficiency.

Rolling circle transcription: A new system to produce RNA microspheres for improving RNAi efficiency in an agriculturally important lepidopteran pest (Mythimna separate).

We applied a new RNA interference (RNAi) system using rolling circle transcription (RCT) technology to generate RNA microspheres (RMS) for targeting two key chitin synthetic pathway genes [chitin synthase A (CHSA), chitin synthase B (CHSB)] in the larvae of the oriental armyworm (Mythimna separate), a RNAi-unsusceptible agriculturally important lepidopteran pest. Feeding the third-instar larvae with the RMS-CHSA- or RMS-CHSB-treated corn leaf discs suppressed the expression of CHSA by 81.7% or CHSB by 88.1%, respectively, at 72 h. The silencing of CHSA consequently affected the larval development, including the reduced body weight (54.0%) and length (41.3%), as evaluated on the 7th day, and caused significant larval mortalities (51.1%) as evaluated on the 14th day. Similar results were obtained with the larvae fed RMS-CHSB. We also compared RNAi efficiencies among different strategies: 1) two multi-target RMS [i.e., RMS-(CHSA + CHSB), RMS-CHSA + RMS-CHSB], and 2) multi-target RMS and single-target RMS (i.e., either RMS-CHSA or RMS-CHSB) and found no significant differences in RNAi efficiency. By using Cy3-labeled RMS, we confirmed that RMS can be rapidly internalized into Sf9 cells (<6 h). The rapid cellular uptake of RMS accompanied with significant RNAi efficiency through larval feeding suggests that the RCT-based RNAi system can be readily applied to study the gene functions and further developed as bio-pesticides for insect pest management. Additionally, our new RNAi system takes the advantage of the microRNA (miRNA)-mediated RNAi pathway using miRNA duplexes generated in vivo from the RMS by the target insect. The system can be used for RNAi in a wide range of insect species, including lepidopteran insects which often exhibit extremely low RNAi efficiency using other RNAi approaches.

Moderating the link between discrimination and adverse mental health outcomes: Examining the protective effects of cognitive flexibility and emotion regulation.

Discrimination is associated with mental health problems. While prior research has demonstrated the significance of emotion regulation in explaining the onset and development of discrimination-related anxiety, few studies investigated this dynamic with cognitive flexibility among sexual and/or racial minority individuals. The current study incorporated cognitive flexibility to investigate its potential buffering effects on discrimination-related anxiety. 221 individuals, 37.6% of whom (n = 83) identified as sexual and/or racial minorities, responded to an online questionnaire about their levels of cognitive flexibility and emotion regulation, perceived discrimination, and anxiety. Moderated mediation analyses were conducted with these variables. Our findings indicated that emotion regulation difficulty (ERD) mediated the relationship between discrimination and anxiety, while cognitive flexibility had a strong moderating effect on the relationship between ERD and anxiety. These results suggested new research directions and implied the therapeutic potential of advancing cognitive flexibility skills with emotion regulation training in depression and anxiety intervention and treatments. Future research is needed to investigate cognitive flexibility as a transdiagnostic mechanism underlying the onset and development of anxiety, to potentially lead to novel prevention or intervention for marginalized people facing additional stressors like discrimination.

Exposure to ambient oxidant pollution associated with ceramide changes and cardiometabolic responses.

Evidence of impact of ambient oxidant pollution on cardiometabolic responses remains limited. We aimed to examine associations of oxidant pollutants with cardiometabolic responses, and effect modification by ceramides. During 2019-2020, 152 healthy adults were visited 4 times in Beijing, China, and indicators of ceramides, glucose homeostasis, and vascular function were measured. We found significant increases in ceramides of 13.9% (p = 0.020) to 110.1% (p = 0.005) associated with an interquartile increase in oxidant pollutants at prior 1-7 days. Exposure to oxidant pollutants was also related to elevations in insulin and reductions in adiponectin, and elevations in systolic and diastolic blood pressure. Further, stratified analyses revealed larger changes in oxidant pollutant related cardiometabolic responses among participants with higher ceramide levels compared to those with lower levels. Our findings suggested cardiometabolic effects associated with exposure to oxidant pollutants, which may be modified by ceramide levels.

Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination.

BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy.