ATF3 as a response factor to regulate Cd-induced reproductive damage by activating the NRF2/HO-1 ferroptosis pathway.

Cadmium (Cd) has garnered significant attention due to reproductive toxicity in inducing ferroptosis. However, the specific mechanisms underlying Cd-induced germ cell ferroptosis remain poorly understood. This study aimed to systematically explore the molecular mechanisms of germ cell ferroptosis by investigating differential changes in transcription factors and proteins in male mice treated orally with CdCl2 (0.5 g/L) reaching postnatal day 60, alongside Leydig cell (TM3) and Sertoli cell (TM4) lines. Results demonstrated that Cd exposure led to increased iron overload and oxidative stress in mouse testes, disrupted intracellular mitochondrial morphology characteristic of ferroptosis. RNA sequencing revealed significant upregulation of Atf3 and Hmox1 in Cd-exposed germ cells, along with increased expression of ATF3 and HO-1. Intervention in ferroptosis or HO-1 effectively rescued cells from Cd-induced mortality by breaking the detrimental cycle between lipid peroxidation and HO-1 activation. Further findings showed that NRF2 and HO-1 expression was notably elevated upon ATF3 overexpression in TM3 and TM4 cells, activating the Keap1-Nrf2 pathway and triggering ferroptosis in testes, whereas NRF2 and HO-1 expression levels were reversed when ATF3 was silenced. This study provides novel insights into ATF3-mediated NRF2/HO-1 signaling in Cd-induced mitochondrial ferroptosis in testes, shedding light on the mechanisms underlying Cd-induced ferroptosis and testicular injury.

Restriction-induced time-dependent transcytolemmal water exchange: Revisiting the Kӓrger exchange model.

The Kӓrger model and its derivatives have been widely used to incorporate transcytolemmal water exchange rate, an essential characteristic of living cells, into analyses of diffusion MRI (dMRI) signals from tissues. The Kӓrger model consists of two homogeneous exchanging components coupled by an exchange rate constant and assumes measurements are made with sufficiently long diffusion time and slow water exchange. Despite successful applications, it remains unclear whether these assumptions are generally valid for practical dMRI sequences and biological tissues. In particular, barrier-induced restrictions to diffusion produce inhomogeneous magnetization distributions in relatively large-sized compartments such as cancer cells, violating the above assumptions. The effects of this inhomogeneity are usually overlooked. We performed computer simulations to quantify how restriction effects, which in images produce edge enhancements at compartment boundaries, influence different variants of the Kӓrger-model. The results show that the edge enhancement effect will produce larger, time-dependent estimates of exchange rates in e.g., tumors with relatively large cell sizes (>10 µm), resulting in overestimations of water exchange as previously reported. Moreover, stronger diffusion gradients, longer diffusion gradient durations, and larger cell sizes, all cause more pronounced edge enhancement effects. This helps us to better understand the feasibility of the Kärger model in estimating water exchange in different tissue types and provides useful guidance on signal acquisition methods that may mitigate the edge enhancement effect. This work also indicates the need to correct the overestimated transcytolemmal water exchange rates obtained assuming the Kärger-model.

Effect of vascular compression and drug injection time on thrombolytic therapy: Numerical simulation and validation.

Venous thromboembolism (VTE) has been occurring frequently in human society. There is an urgent need to study the influence of several factors on thrombolytic therapy, such as the effects of vascular pressure levels (VPL) and the drug injection time (DIT). Considering blood as a non-Newtonian fluid, valve as a hyperelastic material, and thrombus as a porous medium, a new numerical simulation model of biofluid mechanics incorporating fluid-solid coupling phenomena and biochemical substance reactions is established based on the N-S equations and the convection-diffusion reaction equations. Then, a unique in vitro experimental platform is established to verify the correctness of the constructed mathematical model. The results showed that vascular compression resulted in significant differences in blood flow status localized within the vessel. Vascular compression causes the blood boosting index to fluctuate and the valve displacement values are 135% and 158% greater than the lower VPL, respectively. At the same time, vascular compression weakened vortex intensity, accelerated material transport and response, and improved the treatment. Compared with low VPL, the therapeutic efficacy increased by 7% and 15%, respectively. In addition, when the dose of the drug is high, different injection times can increase the therapeutic effect to different degrees, with a maximum difference of 12%. Our in vitro experiments are similar to the results obtained by numerical simulation, which can verify the reliability of numerical simulation. The computational model proposed and the experimental platform designed in this study have the potential to assist in clinical medication prediction in different venous thromboembolism patients.

Research hotspots and trends of epigenetic therapy in oncology: a bibliometric analysis from 2004 to 2023.

Background: Epigenetics denotes heritable alterations in gene expression patterns independent of changes in DNA sequence. Epigenetic therapy seeks to reprogram malignant cells to a normal phenotype and has been extensively investigated in oncology. This study conducts a bibliometric analysis of epigenetic therapy in cancer, providing a comprehensive overview of current research, identifying trends, and highlighting key areas of investigation. Methods: Publications concerning epigenetic inhibitors in cancer spanning 2004 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). Co-occurrence analysis using VOSviewer assessed current status and focal points. Evolutionary trends and bursts in the knowledge domain were analyzed using CiteSpace. Bibliometrix facilitated topic evolution and revealed trends in keywords. National, institutional, and author affiliations and collaborations were also examined. Results: A total of 2,153 articles and reviews on epigenetic therapy in oncology were identified, demonstrating a consistent upward trend over time. The United States (745 papers), University of Texas MD Anderson Cancer Center (57 papers), and Stephen B. Baylin (27 papers) emerged as the most productive country, institution, and author, respectively. Keyword co-occurrence analysis identified five primary clusters: tumor, DNA methylation, epigenetic therapy, expression, and immunotherapy. In the past 5 years, newly emerging themes with increased centrality and density include "drug resistance," "immunotherapy," and "combination therapy." The most cited publication reviewed current understanding of potential causes of epigenetic diseases and proposed future therapeutic strategies. Conclusion: In the past two decades, the importance of epigenetic therapy in cancer research has become increasingly prominent. The United States occupies a key position in this field, while China, despite having published a large number of related papers, still has relatively limited influence. Current research focuses on the "combination therapy" of epigenetic drugs. Future studies should further explore the sequencing and scheduling of combination therapies, optimize trial designs and dosing regimens to improve clinical efficacy.

Therapeutic potential of Shaoyao Gancao Decoction in mitigating anti-tuberculosis drug-induced liver injury through Nrf-2/HO-1/NF-κB signaling.

Tuberculosis (TB) is a persistent global health issue, evidenced by an increasing number of cases. Although anti-TB drugs have proven efficacy, they are often associated with severe liver injury (ATB-DILI). The objective of this research was to uncover the mechanisms through which Shaoyao Gancao Decoction (SGD) mitigates ATB-DILI, emphasizing the role of the Nrf-2/HO-1/NF-κB signaling pathway. We prepared SGD granules and subjected them to HPLC-MS/MS for analysis. An ATB-DILI rat model was then developed and administered SGD. We evaluated liver injury markers, the extent of oxidative stress, inflammation, and the principal proteins involved in the Nrf-2/HO-1/NF-κB pathway. Additionally, network pharmacology techniques were utilized to discern potential SGD targets and their associated pathways. Administering SGD had a notable effect in counteracting the elevation of liver injury markers and pathological alterations induced by ATB-DILI. Moreover, there was a marked reduction in oxidative stress and inflammation in the treated rats. We identified 12 active compounds in SGD, with 88 shared targets between SGD and ATB-DILI. Subsequent KEGG analysis brought attention to pathways like MAPK, NF-κB, and IL-17 signaling. Our findings pave the way for more in-depth studies into the application of SGD in treating drug-induced liver injuries.

Promotion or prevention: regulatory foci as moderators in the job demands-resources model.

BACKGROUND: Building on the job demands-resources (JD-R) model and regulatory focus theory, this study examined how regulatory foci shaped the effects of different job demands and resources on both negative and positive workplace outcomes among medical staff. METHODS: Two independent studies (NStudy 1 = 267; NStudy 2 = 350) were designed for cross-validation. Participants completed a battery of measures evaluating job demands (workload, emotional demands, interpersonal stress), job resources (psychological safety, perceived organizational support, servant leadership), and well-being (job burnout, affective commitment, job satisfaction). RESULTS: Multiple linear regression analyses showed employees' well-being was affected by job demands and resources through energetic and motivational processes, respectively. The deleterious effect of emotional demands on job burnout was pronounced in individuals with weak prevention focus (B = 0.392, standard error [SE] = 0.069, p < .001). Psychological safety (Study 1) and servant leadership (Study 2) had stronger positive associations with motivational outcomes among individuals with weak promotion focus than those with strong promotion focus (B = 0.394, SE = 0.069, p < .001; B = 0.679, SE = 0.121, p < .001; and B = 0.476, SE = 0.072, p < .001, respectively). CONCLUSION: We used two samples to examine and cross-validate the joint effects of job characteristics and personal traits on workplace well-being among Chinese medical staff. Although heterogenous, the results showed regulatory foci were especially important in determining the effects of job demands and resources on well-being when there was (autonomous) self-regulation in the workplace.

Acute T-cell lymphoblastic leukemia: chimeric antigen receptor technology may offer a new hope.

Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment.

Comprehensive characterization of tumor therapeutic response with simultaneous mapping cell size, density, and transcytolemmal water exchange.

Early assessment of tumor therapeutic response is an important topic in precision medicine to optimize personalized treatment regimens and reduce unnecessary toxicity, cost, and delay. Although diffusion MRI (dMRI) has shown potential to address this need, its predictive accuracy is limited, likely due to its unspecific sensitivity to overall pathological changes. In this work, we propose a new quantitative dMRI-based method dubbed EXCHANGE (MRI of water Exchange, Confined and Hindered diffusion under Arbitrary Gradient waveform Encodings) for simultaneous mapping of cell size, cell density, and transcytolemmal water exchange. Such rich microstructural information comprehensively evaluates tumor pathologies at the cellular level. Validations using numerical simulations and in vitro cell experiments confirmed that the EXCHANGE method can accurately estimate mean cell size, density, and water exchange rate constants. The results from in vivo animal experiments show the potential of EXCHANGE for monitoring tumor treatment response. Finally, the EXCHANGE method was implemented in breast cancer patients with neoadjuvant chemotherapy, demonstrating its feasibility in assessing tumor therapeutic response in clinics. In summary, a new, quantitative dMRI-based EXCHANGE method was proposed to comprehensively characterize tumor microstructural properties at the cellular level, suggesting a unique means to monitor tumor treatment response in clinical practice.

Enhancing nitrate removal from small wetlands via regulating bacterial-algal symbiosis with macrophyte coverage.

With increasing land resource constraints, wetlands, as ecological hotspots, are expected to enhance biogeochemical processes to mitigate nitrogen (N) pollution, particularly nitrate-nitrogen (NO3--N). However, the interactions among bacteria, algae, and macrophytes in wetlands, which are crucial for N removal, remain largely unknown. This study explored how macrophyte coverage influences bacterial-algal interactions, shifting from mutualism to inhibition, thereby affecting N removal. Moderate coverage enhanced NO3--N and total nitrogen (TN) removal (P < 0.05), which was correlated with increased microbial abundance (P < 0.05). This may have resulted from moderate algal photosynthesis, reduced physiological stress, and the expansion of ecological niches for microbes. Insufficient coverage promoted algal growth (chlorophyll-a > 31.8 µg·L-1), leading to increased competition for substrates and elevated pH, which further inhibited bacterial activity. Excessive coverage also inhibited bacterial activity by reducing illumination and oxidation-reduction potential. Consequently, insufficient and excessive coverage decreased N removal efficiencies by 2.7-15.7 % (NO3--N) and 3.7-11.1 % (TN) while increasing methane emission potential by 1.4-6.9 times compared with moderate coverage. These findings offer insights into solving NO3--N contamination using near-natural methods and balancing the ecological and practical considerations for small wetlands.

Clinical and virological characteristics of coexistent hepatitis B surface antigen and antibody in treatment-naive children with chronic hepatitis B virus infection.

Serological pattern of simultaneous positivity for hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) is considered a specific and atypical phenomenon among patients with chronic hepatitis B virus (HBV) infection, especially in pediatric patients. Unfortunately, there is limited understanding of the clinical and virological characteristics among children having chronic HBV infection and the coexistence of HBsAg and anti-HBs. Hence, our objective was to determine the prevalence of coexistent HBsAg and anti-HBs and to explore the associated clinical and virological features in this patient population. The researchers conducted a retrospective cohort study on the 413 pediatric patients with chronic HBV infection from December 2011 to June 2022. The patients were stratified into two groups based on their anti-HBs status. Demographic, serum biochemical and virological parameters of two group were compared. Of the total 413 enrolled subjects, 94 (22.8%) were tested positive for both HBsAg and anti-HBs. Patients with anti-HBs were younger and demonstrated significantly higher ratio of albumin to globulin (A/G), elevated serum levels of alanine transaminase (ALT), lower ratio of aspartate transaminase (AST)/ALT (AST/ALT) and reduced serum levels of globulin, HBsAg and HBV DNA, Additionally, these patients were more likely to show coexistent HBeAg and anti-HBe when compared to patients without anti-HBs. The results of multivariate logistical analysis revealed that AST/ALT, serum levels of globulin and HBsAg were negatively associated with coexistence of HBsAg and anti-HBs. Our data demonstrated a considerable prevalence of coexisting HBsAg and anti-HBs in pediatric patients. Children with this specific serological pattern were commonly of a younger age, seemly predisposing them to early liver impairment and lower HBV replication activity.