Correlation between cerebral neurotransmitters levels by proton magnetic resonance spectroscopy and HbA1c in patients with type 2 diabetes.

BACKGROUND: Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM). AIM: To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels. METHODS: A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy. RESULTS: The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-ß), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P < 0.05), whereas HOMA-ß was negatively correlated with the HbA1c level (P < 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P < 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P < 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P < 0.01) were independent predictors of poor glycemic control. CONCLUSION: The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.

Helicobacter pylori infection alters gastric microbiota structure and biological functions in patients with gastric ulcer or duodenal ulcer.

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with gastrointestinal diseases. Our preliminary studies have indicated that H. pylori infection had a significant impact on the mucosal microbiome structure in patients with gastric ulcer (GU) or duodenal ulcer (DU). AIM: To investigate the contributions of H. pylori infection and the mucosal microbiome to the pathogenesis and progression of ulcerative diseases. METHODS: Patients with H. pylori infection and either GU or DU, and healthy individuals without H. pylori infection were included. Gastric or duodenal mucosal samples was obtained and subjected to metagenomic sequencing. The compositions of the microbial communities and their metabolic functions in the mucosal tissues were analyzed. RESULTS: Compared with that in the healthy individuals, the gastric mucosal microbiota in the H. pylori-positive patients with GU was dominated by H. pylori, with significantly reduced biodiversity. The intergroup differential functions, which were enriched in the H. pylori-positive GU patients, were all derived from H. pylori, particularly those concerning transfer RNA queuosine-modification and the synthesis of demethylmenaquinones or menaquinones. A significant enrichment of the uibE gene was detected in the synthesis pathway. There was no significant difference in microbial diversity between the H. pylori-positive DU patients and healthy controls. CONCLUSION: H. pylori infection significantly alters the gastric microbiota structure, diversity, and biological functions, which may be important contributing factors for GU.

Causal effect analysis of estrogen receptor associated breast cancer and clear cell ovarian cancer.

BACKGROUND: Evidence indicates that the risk of developing a secondary ovarian cancer (OC) is correlated with estrogen receptor (ER) status. However, the clinical significance of the relationship between ER-associated breast cancer (BC) and clear cell ovarian cancer (CCOC) remains elusive. METHODS: Independent single nucleotide polymorphisms (SNPs) strongly correlated with exposure were extracted, and those associated with confounders and outcomes were removed using the PhenoScanner database. SNP effects were extracted from the outcome datasets with minor allele frequency > 0.01 as the filtration criterion. Next, valid instrumental variables (IVs) were obtained by harmonizing exposure and outcome effects and further filtered based on F-statistics (> 10). Mendelian randomization (MR) assessment of valid IVs was carried out using inverse variance weighted (IVW), MR Egger (ME), weighted median (WM), and multiplicative random effects-inverse variance weighted (MRE-IVW) methods. For sensitivity analysis and visualization of MR findings, a heterogeneity test, a pleiotropy test, a leave-one-out test, scatter plots, forest plots, and funnel plots were employed. RESULTS: MR analyses with all four methods revealed that CCOC was not causally associated with ER-negative BC (IVW results: odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.66-1.20, P = 0.431) or ER-positive BC (IVW results: OR = 0.99, 95% CI = 0.88-1.12, P = 0.901). F-statistics were computed for each valid IV, all of which exceeded 10. The stability and reliability of the results were confirmed by sensitivity analysis. CONCLUSIONS: Our findings indicated that CCOC dids not have a causal association with ER-associated BC. The absence of a definitive causal link between ER-associated BC and CCOC suggested a minimal true causal influence of ER-associated BC exposure factors on CCOC. These results indicated that individuals afflicted by ER-associated BC could alleviate concerns regarding the developing of CCOC, thereby aiding in preserving their mental well-being stability and optimizing the efficacy of primary disease treatment.

The attitudes of nonpsychiatric nurses towards mental disorders in China.

Background: Few studies have explored the associated factors of attitudes of nonpsychiatric nurses towards mental disorders. Therefore, this study is aimed to evaluate the attitudes of nonpsychiatric nurses towards mental disorders and especially explore the association between psychiatric clinical practice and these attitudes. Methods: A total of 1324 nonpsychiatric nurses and students majoring in nursing were recruited through an online questionnaire from December 2021 to March 2022 in Sichuan Province, China. Demographic information, personal care experience, psychiatric nursing education and the Community Attitudes towards the Mentally Ill (CAMI) were collected. A higher score indicates a stigmatizing attitude in the authoritarianism and social restrictiveness (SR) subscales and a positive attitude in the benevolence and community mental health ideology (CMHI) subscales. Multivariate linear regression was employed to analyze associated factors of attitudes towards mental disorders, and hierarchical linear regression was used to analyze the association between psychiatric clinical practice and the attitudes towards mental disorders. Results: Under the control of confounders, high education level, long residence in urban and personal care experience were positively correlated with score of authoritarianism and SR (p < 0.05), and negatively correlated with score of benevolence (p < 0.05). Long residence in urban and personal care experience were negatively correlated with score of CMHI (p < 0.05). Hierarchical linear regression analysis showed that after adjusting for demographic information, psychiatric clinical practice was associated with lower score of benevolence (B = -0.09, 95%CI = -0.17 ~ -0.003, p = 0.043) and CMHI (B = -0.09, 95%CI = -0.17 ~ -0.01, p = 0.027), but the initial associations between psychiatric clinical practice and authoritarianism, SR disappeared. Conclusions: High education level, long residence in urban, personal care experience and the psychiatric clinical practice were associated with the discrimination of nonpsychiatric nurses towards mental disorders. Further exploring practical strategies to optimize the psychiatric clinical practice experience of nonpsychiatric nurses could help improve their attitudes towards mental disorders.

Serum levels of vitamin B12 combined with folate and plasma total homocysteine predict ischemic stroke disease: a retrospective case-control study.

PURPOSE: This study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke. MATERIALS AND METHODS: This retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke. RESULTS: Serum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098-4.770), SVD (aOR = 4.471, 95% CI = 1.110-4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733-5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954-6.449), CEI (aOR = 2.809, 95% CI = 1.073-4.991), SVD (aOR = 5.376, 95% CI = 1.708-6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535-7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008-5.148), CEI (aOR = 2.212, 95% CI = 1.247-5.946), SVD (aOR = 2.957, 95% CI = 1.324-6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586-4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR. CONCLUSIONS: Vitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.

Clinical analysis of 23 cases of epidermoid cyst of testis in children.

OBJECTIVE: This study aims to examine the clinical characteristics and surgical management of pediatric testicular epidermoid cysts, thereby contributing to the existing body of knowledge pertinent to the diagnosis and therapeutic intervention s for this condition. METHODS: A retrospective analysis was conducted on the clinical records of 23 pediatric patients diagnosed with testicular epidermoid cysts, who were admitted to our institution between April 2013 and February 2024. Concurrently, a comprehensive review and analysis of pertinent literature were undertaken to augment the findings. RESULTS: The mean age at which the onset of epidermoid cysts was observed was 6.0 years. All cases were singular and unilateral. B-ultrasound diagnosis categorized 6 cases as epidermoid cysts, 11 as teratomas, and 6 as indeterminate, yielding a diagnostic sensitivity of 26.1%. All patients underwent testicle-sparing mass resection, and nine patients underwent rapid intraoperative frozen section analysis, revealing eight cases of testicular epidermoid cysts and one teratoma, with a diagnostic sensitivity of 88.89%. Postoperative histopathological examination confirmed the diagnosis of testicular epidermoid cyst. CONCLUSIONS: Pediatric testicular epidermoid cysts are an uncommon occurrence, primarily presenting as a painless scrotal mass, which can mimic the clinical features of malignant testicular tumors. Imaging modalities and histopathological assessment are pivotal in the diagnostic process for pediatric testicular epidermoid cysts. For cases where B-ultrasound is inconclusive, rapid intraoperative pathological examination should be considered.

Suicidal ideation and suicide attempts among students aged 12 to 24 after the lifting of COVID-19 restrictions in China: prevalence and associated factors.

Objective: To investigate the prevalence and associated factors of suicidal ideation and suicide attempts among adolescent and young adults in China from December 14, 2022 to February 28, 2023, when COVID-19 restrictions were lifted. Methods: Students in middle and high schools and colleges and universities in the province of Sichuan, China were asked to complete on-line cross-sectional surveys. Information was collected about sociodemographics, experiences related to the COVID-19 pandemic, suicidal ideation and suicide attempts. Participants also filled out the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 and the Social Support Rate Scale surveys. Factors associated with suicidal ideation or suicide attempts were explored using logistic regression. Results: Of the 82,873 respondents (aged 12 to 24 years), 21,292 (25.7%) reported having thought of suicide at least once in their lifetime, 10,382 (12.5%) reported having thought about suicide within the previous 12 months, and 1,123 (1.4%) reported having attempted it within the previous 12 months. Risk of lifetime suicidal ideation was higher among middle school students than among older students. Risk of suicidal ideation and risk of suicide attempts correlated directly with severity of symptoms of depression and anxiety, and inversely with level of social support. Greater risk of suicidal ideation and suicidal attempts was associated with: being female, living in an urban environment, attending a boarding school, currently being in love, having parents who divorced or remarried, having parents who exhibit non-authoritative parenting behavior, having higher family income, having been COVID-19 infected, having been quarantined for a long time, and being dissatisfied with one's education. Conclusions: Suicidal ideation and suicide attempts remain prevalent among young people in China. The potential associated factors identified in our study may be useful for targeting appropriate psychosocial interventions and developing mental health policies.

A study of latent profile analysis of empathic competence and factors influencing it in nursing interns: a multicenter cross-sectional study.

Background: Empathy, as one of the fundamental principles of nursing professionalism, plays a pivotal role in the formation and advancement of the nursing team. Nursing interns, as a reserve force within the nursing team, are of significant importance in terms of their ability to empathize. This quality is not only directly related to the degree of harmony in the nurse-patient relationship and the enhancement of patient satisfaction, but also plays a pivotal role in the promotion of the quality of nursing services to a new level. Aim: The objective of this study was to gain a deeper understanding of the current state of nursing interns' empathic abilities. To this end, we sought to examine empathic performance under different profile models and to identify the key factors influencing these profile models. Methods: The study utilized 444 nursing interns from 11 tertiary general hospitals in Inner Mongolia as research subjects. The study employed a number of research tools, including demographic characteristics, the Jefferson Scale of Empathy, and the Professional Quality of Life Scale. A latent profile model of nursing interns' empathy ability was analyzed using Mplus 8.3. The test of variability of intergroup variables was performed using the chi-square test. Finally, the influencing factors of each profile model were analyzed by unordered multi-categorical logistic regression analysis. Results: The overall level of empathy among nursing interns was found to be low, with 45% belonging to the humanistic care group, 43% exhibiting low empathy, and 12% demonstrating high empathy. The internship duration, empathy satisfaction, secondary traumatic stress, only child, place of birth, and satisfaction with nursing were identified as factors influencing the latent profiles of empathy in nursing interns (p < 0.05). Conclusion: There is considerable heterogeneity in nursing interns' ability to empathize. Consequently, nursing educators and administrators should direct greater attention to interns with lower empathy and develop targeted intervention strategies based on the influences of the different underlying profiles.

Peroxymonosulfate activation by cobalt-doped ferromanganese magnetic oxides through singlet oxygen and radical pathways for efficient sulfadiazine degradation.

In this paper, cobalt-doped MnFe2O4 (CMFO-0.4) with oxygen vacancies was successfully synthesised by the sol-gel method and applied as a high-performance catalyst for the activation of peroxomonosulfate (PMS). The catalyst showed an excellent catalytic effect for the degradation of sulfadiazine (SDZ) by activated PMS, and the degradation rate can reach 100% in 10 minutes. The effects of different conditions on the degradation of SDZ were investigated, and it was determined that the optimal concentrations of catalyst and PMS were 0.2 g L-1 and 1 mM, respectively, and had good degradation effects in the pH 5-11 range. Free radical quenching experiments, XPS, and electron paramagnetic resonance (EPR) analyses revealed the presence of hydroxyl radicals (˙OH), sulphate radicals (SO4˙-), singlet oxygen (1O2), and superoxide radicals (˙O2 -) in the CMFO-0.4/PMS system, with 1O2 being the main reactive oxygen species (ROS). In addition, CMFO-0.4 has good reusability and adaptability to the presence of other substances.

Burnout among care workers in long-term care institutions: a systematic review and meta-analysis protocol.

INTRODUCTION: Care workers play a fundamental role in delivering care services in long-term care institutions. Burnout has been found to have a negative impact on care recipients and organisations providing care. Little is known about the key factors associated with care workers' burnout. This systematic review aims to explore the prevalence, severity and correlates of burnout among care workers before and during COVID-19 pandemic. METHODS AND ANALYSIS: A five-stage framework outlined by Whittemore and Knafl will be used. The following databases will be used to identify relevant literature, including Medline (PubMed), EMBASE, Cochrane library, PsycINFO, CINAHL, Scopus and Web of Science. RevMan will be used to assist the meta-analysis. Heterogeneity of the included studies will be tested using the I 2 test. ETHICS AND DISSEMINATION: No ethics approval is required as this study only involves secondary data analysis. The findings will be published in peer-reviewed journals and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42024499178.

[Risk factors for recurrence of childhood acute lymphoblastic leukemia after treatment with the Chinese Children's Cancer Group ALL-2015 protocol]. / CCCG-ALL-2015æ–¹æ¡ˆæ²»ç–—å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— å¤å‘çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To investigate the cumulative incidence of recurrence (CIR) in children with acute lymphoblastic leukemia (ALL) after treatment with the Chinese Children's Cancer Group ALL-2015 (CCCG-ALL-2015) protocol and the risk factors for recurrence. METHODS: A retrospective analysis was conducted on the clinical data of 852 children who were treated with the CCCG-ALL-2015 protocol from January 2015 to December 2019. CIR was calculated, and the risk factors for the recurrence of B-lineage acute lymphoblastic leukemia (B-ALL) were analyzed. RESULTS: Among the 852 children with ALL, 146 (17.1%) experienced recurrence, with an 8-year CIR of 19.8%±1.6%. There was no significant difference in 8-year CIR between the B-ALL group and the acute T lymphocyte leukemia group (P>0.05). For the 146 children with recurrence, recurrence was mainly observed in the very early stage (n=62, 42.5%) and the early stage (n=46, 31.5%), and there were 42 children with bone marrow recurrence alone (28.8%) in the very early stage and 27 children with bone marrow recurrence alone (18.5%) in the early stage. The Cox proportional-hazards regression model analysis showed that positive MLLr fusion gene (HR=4.177, 95%CI: 2.086-8.364, P<0.001) and minimal residual disease≥0.01% on day 46 (HR=2.013, 95%CI: 1.163-3.483, P=0.012) were independent risk factors for recurrence in children with B-ALL after treatment with the CCCG-ALL-2015 protocol. CONCLUSIONS: There is still a relatively high recurrence rate in children with ALL after treatment with the CCCG-ALL-2015 protocol, mainly bone marrow recurrence alone in the very early stage and the early stage, and minimal residual disease≥0.01% on day 46 and positive MLLr fusion gene are closely associated with the recurrence of B-ALL.

Reflectivity and Angular Anisotropy of Liquid Crystal Microcapsules with Different Particle Sizes by Complex Coalescence.

Cholesteric liquid crystal microcapsules (CLCMs) are used to improve the stability of liquid crystals while ensuring their stimulus response performance and versatility, with representative applications such as sensing, anticounterfeiting, and smart fabrics. However, the reflectivity and angular anisotropy decrease because of the anchoring effect of the polymer shell matrix, and the influence of particle size on this has not been thoroughly studied. In this study, the effect of synthesis technology on microcapsule particle size was investigated using a complex coalescence method, and the effect of particle size on the reflectivity and angular anisotropy of CLCMs was investigated in detail. A particle size of approximately 66 µm with polyvinyl alcohol (PVA, 1:1) exhibited a relative reflectivity of 16.6% and a bandwidth of 20 nm, as well as a narrow particle size distribution of 22 µm. The thermosetting of microcapsules coated with PVA was adjusted and systematically investigated by controlling the mass ratio. The optimized mass ratio of microcapsules (66 µm) to PVA was 2:1, increasing the relative reflectivity from 16.6% (1:1) to 32.0% (2:1) because of both the higher CLCM content and the matching between the birefringence of the gelatin-arabic shell system and PVA. Furthermore, color based on Bragg reflections was observed in the CLCM-coated ortho-axis and blue-shifted off-axis, and this change was correlated with the CLCM particle size. Such materials are promising for anticounterfeiting and color-based applications with bright colors and angular anisotropy in reflection.

A Difluoromethylation Reagent: Access to Difluoromethyl Arenes through Palladium Catalysis.

A new radical difluoromethylation was developed by using inexpensive and readily available difluoroacetic anhydride and N-phenyl-4-methylbenzenesulfonamide for the first time. The reaction of arylboronic acids with the new difluoromethylation reagent, N-phenyl-N-tosyldifluoroacetamide, proceeded smoothly in the presence of palladium catalyst to provide difluoromethylarenes in satisfactory to excellent yields. The electronic property (electron-donating or electron-withdrawing) of the substituent linked to the aromatic ring did not considerably influence the reactivity of arylboronic acid. Various groups, including the synthetically useful functional groups Cl, CN, and NO2, were tolerated well under the current reaction conditions.

Efficient production of a highly active lysozyme from European flat oyster Ostrea edulis.

Lysozyme, an antimicrobial agent, is extensively employed in the food and healthcare sectors to facilitate the breakdown of peptidoglycan. However, the methods to improve its catalytic activity and secretory expression still need to be studied. In the present study, twelve lysozymes from different origins were heterologously expressed using the Komagataella phaffii expression system. Among them, the lysozyme from the European flat oyster Ostrea edulis (oeLYZ) showed the highest activity. Via a semi-rational approach to reduce the structural free energy, the double mutant Y15A/S39R (oeLYZdm) with the catalytic activity 1.8-fold greater than that of the wild type was generated. Subsequently, different N-terminal fusion tags were employed to enhance oeLYZdm expression. The fusion with peptide tag 6×Glu resulted in a remarkable increase in the recombinant oeLYZdm expression, from 2.81 × 103 U mL-1 to 2.11 × 104 U mL-1 in shake flask culture, and eventually reaching 2.05 × 105 U mL-1 in a 3-L fermenter. The work produced the greatest amount of heterologous oeLYZ expression in microbial systems that are known to exist. Reducing the structural free energy and employing the N-terminal fusion tags are effective strategies to improve the catalytic activity and secretory expression of lysozyme.

Dynamic Changes in Ion Channels during Myocardial Infarction and Therapeutic Challenges.

In different areas of the heart, action potential waveforms differ due to differences in the expressions of sodium, calcium, and potassium channels. One of the characteristics of myocardial infarction (MI) is an imbalance in oxygen supply and demand, leading to ion imbalance. After MI, the regulation and expression levels of K+, Ca2+, and Na+ ion channels in cardiomyocytes are altered, which affects the regularity of cardiac rhythm and leads to myocardial injury. Myocardial fibroblasts are the main effector cells in the process of MI repair. The ion channels of myocardial fibroblasts play an important role in the process of MI. At the same time, a large number of ion channels are expressed in immune cells, which play an important role by regulating the in- and outflow of ions to complete intracellular signal transduction. Ion channels are widely distributed in a variety of cells and are attractive targets for drug development. This article reviews the changes in different ion channels after MI and the therapeutic drugs for these channels. We analyze the complex molecular mechanisms behind myocardial ion channel regulation and the challenges in ion channel drug therapy.

ATP-elicited Cation Fluxes Promote Volume-regulated Anion Channel LRRC8/VRAC Transport cGAMP for Antitumor Immunity.

The cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells' cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-ß response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-ß response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-ß response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC's obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.

Gut-derived metabolite 3-methylxanthine enhances cisplatin-induced apoptosis via dopamine receptor D1 in a mouse model of ovarian cancer.

Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

Self-assembled carbon monoxide nanogenerators managing sepsis through scavenging multiple inflammatory mediators.

Sepsis, a life-threatening syndrome of organ damage resulting from dysregulated inflammatory response, is distinguished by overexpression of inflammatory cytokines, excessive generation of reactive oxygen/nitrogen species (RONS), heightened activation of pyroptosis, and suppression of autophagy. However, current clinical symptomatic supportive treatment has failed to reduce the high mortality. Herein, we developed self-assembled multifunctional carbon monoxide nanogenerators (Nano CO), as sepsis drug candidates, which can release CO in response to ROS, resulting in clearing bacteria and activating the heme oxygenase-1/CO system. This activation strengthened endogenous protection and scavenged multiple inflammatory mediators to alleviate the cytokine storm, including scavenging RONS and cfDNA, inhibiting macrophage activation, blocking pyroptosis and activating autophagy. Animal experiments show that Nano CO has a good therapeutic effect on mice with LPS-induced sepsis, which is manifested in hypothermia recovery, organ damage repair, and a 50% decrease in mortality rates. Taken together, these results illustrated the efficacy of multifunctional Nano CO to target clearance of multiple mediators in sepsis treatment and act against other refractory inflammation-related diseases.

Identification of the central role of RNA polymerase mitochondrial for angiogenesis.

Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.