Investigation on the mechanism of hepatotoxicity of dictamnine on juvenile zebrafish by integrating metabolomics and transcriptomics.

Dictamnine(DIC), as the key pharmacological component of the classical Chinese herbal medicine cortex dictamni, possesses multiple pharmacological activities such as anti-microbial, anti-allergic, anti-cancer, and anti-inflammatory activities, however it is also the main toxicant of cortex dictamni induced hepatic damage, yet the underlying molecular mechanisms causing hepatic damage are still largely unknown. With the purpose of explore possibilities hepatotoxicity of dictamnine in zebrafish and to identify the key regulators and metabolites involved in the biological process, we administered zebrafish to dictamnine at a sub-lethal dose (

Current developments of gene therapy in human diseases.

Gene therapy has witnessed substantial advancements in recent years, becoming a constructive tactic for treating various human diseases. This review presents a comprehensive overview of these developments, with a focus on their diverse applications in different disease contexts. It explores the evolution of gene delivery systems, encompassing viral (like adeno-associated virus; AAV) and nonviral approaches, and evaluates their inherent strengths and limitations. Moreover, the review delves into the progress made in targeting specific tissues and cell types, spanning the eye, liver, muscles, and central nervous system, among others, using these gene technologies. This targeted approach is crucial in addressing a broad spectrum of genetic disorders, such as inherited lysosomal storage diseases, neurodegenerative disorders, and cardiovascular diseases. Recent clinical trials and successful outcomes in gene therapy, particularly those involving AAV and the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated proteins, are highlighted, illuminating the transformative potentials of this approach in disease treatment. The review summarizes the current status of gene therapy, its prospects, and its capacity to significantly ameliorate patient outcomes and quality of life. By offering comprehensive analysis, this review provides invaluable insights for researchers, clinicians, and stakeholders, enriching the ongoing discourse on the trajectory of disease treatment.

VKH-like uveitis during donafenib therapy for hepatocellular carcinoma: a case report and review of the literature.

Background: The incidence of uveitis has risen with the use of targeted therapies, particularly prevalent in the administration of immune checkpoint inhibitors and MAP-kinase pathway inhibitors. We report the first case of VKH-like uveitis linked to Donafenib employed for the primary hepatocellular carcinoma, highlighting the necessity of ophthalmological follow-up in patients undergoing treatment with Donafenib. Case presentation: A 55-year-old man developed VKH-like symptoms, including sporadic white patches, tinnitus, headache, and mild bilateral vision reduction, after 18 months of treatment with Donafenib and Sintilimab for hepatocellular carcinoma. Based on ophthalmological examinations that fundus fluorescein angiography images demonstrating multiple focal areas of pinpoint hyperfluorescence, along with pooling indicative of neurosensory detachment and disc leakage in both eyes, choroid thickening in swept-source optical coherence tomography, and "sunset-glow" fundus appearance, a tentative diagnosis of VKH-like uveitis was made. Initially, his best-corrected visual acuity (BCVA) was 20/200 in the right eye and 20/80 in the left eye. Upon discontinuing Donafenib and starting a 3-month course of oral glucocorticoids, his BCVA improved to 20/30 in the right eye and 20/40 in the left eye. Conclusion: Targeted drugs have been commonly used for cancer treatment in recent years, but challenges of ocular side effects emerged gradually. To optimize patient outcomes, regular ophthalmological follow-ups are essential for those undergoing treatment with targeted therapies like Donafenib.

Programmed cell death in Helicobacter pylori infection and related gastric cancer.

Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.

Respiratory diseases and gut microbiota: relevance, pathogenesis, and treatment.

Preclinical evidence has firmly established a bidirectional interaction among the lung, gut, and gut microbiome. There are many complex communication pathways between the lung and intestine, which affect each other's balance. Some metabolites produced by intestinal microorganisms, intestinal immune cells, and immune factors enter lung tissue through blood circulation and participate in lung immune function. Altered gut-lung-microbiome interactions have been identified in rodent models and humans of several lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, asthma, etc. Emerging evidence suggests that microbial therapies can prevent and treat respiratory diseases, but it is unclear whether this association is a simple correlation with the pathological mechanisms of the disease or the result of causation. In this review, we summarize the complex and critical link between the gut microbiota and the lung, as well as the influence and mechanism of the gut microbiota on respiratory diseases, and discuss the role of interventions such as prebiotics and fecal bacteria transplantation on respiratory diseases. To provide a reference for the rational design of large-scale clinical studies, the direct application of microbial therapy to respiratory-related diseases can reduce the incidence and severity of diseases and accompanying complications.

Correlation of CT features of lung adenocarcinoma with sex and age.

This study aimed to retrospectively examine the computed tomography (CT) features of lung adenocarcinoma across different demographic groups. Preoperative chest CT findings from 1266 surgically resected lung adenocarcinoma cases were retrospectively analyzed. Lung adenocarcinomas were categorized based on CT characteristics into pure ground glass (pGGO), nodule-containing ground glass opacity (mGGO), and pure solid without containing ground glass opacity (pSD). These categories were correlated with sex, age, EGFR status, and five histopathological subtypes. The diameters of pGGO, mGGO, and pSD significantly increased across all patient groups (P < 0.05). Males exhibited a significantly higher proportion of pSD than females (P = 0.002). The mean diameters of pGGO and pSD were significantly larger in males than in females (P = 0.0017 and P = 0.043, respectively). The frequency of pGGO was higher in the younger age group (≤ 60 years) compared to the older group (> 60 years) for both males (P = 0.002) and females (P = 0.027). The frequency of pSD was higher in the older age group for both sexes. A linear correlation between age and diameter was observed in the entire cohort as well as in the male and female groups (P < 0.0001 for all groups). EGFR mutations were less frequent in pSD compared to pGGO (P = 0.0002) and mGGO (P < 0.0001). The frequency of lesions containing micropapillary components increased from pGGO to mGGO and pSD (P < 0.0001 for all). The frequency of lesions containing solid components also increased from pGGO to mGGO and pSD (P = 0.045, P < 0.0001, and P < 0.0001, respectively). The CT features of lung adenocarcinoma exhibit differences across genders and age groups. Male gender and older age are risk factors for lung adenocarcinoma growth.

Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. METHODS: 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. RESULTS: In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. CONCLUSIONS: FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

Impact of specialized nursing outpatient case management on post-coronary artery bypass grafting patients.

BACKGROUND: Some patients with coronary atherosclerotic heart disease experience major adverse cardiac events (MACE) and require readmission after Coronary Artery Bypass Grafting (CABG) surgery. This is often attributed to patients' unhealthy lifestyles and dietary habits, inadequate understanding of the disease, and poor disease management compliance. Thus, searching for more targeted nursing intervention models that can enhance patients' self-management abilities and reduce the risk of readmission after CABG surgery is significant. AIM: To observe the impact of specialized nursing outpatient case management on patients after CABG surgery. METHODS: A total of 103 patients who underwent CABG surgery in our hospital between April 2021 and April 2022 comprised the study sample. The patients were divided into two groups using an odd-even number grouping method. The control group received routine nursing care, while the case management group received specialized nursing outpatient case management. The differences in psychological status, adherence to medical treatment, self-care ability, knowledge mastery, quality of life scores, and the occurrence rate of MACE were compared between the two groups. RESULTS: After the intervention, the case management group had lower scores on the self-rating depression scale and self-rating anxiety scale and lower MACE rate, as well as higher scores for adherence to a healthy diet, medication adherence, good lifestyle habits, regular exercise, and timely follow-up, higher scores on the Coronary Heart Disease Self-Management Scale, higher scores for managing adverse habits, symptoms, emotional cognition, emergency response, disease knowledge, general lifestyle, and treatment adherence, higher scores for understanding coronary heart disease, recognizing the importance of medication adherence, understanding self-care points after CABG surgery, and being aware of post-CABG precautions, higher scores for physical well-being, disease condition, general health, social-psychological well-being, and work-related aspects (P < 0.05). CONCLUSION: Specialized nursing outpatient case management can enhance patient adherence to medical treatment, knowledge mastery, psychological well-being, and overall quality of life in patients after CABG surgery.

Factors correlating the expression of PD-L1.

OBJECTIVE: PD-L1 was an important biomarker in lung adenocarcinoma. The study was to confirm the most important factor affecting the expression of PD-L1 remains undetermined. METHODS: The clinical records of 1045 lung adenocarcinoma patients were retrospectively reviewed. The High-Resolution Computed Tomography (HRCT) scanning images of all the participants were analyzed, and based on the CT characteristics, the adenocarcinomas were categorized according to CT textures. Furthermore, PD-L1 expression and Ki67 index were detected by immunohistochemistry. All patients underwent EGFR mutation detection. RESULTS: Multivariate logistic regression analysis revealed that smoking (OR: 1.73, 95% CI: 1.04-2.89, p = 0.004), EGFR wild (OR: 1.52, 95% CI: 1.11-2.07, p = 0.009), micropapillary subtypes (OR: 2.05, 95% CI: 1.46-2.89, p < 0.0001), and high expression of Ki67 (OR: 2.02, 95% CI: 1.44-2.82, p < 0.0001) were independent factors which influence PD-L1 expression. In univariate analysis, tumor size > 3 cm and CT textures of pSD showed a correlation with high expression of PD-L1. Further analysis revealed that smoking, micropapillary subtype, and EGFR wild type were also associated with high Ki67 expression. Moreover, high Ki67 expression was observed more frequently in tumors of size > 3 cm than in tumors with ≤ 3 cm size as well as in CT texture of pSD than lesions with GGO components. In addition, multivariate logistic regression analysis revealed that only lesions with micropapillary components correlated with pSD (OR: 3.96, 95% CI: 2.52-5.37, p < 0.0001). CONCLUSION: This study revealed that in lung adenocarcinoma high Ki67 expression significantly influenced PD-L1 expression, an important biomarker for immune checkpoint treatment.

The impact of fear of cancer recurrence on the quality of life of breast cancer patients: A longitudinal study of the mediation effect of cortisol and hope.

OBJECTIVE: This longitudinal study sought to explore the impact of cortisol and hope levels on Fear of Cancer Recurrence (FCR) and Quality of Life (QOL) in a cohort of 552 breast cancer patients from three centers in Wuhan City. METHOD: A longitudinal study involving 552 breast cancer patients from three centers in Wuhan City utilized Chinese versions of the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), the Herth Hope Index (HHI), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Cortisol levels were measured thrice daily, and data was collected longitudinally three times. Data analysis was conducted using SPSS 26.0 and Mplus 8.3, employing a longitudinal path model constructed via the cross-lagged method. RESULTS: The results showed there were significant correlations between FCR, cortisol levels, and QOL at different time points. A significant mediating model was found with outcomes related to hope levels. Specifically, FCR predicted a decrease in hope levels (ß = -0.163, p < 0.001), which in turn led to a decrease in overall QOL (ß = -0.078, p < 0.001), with a mediation effect accounting for 10.34%. Although there were correlations between FCR, cortisol levels, and QOL at different time points, further analysis revealed that cortisol levels did not exhibit a mediating effect between the two (95% confidence interval: -0.002 to 0.001). CONCLUSION: This study demonstrated there were significant correlations among FCR, QOL, and hope levels. Considering hope as a crucial mediator between FCR and QOL, potential intervention strategies for optimizing the QOL of breast cancer patients are proposed.

Relationship between social support and self-care ability among patients with breast cancer during rehabilitation: The multiple mediating roles of resilience and depression.

AIMS: To identify the multiple mediating effects of resilience and depression between social support and self-care ability among patients with breast cancer during rehabilitation to provide reference for developing and implementing targeted interventions. DESIGN: A cross-sectional study reported according to the STROBE checklist. METHODS: A convenience sample of 320 patients with breast cancer during rehabilitation was recruited from one hospital in China. Data were collected from April to August 2022 using a self-report questionnaire, including the demographic and clinical information, Appraisal of Self-Care Agency Scale-Revised, Multidimensional Scale of Perceived Social Support, Connor-Davidson Resilience Scale-10 item, and Patient Health Questionnaire-9. The mediation analysis was conducted using the SPSS Process macro. RESULTS: Self-care ability was positively associated with social support (ß = .229) and resilience (ß = .290), and negatively associated with depression (ß = -.208). The relationship between social support and self-care ability was mediated by resilience and depression, respectively, and together in serial. The multiple mediating effects accounted for 34.0% of the total effect of social support on self-care ability. CONCLUSION: Our findings identify resilience and depression as multiple mediators between social support and self-care ability and highlight the important roles of social support, resilience and depression in improving self-care ability. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should pay great attention to the underlying mechanisms of how social support affects patients' self-care ability during breast cancer rehabilitation. Integrated intervention programmes targeted at enhancing social support, building resilience and alleviating depression might be beneficial to the improvement of self-care ability. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. REPORTING METHOD: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cross-sectional studies was applied to report the results.

Non-POEMS osteosclerotic multiple myeloma: Clinical characteristics and differential diagnosis.

Osteosclerosis in multiple myeloma (MM) is typically associated with rare POEMS syndrome, characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S). However, osteosclerosis in multiple myeloma (MM) without POEMS syndrome, defined as non-POEMS Osteosclerotic MM, is exceedingly rare. We report a 70-year-old man with rib pain, remarkably high bone mineral density and diffuse osteosclerosis. The diagnosis of non-POEMS osteosclerotic MM was confirmed by biopsy and aspiration of bone marrow through surgery. A literature review spanning from 1990 identified 12 cases of similar non-POEMS osteosclerotic MM, including 5 males and 7 females with a mean age of 59.7 ± 10.6 years. The non-POEMS osteosclerotic MM can be divided into two subtypes, the osteosclerotic lesion subtype and the diffuse osteosclerosis subtype. Absence of polyneuropathy and organomegaly are the main factors that differentiate non-POEMS osteosclerotic MM from POEMS. A hyperactive osteoblastic process might be the etiology of diffuse osteosclerosis. Further research is needed to understand its etiology and pathophysiology.

Shen Shuai II recipe improves renal hypoxia to attenuate renal injury in 5/6 renal ablation/infarction rats and effect evaluation using blood oxygenation level-dependent functional magnetic resonance imaging.

Background: Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Methods: Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Results: Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). Conclusion: The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.

Efficacy and safety of a combination treatment of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) in combination with chemotherapy have showed its benefits in clinical studies, and here we conducted a further evaluation on the safety and efficacy of this treatment strategy. METHODS: A systematic literature review was conducted in PubMed, Embase and Cochrane Library to identify clinical studies on ICIs and chemotherapy for metastatic breast cancer. The primary efficacy endpoints were progression-free survival (PFS) and overall survival (OS), and adverse events (AEs) were analyzed. Random or fixed effects models were used to estimate pooled Hazard ratio (HR), odds ratio (OR) and the data of 95% confidence interval (CI) depend on the Heterogeneity. Cochrane risk assessment tool was used to assess risk of bias. We also drew forest plots and funnel plots, respectively. RESULTS: Seven studies with intend-to-treat (ITT) population for 3255 patients were analyzed. ICIs pooled therapy showed clinical benefits compared with chemotherapy alone, improving PFS (HR = 0.81, 95% CI: 0.74-0.90) of patients with metastatic triple negative breast cancer (mTNBC), especially in patients with PD-L1-positive tumors. However, it had no effect on OS (HR = 0.92, 95% CI 0.85-1.01). Besides, mTNBC patients received pooled therapy were less frequently to have AEs (OR = 1.30, 95% CI: 1.09-1.54). In patients with metastatic Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer, pooled therapy showed no benefit for PFS (HR = 0.80, 95% CI: 0.50-1.28) and OS (HR = 0.87, 95% CI: 0.48-1.58). CONCLUSION: Pooled therapy had improved PFS in mTNBC patients, especially in patients with PD-L1-positive tumors, and it was less likely to cause grade ≥ 3 AEs.

Risk stratification by systemic manifestations secondary to hemodynamic disorders of patients with severe tricuspid regurgitation.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent disease that triggers systemic pathological changes including cardiac, respiratory, hepatic and digestive, hematopoietic, renal and skin issues. The burden of extra-cardiac manifestations has not been well described in TR patients and the clinical impact is unknown. METHODS: Patients with severe or more-than-severe TR during hospitalization, who did not have any previous cardiac procedures, hemodynamically significant congenital heart disease or concomitant severe aortic or mitral valve disease, were retrospectively analyzed. Pre-specified criteria and diagnosis of baseline characteristics were used to evaluate the presence of extra-cardiac manifestations secondary to TR after excluding comorbidities that may also lead to corresponding abnormalities. Extra-cardiac involvements encompass respiratory, hepatic and, digestive, renal, hematopoietic and dermatic system. Staging criteria are defined as no extra-cardiac system involvement in Stage 1, one in Stage 2, at least two extra-cardiac involvements in Stage 3 and any end-stage organ failure in Stage 4. A telephone follow-up was conducted to record the composite endpoint namely all-cause death or cardiac rehospitalization after the index hospitalization. RESULTS: A total of 258 patients were identified with a median age of 73 (interquartile range [IQR]: 62-83) years and 52.3% were female. Severe TR and more-than-severe TR patients accounted for 92.6% and 7.4% of the cohort. There were 20.5%, 27.5%, 37.6% and 14.3% of patients from Stage 1 to 4 respectively. The follow-up time was at a median of 251 (IQR: 183-324) days. TR Patients in Stage 3&4 were at an increased risk with borderline statistical significance to experience the composite endpoint compared to patients in Stage 1&2 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.0 to 3.7, P = 0.049). CONCLUSIONS: Approximately half of patients with at least severe TR presented with two or more extra-cardiac systemic manifestations, which may incur a 1.9-fold higher risk of all-cause death or cardiac rehospitalization than TR patients with one or less extra-cardiac involvement.

Multi-b-value DWI to evaluate the synergistic antiproliferation and anti-heterogeneity effects of bufalin plus sorafenib in an orthotopic HCC model.

BACKGROUND: Multi-b-value diffusion-weighted imaging (DWI) with different postprocessing models allows for evaluating hepatocellular carcinoma (HCC) proliferation, spatial heterogeneity, and feasibility of treatment strategies. We assessed synergistic effects of bufalin+sorafenib in orthotopic HCC-LM3 xenograft nude mice by using intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), a stretched exponential model (SEM), and a fractional-order calculus (FROC) model. METHODS: Twenty-four orthotopic HCC-LM3 xenograft mice were divided into bufalin+sorafenib, bufalin, sorafenib treatment groups, and a control group. Multi-b-value DWI was performed using a 3-T scanner after 3 weeks' treatment to obtain true diffusion coefficient Dt, pseudo-diffusion coefficient Dp, perfusion fraction f, mean diffusivity (MD), mean kurtosis (MK), distributed diffusion coefficient (DDC), heterogeneity index α, diffusion coefficient D, fractional order parameter ß, and microstructural quantity µ. Necrotic fraction (NF), standard deviation (SD) of hematoxylin-eosin staining, and microvessel density (MVD) of anti-CD31 staining were evaluated. Correlations of DWI parameters with histopathological results were analyzed, and measurements were compared among four groups. RESULTS: In the final 22 mice, f positively correlated with MVD (r = 0.679, p = 0.001). Significantly good correlations of MK (r = 0.677), α (r = -0.696), and ß (r= -0.639) with SD were observed (all p < 0.010). f, MK, MVD, and SD were much lower, while MD, α, ß, and NF were higher in bufalin plus sorafenib group than control group (all p < 0.050). CONCLUSION: Evaluated by IVIM, DKI, SEM, and FROC, bufalin+sorafenib was found to inhibit tumor proliferation and angiogenesis and reduce spatial heterogeneity in HCC-LM3 models. RELEVANCE STATEMENT: Multi-b-value DWI provides potential metrics for evaluating the efficacy of treatment in HCC. KEY POINTS: • Bufalin plus sorafenib combination may increase the effectiveness of HCC therapy. • Multi-b-value DWI depicted HCC proliferation, angiogenesis, and spatial heterogeneity. • Multi-b-value DWI may be a noninvasive method to assess HCC therapeutic efficacy.

Linking renal hypoxia and oxidative stress in chronic kidney disease: Based on clinical subjects and animal models.

This study aims to explore the relationships between renal function, hypoxia, and oxidative stress in chronic kidney disease (CKD). Seventy-six non-dialysis patients with CKD stages 1-5 and eight healthy subjects were included in the clinical research. They were divided into three groups: healthy subjects, CKD stages 1-3, and CKD stages 4-5. In the animal study, 16 rat models of CKD were established through 5/6 renal ablation/infarction (A/I) surgery, and 8 normal rats were split into 3 groups: Sham, CKD, and losartan groups. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) was used to measure cortical and medullary T2* values (COT2* and MET2*) in all subjects and rats to evaluate renal oxygenation. Biochemical indicators were used to assess renal function and antioxidant capacity. Furthermore, the effects of losartan on renal fibrosis, hypoxia, and oxidative stress were examined using immunoblotting, colorimetric, and fluorometric assays. The results demonstrated significant positive associations between COT2* and MET2* with estimated glomerular filtration rate (eGFR). Patients with CKD stages 4-5 showed significantly lower serum superoxide dismutase (SOD) levels, which also had positive correlations with eGFR, COT2*, and MET2*. Furthermore, losartan treatment resulted in improved renal function and fibrosis, leading to increased levels of COT2*, MET2*, and SOD levels in 5/6 A/I rats. This was accompanied by reduced levels of hypoxia-inducible factor-1 alpha (HIF-1α) and malondialdehyde. Furthermore, losartan restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and suppressed the expression of Kelch-like ECH-associated protein 1 (Keap1) in 5/6 A/I kidneys. The study indicates that decline in renal oxygenation and antioxidant capacity is associated with the severity of renal failure in CKD. Losartan can potentially alleviate renal hypoxia and oxidative stress in the treatment of CKD via Keap1-Nrf2/HO-1 pathway.

[Mechanism of acteoside in prevention and treatment of gouty arthritis based on liver metabolomics].

This study aims to reveal the effect of acteoside on gouty arthritis(GA) in rats based on liver metabolomics. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to search for the potential biomarkers and metabolic pathways. SD rats were randomly assigned into blank, model, colchicine(0.3 mg·kg~(-1)), and high-, medium-, low-dose(200, 100, and 50 mg·kg~(-1), respectively) acteoside groups(n=7). The rats were administrated once a day for 7 continuous days. Monosodium urate(MSU) was used to induce GA model in rats during administration. The degree of joint swelling and pathological changes of synovial tissue in rats were observed, and the levels of interleukin(IL)-1ß, IL-18 and tumor necrosis factor(TNF)-α in the synovial tissue of rats were measured. UPLC-Q-TOF-MS was employed to collect rat liver data, and Progenesis QI and EZ info were used for data analysis. Human Metabolomics Database(HMDB) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were employed to predict the potential biomarkers and metabolic pathways. The results showed that acteoside alleviated joint swelling, reduced synovial tissue damage, and lowered the levels of inflammatory cytokines in GA rats. A total of 19 common biomarkers were identified, 17 of which can be regulated by acteoside. Seven metabolic pathways were enriched, such as glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism, among which glycerophospholipid metabolism was strongly disturbed. The metabolomics analysis suggested that acteoside may down-regulate the expression of inflammatory cytokines and alleviate the symptoms of GA rats by regulating glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism. The findings provide a reference for future research and development of acteoside.

Utilization of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for noninvasive assessment of chronic kidney disease in type 2 diabetes.

BACKGROUNDS: Accumulating data demonstrated that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) of diffusion-weighted magnetic resonance imaging (DWI) was a better correlation with kidney fibrosis, tubular atrophy progression, and a predictor of kidney function evolution in chronic kidney disease (CKD). OBJECTIVES: We aimed to assess the value of ΔADC in evaluating disease severity, differential diagnosis, and the prognostic risk stratification for patients with type 2 diabetes (T2D) and CKD. METHODS: Total 119 patients with T2D and CKD who underwent renal MRI were prospectively enrolled. Of them, 89 patients had performed kidney biopsy for pathological examination, including 38 patients with biopsy-proven diabetic kidney disease (DKD) and 51 patients with biopsy-proven non-diabetic kidney disease (NDKD) and Mix (DKD + NDKD). Clinicopathological characteristics were compared according to different ΔADC levels. Moreover, univariate and multivariate-linear regression analyses were performed to explore whether ΔADC was independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR). The diagnostic performance of ΔADC for discriminating DKD from NDKD + Mix was evaluated by receiver operating characteristic (ROC) analysis. In addition, an individual's 2- or 5-year risk probability of progressing to end-stage kidney disease (ESKD) was calculated by the kidney failure risk equation (KFRE). The effect of ΔADC on prognostic risk stratification was assessed. Additionally, net reclassification improvement (NRI) was used to evaluate the model performance. RESULTS: All enrolled patients had a median ΔADC level of 86 (IQR 28, 155) × 10-6 mm2/s. ΔADC significantly decreased across the increasing staging of CKD (P < 0.001). Moreover, those with pathological-confirmed DKD has a significantly lower level of ΔADC than those with NDKD and Mix (P < 0.001). It showed that ΔADC was independently associated with eGFR (ß = 1.058, 95% CI = [1.002,1.118], P = 0.042) and UACR (ß = -3.862, 95% CI = [-7.360, -0.365], P = 0.031) at multivariate linear regression analyses. Besides, ΔADC achieved an AUC of 0.707 (71% sensitivity and 75% specificity) and AUC of 0.823 (94% sensitivity and 67% specificity) for discriminating DKD from NDKD + Mix and higher ESKD risk categories (≥50% at 5 years; ≥10% at 2 years) from lower risk categories (<50% at 5 years; <10% at 2 years). Accordingly, the optimal cutoff value of ΔADC for higher ESKD risk categories was 66 × 10-6 mm2/s, and the group with the low-cutoff level of ΔADC group was associated with 1.232 -fold (95% CI 1.086, 1.398) likelihood of higher ESKD risk categories as compared to the high-cutoff level of ΔADC group in the fully-adjusted model. Reclassification analyses confirmed that the final adjusted model improved NRI. CONCLUSIONS: ΔADC was strongly associated with eGFR and UACR in patients with T2D and CKD. More importantly, baseline ΔADC was predictive of higher ESKD risk, independently of significant clinical confounding. Specifically, ΔADC <78 × 10-6 mm2/s and <66 × 10-6 mm2/s would help to identify T2D patients with the diagnosis of DKD and higher ESKD risk categories, respectively.

MicroRNA-377-3p exacerbates chronic obstructive pulmonary disease through suppressing ZFP36L1 expression and inducing lung fibroblast senescence.

Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.