Assessing the role of programmed cell death signatures and related gene TOP2A in progression and prognostic prediction of clear cell renal cell carcinoma.

Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Combination of click chemistry and Schiff base reaction: Post-synthesis of covalent organic frameworks as an immobilized metal ion affinity chromatography platform for efficient capture of global phosphopeptides in serum with chronic obstructive pulmonary disease.

Reasonable design and construction of functionalized materials are of great importance for the enrichment of global phosphopeptides. In this work, Ti4+ functionalized hydrophilic covalent organic frameworks by introducing glutathione (GSH) and 2,3,4-trihydroxy benzaldehyde (THBA) via click chemistry and Schiff base reaction (COF-V@GSH-THBA-Ti4+ ) was constructed and applied for selective enrichment of phosphopeptides in serum. Benefit from the high surface area, excellent hydrophilicity as well as regular mesoporous structure, COF-V@GSH-THBA-Ti4+ displayed high selectivity (molar ratio of 2000:1), low limit of detection (0.5 fmol), high load capacity (100.0 mg/g) and excellent size-exclusion effect (1:10000) for enrichment of phosphopeptides. For actual bio-sample analysis, 15 phosphopeptides assigned to 10 phosphoproteins with 16 phosphorylated sites and 33 phosphopeptides assigned to 25 phosphoproteins with 34 phosphorylated sites were detected from the serum of patients with chronic obstructive pulmonary disease (COPD), and normal controls. Biological processes and molecular functions analysis further disclosed the difference of serums with phosphoproteomics between COPD and normal controls.

Assessing professional behaviors: a self-administered scale for medical students during clerkships.

BACKGROUND: Medical professionalism is a core competency for medical students during clerkships for further professional development. Given that the behavior-based framework could provide clear insight and is easy to assess, the study aimed to create a self-administered scale to measure the professional behaviors of medical students during their clerkships. METHODS: A comprehensive literature review on medical professional behaviors in English or Chinese and Delphi interviews were used to develop the initial version of the Self-Administered Scale for Professional Behavior of Medical Students During Clerkships. The reliability and validity analysis based on a survey of medical students from China, Cronbach's α calculations, and Confirmatory Factor Analysis (CFA) specifically were conducted to finalize the scale. The associations of professional behaviors with gender, medical programs, and clerkship duration were examined using Wilcoxon rank-sum tests. RESULTS: We included 121 studies and extracted 57 medical professionalism assessment tools, initially forming a pool of 48 items. To refine these items, eighteen experts participated in two rounds of Delphi interviews, ultimately narrowing down the item pool to 24 items. A total of 492 participants effectively completed the questionnaire. One item was removed due to its correlated item-total correlation (CITC) value, resulting in a final scale containing 23 items with six domains: Respect, Altruism, Communication and Collaboration, Integrity, Duty, and Excellence. The overall Cronbach's alpha value was 0.98, ranging from 0.88 to 0.95 for each domain. The fit indices (χ2/df = 4.07, CFI = 0.96, TLI = 0.95, RMSEA = 0.08, and SRMR = 0.02) signified a good fit for the six-domain model. Medical students' professional behavior was significantly associated with gender (p = 0.03) and clerkship duration (p = 0.001). CONCLUSION: The scale was demonstrated to be reliable and valid in assessing the professional behaviors of Chinese medical students during clerkships.

The mediating role of psychological capital in the association between life satisfaction and depressive and anxiety symptoms among Chinese medical students during the COVID-19 pandemic: a cross-sectional study.

BACKGROUND: Although life satisfaction is a predictor of depressive and anxiety symptoms, the mechanisms underlying this association are poorly understood. This study examined how psychological capital (PsyCap), a positive psychological state, mediated the association between life satisfaction and depressive and anxiety symptoms among Chinese medical students during the COVID-19 pandemic. METHODS: A cross-sectional survey was conducted at three medical universities in China. A self-administered questionnaire was distributed to 583 students. Depressive symptoms, anxiety symptoms, life satisfaction, and PsyCap were measured anonymously. A hierarchical linear regression analysis was performed to explore the effects of life satisfaction on depressive and anxiety symptoms. Asymptotic and resampling strategies were used to examine how PsyCap mediates the association between life satisfaction and depressive and anxiety symptoms. RESULTS: Life satisfaction was positively associated with PsyCap and its four components. There were significant negative associations between life satisfaction, psychological capital, resilience, optimism, and depressive and anxiety symptoms among medical students. Self-efficacy was negatively associated with depressive and anxiety symptoms. Psychological capital (a×b = -0.3201, BCa 95% CI: -0.3899, -0.2446; a×b = -0.2749, BCa 95% CI: -0.3817, -0.1996), resilience (a×b = -0.2103, BCa 95% CI: -0.2727, -0.1580; a×b = -0.1871, BCa 95% CI: -0.2520, -0.1414), optimism (a×b = -0.2100, BCa 95% CI: -0.3388, -0.1150; a×b = -0.1998, BCa 95% CI: -0.3307, -0.0980), and self-efficacy (a×b = -0.0916, BCa 95% CI: 0.0048, 0.11629; a×b = 0.1352, BCa 95% CI: 0.0336, 0.2117) significantly mediated the association between life satisfaction and depressive and anxiety symptoms. LIMITATIONS: This was a cross-sectional study, and causal relationships between the variables could not be ascertained. Self-reported questionnaire instruments were used for data collection, which may have recall bias. CONCLUSIONS: Life satisfaction and PsyCap can be used as positive resources to reduce depressive and anxiety symptoms among third-year Chinese medical students during the COVID-19 pandemic. Psychological capital and its components (self-efficacy, resilience, and optimism) partially mediated the relationship between life satisfaction and depressive symptoms, and completely mediated the relationship between life satisfaction and anxiety symptoms. Therefore, improving life satisfaction and investing in psychological capital (especially self-efficacy, resilience, and optimism) should be included in the prevention and treatment of depressive and anxiety symptoms among third-year Chinese medical students. Additional attention is needed to pay for self-efficacy in such disadvantageous contexts.

Noninvasive Prediction of Ki-67 Expression in Hepatocellular Carcinoma Using Machine Learning-Based Ultrasomics: A Multicenter Study.

OBJECTIVES: To investigate the ability of ultrasomics to predict Ki-67 expression in hepatocellular carcinoma (HCC). METHODS: A total of 244 patients from three hospitals were retrospectively recruited (training dataset, n = 168; test dataset, n = 43; and validation dataset, n = 33). Lesion segmentation of the ultrasound images was performed manually by two radiologists. In total, 1409 ultrasomics features were extracted. Feature selection was conducted using the intra-class correlation coefficient, variance threshold, mutual information, and recursive feature elimination plus eXtreme Gradient Boosting. The support vector machine was combined with the learning curve and grid search parameter tuning to construct the clinical, ultrasomics, and combined models. The predictive performance of the models was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity and accuracy. RESULTS: The ultrasomics model performed well on the training, test, and validation datasets. The AUC (95% confidence interval [CI]) for these datasets were 0.955 (0.912-0.981), 0.861 (0.721-0.947), and 0.665 (0.480-0.819), respectively. The combination of ultrasomics and clinical features significantly improved model performance on all three datasets. The AUC (95% CI), sensitivity, specificity, and accuracy were 0.986 (0.955-0.998), 0.973, 0.840, and 0.869 on the training dataset; 0.871 (0.734-0.954), 0.750, 0.829, and 0.814 on the test dataset; and 0.742 (0.560-0.878), 0.714, 0.808, and 0.788 on the validation dataset, respectively. CONCLUSIONS: Ultrasomics was proved to be a potential noninvasive method to predict Ki-67 expression in HCC.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

Development of a UPLC-MS/MS method for the simultaneous determination of atorvastatin, 2-hydroxy atorvastatin, and naringenin in rat plasma and its application to pharmacokinetic interaction studies.

Recent studies have revealed that the combination therapy of atorvastatin (ATV) with naringenin (NG) can offer meaningful benefits in the treatment of hypercholesterolemia, while decreasing adverse side effects. To investigate whether there are pharmacokinetic interactions among ATV, its metabolite 2-hydroxy atorvastatin (2-ATV), and NG, in the current study, we developed and validated a simple, rapid, and specific UPLC-MS/MS method to simultaneously determine the concentrations of these analytes in the rat plasma. Sample preparation was performed using simple protein precipitation. Chromatographic analysis was carried out on an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) using gradient elution mode, and these three analytes were detected using a Xevo® TQD triple quadrupole tandem mass spectrometer, in the positive ion electrospray ionization interface. The developed method showed good linearity over the following concentrations in rat plasma samples: 3-1200 ng/ml (r = 0.9965) for ATV, 1.5-600 ng/ml (r = 0.9934) for 2-ATV, and 3-1200 ng/ml (r = 0.9964) for NG. The assays were validated and satisfied the acceptance criteria recommended by U.S. Food and Drug Administration guidelines. Upon successful application of the method to a pharmacokinetic interaction study, the results indicated that NG significantly enhanced the bioavailability of ATV and 2-ATV.

Dual-Signal Feature Spaces Map Protein Subcellular Locations Based on Immunohistochemistry Image and Protein Sequence.

Protein is one of the primary biochemical macromolecular regulators in the compartmental cellular structure, and the subcellular locations of proteins can therefore provide information on the function of subcellular structures and physiological environments. Recently, data-driven systems have been developed to predict the subcellular location of proteins based on protein sequence, immunohistochemistry (IHC) images, or immunofluorescence (IF) images. However, the research on the fusion of multiple protein signals has received little attention. In this study, we developed a dual-signal computational protocol by incorporating IHC images into protein sequences to learn protein subcellular localization. Three major steps can be summarized as follows in this protocol: first, a benchmark database that includes 281 proteins sorted out from 4722 proteins of the Human Protein Atlas (HPA) and Swiss-Prot database, which is involved in the endoplasmic reticulum (ER), Golgi apparatus, cytosol, and nucleoplasm; second, discriminative feature operators were first employed to quantitate protein image-sequence samples that include IHC images and protein sequence; finally, the feature subspace of different protein signals is absorbed to construct multiple sub-classifiers via dimensionality reduction and binary relevance (BR), and multiple confidence derived from multiple sub-classifiers is adopted to decide subcellular location by the centralized voting mechanism at the decision layer. The experimental results indicated that the dual-signal model embedded IHC images and protein sequences outperformed the single-signal models with accuracy, precision, and recall of 75.41%, 80.38%, and 74.38%, respectively. It is enlightening for further research on protein subcellular location prediction under multi-signal fusion of protein.

Association of pain management and positive expectations with psychological distress and spiritual well­being among terminally ill cancer patients admitted to a palliative care unit.

BACKGROUND: Although palliation of psycho-spiritual distress is of great importance in terminally ill cancer patients, there is a little information about screening patients who benefit from palliative care and identifying the cancer care targets. This study explored the relationship of pain management and positive expectations with depression, anxiety and spiritual well-being (SWB) in terminal cancer patients admitted to a palliative care unit. METHODS: Eighty-four terminal cancer inpatients were recruited from the Hospice Ward, Shengjing Hospital of China Medical University. Optimism and general self-efficacy (GSE) were evaluated at admission. Patients completed self-report questionnaires on SWB, depression, anxiety and pain both on admission and one week later. The repeated designed analysis of variance was used to explore the correlates of depression, anxiety and SWB (meaning, peace, faith). RESULTS: In our sample, only cancer pain diminished significantly one week later. For depression (p = 0.041) and faith (p = 0.013), there was a significant pain group (relieved vs. not relieved) × time interaction effect, such that those with satisfied pain control experienced the improved psycho-spiritual outcomes at 1 week. The relationship between positive expectations, peace and faith was also statistically significant, indicating that the improvement of peace or faith was significant in the low group of optimism and GSE. CONCLUSIONS: Our findings indicated that pain management lied at the center of depression and SWB, meaning that effective pain management may reduce depression, and improve SWB among terminal cancer patients. Moreover, positive expectations, especially for optimism, may be the new target for SWB-related intervention research. Palliative care nurse should require the identification of terminal cancer patients who may more benefit from short-term palliative care, and target them with effective cancer care.

Exploring Early Childhood Educators' Perceptions and Practices Towards Gender Differences in STEM Play: A Multiple-Case Study in China.

Various gender biases have been demonstrated in early childhood educators (ECEs) with unintentional preferential treatment provided to boys during STEM-related play activities. These biases could impact young girls' identity formation, resulting in continued underrepresentation of women in STEM domains in future. In China, however, little research has been conducted on how ECEs perceive gender equity of STEM fields. Consequently, this study aims to close this gap by investigating the educators' perceptions on and responses to gender differences in STEM play, drawing on the cultural-historical theory and incorporating feminist perspectives. Adopting a multiple-case study approach, this study collected perceptions and experiences of six Chinese in-service ECEs regarding STEM play and gender-related issues. The participants recognized and valued children's equal involvement in STEM play, but failed to preclude ingrained gender preconceptions, leading to contradictory beliefs and performs. Meanwhile, Chinese ECEs considered prejudices from the external environment and peer influence the main obstacles to gender inclusion. Inclusive practices and emphasises are thus discussed relating to ECEs' multiple roles in supporting gender-neutral environments for STEM play. These preliminary findings shed light on attaining gender equity in STEM within the context of a feminist discourse, and provide Chinese educators, leaders and even the educational system with pioneering information. However, further research on ECEs' underlying stereotypes and teaching practices is still warranted to examine future professional development possibilities, support ECEs in reducing obstacles to girls' STEM engagement, and ultimately create a welcoming and inclusive STEM play space for girls.

Tefluthrin: metabolism, food residues, toxicity, and mechanisms of action.

Tefluthrin is a Type I pyrethroid insecticide widely used all over the world. Residues of tefluthrin in various agricultural and animal-derived products may be related to potential human health risks. Tefluthrin metabolism in mammals involves hydrolysis of the ester bond to form cyclopropane acid and 4-methylbenzyl alcohol moieties, followed by oxidation. In this review manuscript, we provide crucial information regarding the toxicity of pyrethroids and propose natural antioxidants for amelioration poisoning in humans and animals. We call for the rational use of tefluthrin as an agrochemical product and for greater attention to the residual toxicity caused by tefluthrin in primary and succeeding crops. This greater attention is required given the global use of tefluthrin.

Nitroreductase-induced bioorthogonal ligation for prodrug activation: A traceless strategy for cancer-specific imaging and therapy.

Prodrug development is of great interest in cancer therapy. From bio-friendly standpoints, traceless prodrug activation would be an ideal approach for cancer treatment owning to the avoidance of byproduct which might induce side effects in living system. Here, we report a fully traceless strategy for cancer imaging and therapy via a metal-free bioorthogonal ligation triggered by nitroreductase (NTR) overexpressed in solid tumors. The reduction of nitro substrates to amines by NTR and further condensation of amines with aldehydes can be seamlessly combined to yield imine-based resveratrol (RSV) with water as the only byproduct. In comparison with RSV, this precursor exhibited not only the same level of anticancer efficiency both in vitro and in vivo under hypoxia, but also a high sensitivity to hypoxia and much lower perturbation towards normal cells, which holds a great potential of theranostic prodrug for cancer therapy.

Learning burnout and its association with perceived stress, social support, and the Big Five personality traits in Chinese medical students during the COVID-19 pandemic: a cross-sectional study.

BACKGROUND: Owing to the coronavirus disease 2019, medical learning burnout has attracted increasing attention in educational research. It has a serious negative impact on medical students and their service quality. This could impair the professional development of medical students; weaken their personal and professional quality; and lead to problems such as increased medical errors and reduced patient care quality and satisfaction. This study aimed to examine the effects of perceived stress, social support, and the Big Five personality traits on learning burnout among medical students. METHODS: In November 2021, a cross-sectional survey was conducted at three medical universities in China. A self-administered questionnaire was distributed to 616 third- year students. Learning burnout, perceived stress, social support, and the Big Five personality traits (neuroticism, extroversion, openness, agreeableness, and conscientiousness) were anonymously measured. A total of 583 students were included in the final sample. Hierarchical linear regression was performed to explore the effects of perceived stress, social support, and Big Five personality traits on medical students' learning burnout. RESULTS: Perceived stress was positively associated with learning burnout (emotional exhaustion: ß = 0.577, p < 0.001; cynicism: ß = 0.543, p < 0.001; low professional efficacy: ß = 0.455, p < 0.001) whereas social support was negatively related with it (low professional efficacy: ß = -0.319, p < 0.001). Neuroticism had a positive effect on emotional burnout (ß = 0.152, p = 0.009). Extraversion (ß = -0.116, p = 0.006) and conscientiousness (ß = -0.363, p < 0.001) had a negative effect on low professional efficacy. Agreeableness negatively affected emotional exhaustion (ß = -0.181, p < 0.001) and cynicism (ß = -0.245, p < 0.001) and positively affected low professional efficacy (ß = 0.098, p = 0.008). The associated factors together accounted for an additional variance of learning burnout (emotional exhaustion: 39.0%; cynicism: 36.8%; low professional efficacy: 48.7%). CONCLUSIONS: Social support is a positive resource for fighting medical students' burnout. Perceived stress was the strongest indicator of learning burnout. In addition to reducing perceived stress, developing extraversion, agreeableness, and conscientiousness should be included in burnout prevention and treatment strategies, particularly for medical students.

Ultra-high performance supercritical fluid chromatography-tandem mass spectrometry method for simultaneous determination of atorvastatin, 2-hydroxy atorvastatin, and tangeretin in rat plasma and its application to the pharmacokinetic study.

Recent studies strongly suggest that atorvastatin combination therapy with tangeretin could be beneficial in the treatment of hyperlipidemia. This study aimed to investigate the pharmacokinetic interactions among atorvastatin, its active metabolite 2-hydroxy atorvastatin, and tangeretin after oral administration of atorvastatin with tangeretin in rats. A rapid, selective, and sensitive assay was developed and validated based on ultra-high performance supercritical fluid chromatography-tandem mass spectrometry for the simultaneous measurement of atorvastatin, 2-hydroxy atorvastatin, and tangeretin concentrations in rat plasma. Chromatographic separation of the analytes was conducted on an ACQUITY Torus 1-AA column in gradient elution mode. The mass transition ion pairs were m/z 559.0→440.0 for atorvastatin, m/z 575.2→440.0 for 2-hydroxy atorvastatin, m/z 373.0→358.1 for tangeretin, and m/z 254.8→136.7 for daidzein (internal standard). Calibration curves showed good linear correlations at the following concentration range: 1-400 (r = 0.9952), 1-400 (r = 0.9980), and 3-1200 (r = 0.9945) for atorvastatin, 2-hydroxy atorvastatin, and tangeretin, respectively. The method was fully validated and satisfied the acceptance criteria recommended by the United States Food and Drug Administration. Finally, it was successfully applied in a pharmacokinetic study in rats to evaluate the pharmacokinetic behavior of atorvastatin, 2-hydroxy atorvastatin, and tangeretin.

CB1Rs in VMH neurons regulate glucose homeostasis but not body weight.

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.

The protective mechanism of resveratrol against hepatic injury induced by iron overload in mice.

Excessive iron deposition can produce toxicity. Liver, as the main storage site of iron, is more vulnerable to excessive iron than other organs. Many studies have found that Resveratrol (RES) can effectively eliminate oxygen free radicals and resist lipid peroxide damage. However, studies investigating the mechanism of how RES prevents liver injury induced by iron overload are few. This study aims to observe the protective effect of RES on liver injury induced by iron overload in mice. Mice, except for the control group, received an intraperitoneal injection of iron dextran (50 mg/kg) every morning. The L-RES and H-RES groups received intragastric administration of low- and high-concentration RES solutions (20 or 50 mg/kg). The deferoxamine (DFO) group was intraperitoneally injected with DFO (50 mg/kg), while the control and iron overload groups were intraperitoneally injected with the same amount of normal saline every afternoon. Two weeks after continuous administration, iron-overloaded mice treated with high and low doses of RES significantly improved liver injury (GOT and GPT) and decreased LDH activity and MDA content and increased SOD and GSH activities (P < 0.01). Morphological tests showed that RES treatment can reduce liver iron deposition and improve liver pathological changes in iron-overloaded mice. Furthermore, RES treatment caused a significant decrease in Ft expression (P < 0.01). In conclusion, RES can alleviate liver injury in iron-overloaded mice. The mechanism may be related to improve the antioxidant capacity and reduce excess iron in the liver.

Faster lipid ß-oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1α in human podocytes.

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced ß-oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p-ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh-RNA reduced lipid deposition induced by HG. Additionally, ACC2-shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2-shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC-1α is close related to the insulin metabolism pathway. ACC2-shRNA could restore the expression of SIRT1/PGC-1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX-527 counteracted the effect of ACC2-shRNA. Taken together, our data suggest that podocyte injury mediated by HG-induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC-1α.

Longitudinal changes in spiritual well-being and associations with emotional distress, pain, and optimism-pessimism: a prospective observational study of terminal cancer patients admitted to a palliative care unit.

PURPOSE: Although spiritual well-being (SWB) is gaining increasing attention within the international palliative care (PC) guidelines, a lack of insight exists into the correlates and course of SWB among cancer patients. We therefore conducted a prospective observational study to capture trend of SWB and to identify their predictors in Chinese inpatients with terminal cancer receiving short-term PC. METHODS: A prospective observational study was conducted of terminal cancer inpatients in the hospice ward, Shengjing Hospital of China Medical University. A total of 108 patients completed self-report questionnaires on Functional Assessment of Chronic Illness Therapy-Spiritual Well-being, Hospital Anxiety and Depression Scale, Numerical Rating Scales, and Life Orientation Scale-Revised anonymously at baseline; SWB, depression, anxiety, and pain were subsequently assessed at 1-week interval. Multilevel regression was used to analyze the temporal course and predictors of SWB. RESULTS: Patients' existential well-being (B = - 0.99, p = 0.008; 95%CI = - 1.72 to - 0.26) and meaning dimension (B = - 0.87, p < 0.001; 95% CI = - 1.29 to - 0.43) significantly decreased after admission to the PC unit, but peace and faith did not change over time. Increases in depression and pain were related to lower existential well-being, particularly in the meaning dimension. Optimism-pessimism moderated the linear trend of existential well-being and meaning domain, such that those with higher optimism and lower pessimism paired with a decrease in outcomes. CONCLUSIONS: Terminal cancer patients experienced worsening existential well-being, particularly in the meaning facet while hospitalized, indicating that PC should include content that targets the existential concerns of spirituality in China. These findings also supported the need for an integrated PC to address personality traits and emotional and physical distress in this population.

Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment.

BACKGROUND: Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. METHODS: We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. RESULTS: Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. CONCLUSIONS: Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.