DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control

Background: The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage. Results: We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53. Conclusions: Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.BiologySCI(E)10ARTICLEnull1

Isolation and extraction of glansreginin A from walnut meal and its effect on the proliferation of 3T3-L1 cells

Abstract Glansreginin A is an indicative component in walnut and is abundant in walnut meal. The aim of this study was to isolate and purify glansreginin A from the walnut meal, and to investigate the weight loss and lipid-lowering potential of glansreginin A by studying the effect of glansregin A on the proliferation of 3T3-L1 preadipocytes. Firstly, the response surface methodology was used to effectively improve the extraction yield of glansreginin A. The maximum extraction rate of glansreginin A was 0.363%, and the optimal extraction process conditions were determined. In addition, the lipid-lowering activity of glansreginin A was investigated by cell experiments. The results showed that glansreginin A could inhibit the proliferation of 3T3-L1 preadipocytes in a dose-dependent manner. And cell cycle of different groups of cells treated with glansreginin A was also measured using flow cytometry. The results showed most of the cells were blocked in G0/G1 phase and significantly decreased in S phase. These results suggest that glansreginin A could inhibit the proliferation of 3T3-L1 preadipocytes by causing cell cycle arrest. These findings provided a theoretical basis for the future research of glansreginin A and the development of slimming and fat-reducing foods

Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice

<p>Abstract</p> <p>Background</p> <p>Tumor-associated macrophages (TAMs) are the most abundant immune cells within the tumor stroma and play a crucial role in tumor development. Although clinical investigations indicate that high levels of macrophage (MΦ) infiltration into tumors are associated with a poor prognosis, the exact role played by TAMs during tumor development remains unclear. The present study aimed to investigate dynamic changes in TAM major histocompatibility complex (MHC) class II expression levels and to assess the effects of these changes on tumor progression.</p> <p>Results</p> <p>Significant inhibition of tumor growth in the murine hepatocellular carcinoma Hepa1-6 model was closely associated with partial TAM depletion. Strikingly, two distinct TAM subsets were found to coexist within the tumor microenvironment during Hepa1-6 tumor development. An MHC class II^hiTAM population appeared during the early phase of tumor development and was associated with tumor suppression; however, an MHC class II^lowTAM population became increasingly predominant as the tumor progressed.</p> <p>Conclusions</p> <p>Tumor progression was positively correlated with increasing infiltration of the tumor tissues by MHC class II^lowTAMs. Thus, targeting the transition of MΦ may be a novel strategy for drug development and immunotherapy.</p

Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy

Predictors of weight loss following an intentional weight loss intervention and long-term weight maintenance in overweight and obese young adults

Introduction: Obesity, a major global health concern, predisposes individuals to several comorbidities including coronary heart disease and diabetes. Although weight loss can be achieved through diet and exercise interventions, many individuals regain the weight. The aim of this study was to determine whether psychological and behavioral factors affect weight loss and long-term weight loss maintenance trajectories. Methods: Participants from the Slow the Adverse Vascular Effects of excess weight (SAVE) study, a 12-month, randomized trial of a weight loss and sodium reduction intervention, eligible for a 60-month follow-up visit were contacted. This group of 108 participants was categorized into two outcome groups relative to baseline weight: weight loss group (n=56) and weight gain group (n=52). Depressive symptoms, stress, anger, sleep, self-efficacy, physical activity and diet were measured at baseline and following the intervention and compared between the 2 groups. Linear mixed model analyses were conducted to 1) assess relationships between psychosocial or behavioral factors and weight reduction during the intervention period (baseline to 12-month) and 2) identify predictors of weight maintenance post intervention (12-month to 60-month). Results: The study group (N = 108) was predominantly female (74.1%) with a median age of 39.8 (35.4, 44.5) years. The average weight at baseline was 90.6 ± 14.0 kg and the median BMI was 32.0 kg/m2. Better sleep quality after adjustment for demographics, diet and physical activity (p<0.01) was associated with more weight loss during the intervention. Lower scores on the Beck Depression Inventory (p=0.04) and higher exercise self-efficacy (p=0.03) independently predicted better weight maintenance during the post intervention period adjusting for age, gender, race, income and education. Conclusion: Psychological and behavioral factors impacted the pattern of weight loss and weight maintenance during and after the intervention. Better sleep quality may predict greater weight loss and lower levels of depressive symptoms and higher exercise self-efficacy may be associated with better long-term weight maintenance in overweight and obese young adults. These findings illustrate the importance of a more tailored weight maintenance program focusing on psychological and behavioral factors to achieve successful weight loss and long-term weight maintenance, reducing the public health burden of obesity

The influence and application of SiC MOSFET driver modules in the contemporary power electronics industry

Technological progress has driven the rapid development of power electronics and enhanced the scale of the industry. SiC MOSFET devices have obvious advantages in applications such as high temperature resistance, high voltage resistance, and low switching loss. However, the different characteristics of such devices will bring related problems that seriously affect the reliability of the device and system. The drive circuit is effective in solving these problems with its small input resistance, parasitic inductance, and large enough drive voltage and current. Starting from the concept and related theoretical composition of SiC MOSFET driver module, this paper mainly analyses the impact of the driver module on the contemporary power electronics industry, and explains the application of the core research theory of the circuit to the industrial level. This paper also analyses the current situation of power electronics industry from the perspective of innovation theory, and looks forward to the prospect of power semiconductor devices

Risk factors associated with home care safety for older people with dementia: family caregivers’ perspectives

Abstract Background Many older people with dementia currently prefer home care; however, homes are neither professionally designed nor regulated like health care facilities, and home care is more prone to safety incidents. Many studies have examined home care safety for older people with dementia. However, factors contributing to safety incidents in home care have not been adequately considered. This study explored the risk factors for home care safety for older people with dementia based on the perspective of family caregivers. Methods This study used a qualitative research approach; a total of 24 family caregivers were interviewed face-to-face and semi-structured from February 2022 to May 2022, and the Colaizzi seven-step phenomenological research method was used to analyze the data and refine the themes. Results Safety risks in home care for older people with dementia stem from five areas: poor health of older people with dementia, dementia symptoms, unsafe home environment, the insufficient caring ability of family caregivers, and lack of safety awareness of family caregivers. Conclusion The risk factors for home care safety for older people with dementia are complex. And as the primary caregivers of older people with dementia, the caregiving ability and safety awareness of family caregivers primarily determine the safety of home care for older people with dementia. Therefore, when addressing home care safety for older people with dementia, the focus should be on providing targeted education programs and support services for family caregivers of older people with dementia

The perspectives of family caregivers of people with Alzheimer´s disease regarding advance care planning in China: a qualitative research

Abstract Objectives Advance care planning (ACP) enables people to define goals and preferences for future medical treatment and care. Despite universal recognition of the importance of ACP for people with Alzheimer´s disease (AD) internationally, there is little support for its implementation in China. The viewpoint of family caregivers is crucial in making clinical decisions about AD. Therefore, it’s critical to understand the family caregivers’ perspectives on ACP in order to promote its practice among people with AD in China. Methods Seventeen family caregivers of people with AD were purposively selected in three communities in Guangzhou. Semi-structured interviews were conducted to collect data and the data were analyzed using the thematic analysis. Results Three main themes were extracted: ①Attitudes toward ACP including positive and negative attitudes; ②Social pressure influencing ACP decision; ③Behavioral willingness of the implementation of ACP. Conclusions Attitudes, social pressure, and behavioral willingness characterized the behavioral intentions of family caregivers of people with Alzheimer’s disease. It is recommended to strengthen efforts to publicity of advance care planning and promote legislation in China