β-Arrestin1 Mediates the Endocytosis and Functions of Macrophage Migration Inhibitory Factor

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, regulating inflammatory and immune responses. MIF binds to cell surface receptor CD74, resulting in both rapid and sustained ERK activation. It was reported that MIF-induced rapid ERK activation requires its co-receptor CD44. But the exact mechanism underlying sustained ERK activation is not well understood. In the current study, we described a detailed mechanism of MIF mediated sustained ERK activation. We found that β-arrestin1, a scaffold protein involved in the activation of the MAPK cascade, interacts with CD74 upon MIF stimulation, resulting in CD74-mediated MIF endocytosis in a chlorpromazine (CPZ)-sensitive manner. β-arrestin1 is also involved in endocytotic MIF signaling, leading to sustained ERK activation. Therefore β-arrestin1 plays a central role in coupling MIF endocytosis to sustained ERK activation

Toward a Country-Based Prediction Model of COVID-19 Infections and Deaths Between Disease Apex and End: Evidence From Countries With Contained Numbers of COVID-19

The complexity of COVID-19 and variations in control measures and containment efforts in different countries have caused difficulties in the prediction and modeling of the COVID-19 pandemic. We attempted to predict the scale of the latter half of the pandemic based on real data using the ratio between the early and latter halves from countries where the pandemic is largely over. We collected daily pandemic data from China, South Korea, and Switzerland and subtracted the ratio of pandemic days before and after the disease apex day of COVID-19. We obtained the ratio of pandemic data and created multiple regression models for the relationship between before and after the apex day. We then tested our models using data from the first wave of the disease from 14 countries in Europe and the US. We then tested the models using data from these countries from the entire pandemic up to March 30, 2021. Results indicate that the actual number of cases from these countries during the first wave mostly fall in the predicted ranges of liniar regression, excepting Spain and Russia. Similarly, the actual deaths in these countries mostly fall into the range of predicted data. Using the accumulated data up to the day of apex and total accumulated data up to March 30, 2021, the data of case numbers in these countries are falling into the range of predicted data, except for data from Brazil. The actual number of deaths in all the countries are at or below the predicted data. In conclusion, a linear regression model built with real data from countries or regions from early pandemics can predict pandemic scales of the countries where the pandemics occur late. Such a prediction with a high degree of accuracy provides valuable information for governments and the public

<i>Trans</i>-vaccenic acid reprograms CD8⁺ T cells and anti-tumour immunity

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP–PKA–CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours

The Effect of aerobic exercise interventions on depression and depressive disorder in elderly. : A descriptive literature review

Background: Depression manifests as neurological and psychiatric disorders.Depression is a kind of emotional disorder accompanied by mental retardation symptoms,but also can lead to a variety of functional physical disorders.It can be gradual, can besudden.Its development process varies from person to person, affects people'spsychological and physiological, decreases people's quality of life.Depression is theleading cause of death among the elderly, and the prevalence rate is rising rapidly. Somestudies have shown that aerobic exercise interventions can decrease depression anddepressive disorder in elderly.Aim: To describe the effect of aerobic exercise intervention on depression anddepressive disorder in the elderly.Method: Quantitative literature search was conducted using keywords input fromPubMed and CINAHL databases to understand the influence of aerobic exerciseintervention on depression and depressive disorder in the elderly, and the results wereanalyzed and discussed.Result: Nine studies that met inclusion criteria were included in the review through acomprehensive search. These reviews found that different aerobic interventions, such asyoga, walking and high-intensity progressive exercise, can contribute to depression inelderly. Yoga and high-intensity progressive exercise are often used. In addition, the mostcommonly used duration of intervention was found to be 24 weeks.Conclusion: The review suggests that aerobic exercise interventions can effectivelydecrease depression, depressive disorder and anxiety and improve quality of life in elderly.This suggests that aerobic exercise interventions can be used in clinical care of elderlywith depression or depressive disorder. However, this finding comes from a number ofrandomized controlled studies, some of which have limitations, such as not beingcomprehensive and having a small sample size. To improve effectiveness, more researchis needed to explore further.Keywords: Aerobic exercise intervention, elderly, depression, depressive disorder

The Effect of aerobic exercise interventions on depression and depressive disorder in elderly. : A descriptive literature review

Background: Depression manifests as neurological and psychiatric disorders.Depression is a kind of emotional disorder accompanied by mental retardation symptoms,but also can lead to a variety of functional physical disorders.It can be gradual, can besudden.Its development process varies from person to person, affects people'spsychological and physiological, decreases people's quality of life.Depression is theleading cause of death among the elderly, and the prevalence rate is rising rapidly. Somestudies have shown that aerobic exercise interventions can decrease depression anddepressive disorder in elderly.Aim: To describe the effect of aerobic exercise intervention on depression anddepressive disorder in the elderly.Method: Quantitative literature search was conducted using keywords input fromPubMed and CINAHL databases to understand the influence of aerobic exerciseintervention on depression and depressive disorder in the elderly, and the results wereanalyzed and discussed.Result: Nine studies that met inclusion criteria were included in the review through acomprehensive search. These reviews found that different aerobic interventions, such asyoga, walking and high-intensity progressive exercise, can contribute to depression inelderly. Yoga and high-intensity progressive exercise are often used. In addition, the mostcommonly used duration of intervention was found to be 24 weeks.Conclusion: The review suggests that aerobic exercise interventions can effectivelydecrease depression, depressive disorder and anxiety and improve quality of life in elderly.This suggests that aerobic exercise interventions can be used in clinical care of elderlywith depression or depressive disorder. However, this finding comes from a number ofrandomized controlled studies, some of which have limitations, such as not beingcomprehensive and having a small sample size. To improve effectiveness, more researchis needed to explore further.Keywords: Aerobic exercise intervention, elderly, depression, depressive disorder

Serine 1179 Phosphorylation of Endothelial Nitric Oxide Synthase Increases Superoxide Generation and Alters Cofactor Regulation.

Endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis. In addition to producing NO, eNOS can also generate superoxide (O2-.) in the absence of the cofactor tetrahydrobiopterin (BH4). Previous studies have shown that bovine eNOS serine 1179 (Serine 1177/human) phosphorylation critically modulates NO synthesis. However, the effect of serine 1179 phosphorylation on eNOS superoxide generation is unknown. Here, we used the phosphomimetic form of eNOS (S1179D) to determine the effect of S1179 phosphorylation on superoxide generating activity, and its sensitivity to regulation by BH4, Ca2+, and calmodulin (CAM). S1179D eNOS exhibited significantly increased superoxide generating activity and NADPH consumption compared to wild-type eNOS (WT eNOS). The superoxide generating activities of S1179D eNOS and WT eNOS did not differ significantly in their sensitivity to regulation by either Ca2+ or CaM. The sensitivity of the superoxide generating activity of S1179D eNOS to inhibition by BH4 was significantly reduced compared to WT eNOS. In eNOS-overexpressing 293 cells, BH4 depletion with 10mM DAHP for 48 hours followed by 50ng/ml VEGF for 30 min to phosphorylate eNOS S1179 increased ROS accumulation compared to DAHP-only treated cells. Meanwhile, MTT assay indicated that overexpression of eNOS in HEK293 cells decreased cellular viability compared to control cells at BH4 depletion condition (P<0.01). VEGF-mediated Serine 1179 phosphorylation further decreased the cellular viability in eNOS-overexpressing 293 cells (P<0.01). Our data demonstrate that eNOS serine 1179 phosphorylation, in addition to enhancing NO production, also profoundly affects superoxide generation: S1179 phosphorylation increases superoxide production while decreasing sensitivity to the inhibitory effect of BH4 on this activity

Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer

Exposure to inorganic arsenic in contaminated drinking water poses an environmental public health threat for hundreds of millions of people in the US and around the world. Arsenic is a known carcinogen for skin cancer. However, the mechanism by which arsenic induces skin cancer remains poorly understood. Here, we have shown that arsenic induces p62 expression in an autophagy-independent manner in human HaCaT keratinocytes. In mouse skin, chronic arsenic exposure through drinking water increases p62 protein levels in the epidermis. Nrf2 is required for basal and arsenic-induced p62 up-regulation. p62 knockdown reduces arsenic-induced Nrf2 activity, and induces sustained p21 up-regulation. p62 induction is associated with increased proliferation in mouse epidermis. p62 knockdown had little effect on arsenic-induced apoptosis, while it decreased cell proliferation following arsenic treatment. Our findings indicate that arsenic induces p62 expression to regulate the Nrf2 pathway in human keratinocytes and suggest that targeting p62 may help prevent arsenic-induced skin cancer

Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution

Using primary cultures of normal human prostate epithelial cells, we developed a novel prostasphere-based, label-retention assay that permits identification and isolation of stem cells at a single cell level. Their bona fide stem cell nature was corroborated using in vitro and in vivo regenerative assays and documentation of symmetric/asymmetric division. Robust WNT10B and KRT13 levels without E-cadherin or KRT14 staining distinguished individual stem cells from daughter progenitors in spheroids. Following FACS to isolate label-retaining stem cells from label-free progenitors, RNA-seq identified unique gene signatures for the separate populations which may serve as useful biomarkers. Knockdown of KRT13 or PRAC1 reduced sphere formation and symmetric self-renewal highlighting their role in stem cell maintenance. Pathways analysis identified ribosome biogenesis and membrane estrogen-receptor signaling enriched in stem cells with NF-ĸB signaling enriched in progenitors; activities that were biologically confirmed. Further, bioassays identified heightened autophagy flux and reduced metabolism in stem cells relative to progenitors. These approaches similarly identified stem-like cells from prostate cancer specimens and prostate, breast and colon cancer cell lines suggesting wide applicability. Together, the present studies isolate and identify unique characteristics of normal human prostate stem cells and uncover processes that maintain stem cell homeostasis in the prostate gland