Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma.

BACKGROUND: The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. METHODS: The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. RESULTS: The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. CONCLUSIONS: PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.

PLAG co-treatment increases the anticancer effect of Adriamycin and cyclophosphamide in a triple-negative breast cancer xenograft mouse model.

Chemotherapy induces tumor cell death and inhibits tumor progression, but the accompanying immune responses in the surrounding dying tissue cause significant inflammation. These responses, such as excessive neutrophil infiltration into tumor tissue, are the main causes of resistance to anticancer treatment. The development of drugs that reduce neutrophil infiltration into tumors is necessary to increase the anticancer effect of chemotherapy. Here, we show that the antitumor effect of the chemotherapy AC regimen (Adriamycin and cyclophosphamide) was increased by 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) cotreatment in the MDA-MB-231 triple-negative breast cancer xenograft mouse model. Tumor growth was inhibited up to 56% in mice treated with AC and inhibited up to 94% in mice cotreated with AC and PLAG. Side effects of chemotherapy, such as a reduction in body weight, were alleviated in mice cotreated with AC and PLAG. Excessive neutrophil infiltration caused by the AC regimen was successfully cleared in mice cotreated with AC and PLAG. We conclude that PLAG inhibits excessive neutrophil infiltration that aids tumor growth. Reduced neutrophils and increased lymphocytes in PLAG-treated mice can maximize the antitumor effect of the AC regimen and inhibit tumor growth.

Suppression of tumor progression by thioredoxin-interacting protein-dependent adenosine 2B receptor degradation in a PLAG-treated Lewis lung carcinoma-1 model of non-small cell lung cancer.

Extracellular adenosine in the tumor microenvironment plays a vital role in cancer development. Specifically, activation of adenosine receptors affects tumor cell growth and adenosine release. We examined the anti-tumor efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in animal models, revealing the role of PLAG in inhibiting tumor progression by promoting the degradation of adenosine 2B receptors (A2BRs) in tumors. PLAG induced the expression of thioredoxin-interacting protein (TXNIP), a type of α-arrestin that accelerates A2BR internalization by interacting with A2BR complexes containing ß-arrestin. Engulfed receptors bound to TXNIP were rapidly degraded after E3 ligase recruitment and ubiquitination, resulting in early termination of intracellular signals that promote tumor overgrowth. However, in control cancer cells, A2BRs bound to protein phosphatase 2A and were returned to the cell membrane instead of being degraded, resulting in continuous receptor-mediated signaling by pathways including the Raf-Erk axis, which promotes tumor proliferation. A TXNIP-silenced cell-implanted mouse model and TXNIP knockout (KO) mice were used to verify that PLAG-mediated suppression of tumor progression is dependent on TXNIP expression. Increased tumor growth was observed in TXNIP-silenced cell-implanted mice, and the anti-tumor effects of PLAG, including delayed tumor overgrowth, were greatly reduced. However, the anti-tumor effects of PLAG were observed in cancer cell-implanted TXNIP-KO mice, which indicates that PLAG produces anti-tumor effects by enhancing TXNIP expression in tumor cells. These essential functions of PLAG, including delaying tumor growth via A2BR degradation, suggest innovative directions for anticancer drug development.

Racial/Ethnic disparities in drug use during the COVID 19 pandemic: Moderating effects of non-profit substance use disorder service expenditures.

The COVID-19 pandemic influenced individuals' anxiety and depression across the United States over a short period, and some Americans relied on drugs for coping. This study examines American adults' drug use trajectories in response to changing anxiety and depression levels during the COVID-19 pandemic and the moderating role of substance use disorder (SUD) services provided by non-profit facilities in anxiety/depression-induced drug use. Heterogeneity in such relationships is further explored based on race/ethnicity. This study used a nationally representative sample of 1,176 American adults who reported drug use between May 1, 2020, and June 30, 2021. Using individual-fixed effects Poisson estimators, the current study empirically modeled drug use changes according to changing anxiety/depression levels. Interaction terms between anxiety/depression levels and per capita spending by non-profit SUD facilities were used to explore the moderating effect of SUD service expenditures. Racial/ethnic disparities were explored in subgroup analyses on non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Asian samples. We found more frequent drug use in response to elevated anxiety and depression during the COVID-19 pandemic. Greater spending on SUD service by non-profit facilities at the county level was associated with reduced drug consumption associated with anxiety and depression, with greater benefits for racial/ethnic minorities. Findings provide important policy implications for distributing public funds for non-profit SUD facilities for mitigating SUD risks, especially among racial/ethnic minorities.

PLAG alleviates cisplatin-induced cachexia in lung cancer implanted mice.

Chemotherapy-induced cachexia has been a significant challenge to the successful treatment of cancer patients. Chemotherapy leads to loss of muscle, loss of appetite, and excessive weight loss, which makes these necessary treatments intolerable for most patients. Therefore, it is necessary to alleviate cachexia to successfully treat cancer patients. In this study, tumor-implanted mouse models administered cisplatin showed rapid weight loss and reduced feeding rate by the second week of treatment, and 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) effectively alleviated cisplatin-induced cachexia. In mice treated with cisplatin on a sacrificial day after 6 weeks, the weight of the two major leg muscles (quadriceps femoris and gastrocnemius) were reduced by up to 70%, but this muscle reduction was successfully prevented in the PLAG co-treatment group. The distribution and size of muscle fibers that appear in small units in cisplatin-treated mice were restored to normal levels by PLAG co-treatment. Furthermore, myostatin expression levels were upregulated by cisplatin, whereas myostatin decreased to normal levels with muscle recovery in the PLAG co-treated group. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which are commonly expressed in cachexia, were significantly increased in cisplatin-treated mice but were reduced to normal levels in PLAG co-treated mice. Glucose absorption, an indicator of muscle tissue activity, decreased with cisplatin treatment and recovered to normal levels with PLAG co-treatment. Overall, PLAG effectively alleviated cisplatin-induced cachexia symptoms and reduced tumor growth in tumor-implanted mice. These findings suggest PLAG may be a promising drug to alleviate cachexia in cancer patients receiving chemotherapy.

The Role of Purpose in Life in the Relationship Between Widowhood and Cognitive Decline Among Older Adults in the U.S.

OBJECTIVES: The objective of this study was to examine the role of purpose in life in the relationship between widowhood and cognitive decline. METHODS: This study used a sample of 12,856 respondents (20,408 observations) collected from a national panel survey, the 2006-2014 waves of the Health and Retirement Study (HRS), that sampled older adults aged 50 or older. The study estimated growth-curve models with years since spousal death, purpose in life, and interaction between the two to predict cognition using three measures-total cognition, fluid, and crystallized intelligence scores. We also estimated growth-curve models by sex, race/ethnicity, and education. RESULTS: While years since spousal death negatively correlated with cognition, purpose in life positively correlated with cognition. Furthermore, purpose in life had a moderating effect on the relationship between years since spousal death and cognition. This effect was found by using total cognition (coef. = 0.0515; z = 2.64; p < 0.01) and fluid intelligence scores (coef. = 0.0576; z = 3.23; p < 0.05). The same effects were salient among females (coef. = 0.0556; z = 2.19; p < 0.05), Whites (coef. = 0.0526; z = 2.52; p < 0.05), and older adults with more education (coef. = 0.0635; z = 2.10; p < 0.05). CONCLUSION: Higher purpose in life relates to the negative correlations between widowhood and cognition of older adults. Educational programs improving purpose in life are a possible avenue for reducing the adverse effect of widowhood on cognition and warrant future exploration.

How widowhood status relates to engagement in advance care planning among older adults: does race/ethnicity matter?

OBJECTIVES: This study investigated whether and to what extent widowhood status is related to engagement in advance care planning (ACP), and further whether race/ethnicity moderated the relation. METHODS: We analyzed a total of 11,257 older Americans from the Health and Retirement Study using random-effect regression models after controlling for covariates and year-fixed effects. RESULTS: We found that both being a widow/widower ever and having been widowed for a longer period of time were associated with a higher probability of engagement in ACP. Specifically, we found that a one-year increase in the number of years since spousal death was associated with 1.02 (p < 0.05, 95% CI = 1.00, 1.03) changes in the odds ratios of informal ACP; however, inclusion of a quadratic term indicated that this association reversed after the peak. Moreover, our findings suggested a moderating effect of race/ethnicity on the relations of the length of time since spousal loss with engagement in ACP. Specifically, the odds of widowed non-Hispanic Blacks discussing with someone the care or medical treatment (informal ACP) and having a living will (formal ACP) were 0.96 (p < 0.05, 95% CI = 0.93, 1.00) and 0.88 (p < 0.05, 95% CI = 0.79, 0.97) times that of non-widowed non-Hispanic Whites. Compared with their non-Hispanic White counterparts, widowed non-Hispanic Blacks were less likely to engage in ACP, and the negative relations were exacerbated when they became widows/widowers. CONCLUSION: We elaborated on these findings and discussed their implications for understanding the moderating effect of race/ethnicity on the relation between late-life widowhood and engagement in ACP. In order to develop programs that enhance engagement in ACP and reduce racial/ethnic disparities, research must incorporate intersectionality theory with attention to motivations and decision-making style among diverse widows/widowers. The findings from this study could help inform policy makers when developing public health programs and health care reimbursement programs that enhance engagement in ACP among widows/widowers.

The positive impact of informal spousal caregiving on the physical activity of older adults.

Introduction: Although physical activity (PA) is crucial for health, the literature is mixed about how individuals' PA decisions are affected by their spouses. To fill this gap, we examined the extent to which providing care for one spouse affects the PA of the other spouse among those aged 50 or older in the United States. Methods: We analyzed 9,173 older adults living with their spouses or partners from the 2004 to 2016 waves of the Health and Retirement Study. To identify the causal effect of spousal caregiving on the PA of older adults, we estimated individual-fixed effects models using a two-stage least squared instrumental variable approach with spousal falls as our instrument. We also estimated the models by splitting the sample by gender and race/ethnicity to identify heterogeneous impacts of spousal caregiving on PA decisions among subgroups. Results: We found that a one percentage point increase in the probability of providing care to spouses led to an increase in the probability of initiating moderate or vigorous PA (MVPA) by 0.34-0.52 percentage points. This effect was salient, especially among female and non-Hispanic white older adults. Discussion: Caregiving experience might provide opportunities to learn about caregiving burdens and trigger an emotional response about the salience of an event (i.e., they need care in the future). Older caregivers might start MVPA in an effort to improve or maintain their health and avoid burdening their families for caregiving in the future. This study demonstrated spousal influence on PA. Instead of delivering PA-promotion information (e.g., the harm of sedentary lifestyle and benefits of regular PA) to individuals, risk communication and education efforts on PA promotion might be more effective considering the family context. Family events such as health shocks or the emergence of caregiving needs from family members provide windows of opportunities for intervening. Subgroup differences should also be considered in targeted interventions.

Early Life Experiences Moderate the Relationship Between Genetic Risk of Autism and Current and Lifetime Mental Health.

Although individuals with autism are at greater risk of mental health challenges than others, we know little about the relationship between the mental health of older adults (50+) and autism because they are less likely to be diagnosed. Identifying the risk and protective factors that are associated with mental health can increase educational awareness, inform clinical practice, and provide information to help diagnose and treat older adults with autism. This study used longitudinal panel data of the 2008-2016 waves of the Health and Retirement Study. It estimated individual random-effect models by interacting a genetic propensity toward autism and early life experiences to test whether the latter has a moderating effect on the relationships between genetics and the Center for Epidemiologic Studies Depression (CES-D) score, self-reported depression, and history of psychiatric problems. Results suggest that individuals with a higher genetic propensity for autism are less likely to develop psychiatric problems if they report a positive maternal relationship early in life. Further, a combined effect of police encounters early in life and genetic risk for autism is associated with higher CES-D scores, increased odds of self-reported depression, and a history of psychiatric problems. Clinical applications of these findings include the need to establish and support high-quality relationships by addressing both child and caregiver needs. Further, these findings support the need to design and implement proactive interventions to teach police and autistic individuals how to successfully navigate these encounters.

Health risks of natural hazards and resilience resources: Evidence from a U.S. nationwide longitudinal study.

BACKGROUND: Although natural disasters can threaten health and well-being, some people show greater resilience to their effects than others. Identifying the characteristics related to resilience has important implications for reducing the health risks in the aftermath of a disaster. OBJECTIVE: Using the Conservation of Resources Theory as a framework, we study the role of resources in moderating the adverse effects of natural disasters on people's health and coping behaviors. METHOD: We match 20,658 unique individuals aged 50 or older from the 2012-2016 waves of the Health and Retirement Study to the county-level annual natural hazard data provided by the Federal Emergency Management Agency. Using individual-fixed effect models, we first model whether the experience of natural disasters can predict people's health and coping behaviors. We then explore heterogeneity in such effects by interacting individual- and county-level resilience resources with the number of natural disasters. RESULTS: The results show that with increased exposure to natural disasters, older adults are more likely to experience difficulties performing instrumental daily activities. They also tend to have fewer overnight hospital stays, higher out-of-pocket medical expenses, and increased alcohol dependency. However, older adults with certain socio-economic characteristics ‒ white, higher education, higher income, and homeownership ‒ are better able than others to mitigate any adverse health effects of natural disasters. One significant community-level resource is a robust healthcare capacity in a county with a high ratio of healthcare practitioners, where older adults are more likely to seek hospital care and have lower alcohol dependency. CONCLUSIONS: Health resilience can be improved by strengthening community-level healthcare capacity, with a particular focus on residents with lower socio-economic resources. Failing to address healthcare provision inequalities may exacerbate health disparities.

Heterogeneity in preventive behaviors during COVID-19: Health risk, economic insecurity, and slanted information.

The present study examines whether people respond heterogeneously to statewide social distancing mandates as a function of factors that proxy for health risk, economic insecurity, and media consumption. Using longitudinal data of 7400 American adults between March 10 and June 23, 2020, the study examines social-distancing and mask-wearing behaviors. We use a staggered difference-in-difference model to explore whether state policies lead to preventive behaviors. We further examine heterogeneity in individual responses to state mandates by including interaction terms with health risk, economic insecurity, and media consumption. The study finds that state policies lead to increased adoption of these behaviors. Our findings also suggest that old age and living with the elderly are key predictors of preventive behavior adoption in the presence or even absence of state mandates. However, the economically insecure, such as the unemployed, those with low incomes and net worth, or without health insurance, are less likely to adopt preventive behaviors regardless of the mandates. The adoption of the behaviors is also polarized between CNN users and Fox News/Social Media users, with greater compliance by the former.

The Role of Polygenic Score and Cognitive Activity in Cognitive Functioning Among Older Adults.

BACKGROUND AND OBJECTIVES: This study explored whether the intensity of cognitive activities could moderate the relationship between a genetic predisposition for developing Alzheimer's disease (AD) and cognitive functioning among older adults in the United States. Furthermore, we examined whether the same moderating effects were dependent on different measures of cognition. RESEARCH DESIGN AND METHODS: We used a data set from the 2000-2014 waves of the Health and Retirement Study and the Consumption and Activities Mail Survey. Our sample included 3,793 individuals aged 50 or older. We used the polygenic score (PGS) for AD as a genetic trait for cognitive functioning. Reading, listening to music, using a computer, playing cards/games/solving puzzles, singing/playing musical instruments, and creating art and crafts were included as cognitive activities, and TV viewing as passive activities. We used total cognition, fluid intelligence, and crystallized intelligence as proxies for cognitive functioning. Growth-curve models were conducted. RESULTS: After controlling for covariates, we found that reading books, using a computer, and playing cards/games/solving puzzles had a positive effect on cognitive functioning. An additional hour spent reading books moderated the negative effect of AD PGS on cognition. The measure of fluid, when compared with crystallized intelligence, appeared to drive these results. DISCUSSION AND IMPLICATIONS: Reading could be a protective factor against cognitive decline among older adults who are genetically predisposed to developing AD. Implications for individuals, caregivers, clinicians, and policymakers are suggested. Furthermore, the onset of AD in those at greater genetic risk may be delayed with this intervention.

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice.

Acute gouty arthritis is an auto-inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Excessive neutrophil recruitment into gouty lesions is a general clinical sign and induces a pain phenotype. Attenuation of successive periods of neutrophil infiltration might be a beneficial approach to achieve therapeutic efficacy. In this study, the activity of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in attenuation of excess neutrophil infiltration was assessed in gout-induced lesions of BALB/c mice. Neutrophil infiltration in MSU-induced gouty lesions was analyzed using immunohistochemical staining. ELISA and RT-PCR were used to measure attenuation of expression of the major neutrophil chemoattractant, CXC motif chemokine ligand 8 (CXCL8), in a PLAG-treated animal model and in cells in vitro. The animal model revealed massive increased neutrophil infiltration in the MSU-induced gouty lesions, but the PLAG-treated mice had significantly reduced neutrophil numbers in these lesions. The results also indicated that the MSU crystals stimulated a damage-associated molecular pattern that was recognized by the P2Y6 purinergic receptor. This MSU-stimulated P2Y6 receptor was destined to intracellular trafficking. During intracellular endosomal trafficking of the receptor, endosome-dependent signaling provided expression of CXCL8 chemokines for neutrophil recruitment. PLAG accelerated initiation of the intracellular trafficking of the P2Y6 receptor and returning the receptor to the membrane. This process shortened the intracellular retention time of the receptor anchoring endosome and subsequently attenuated endosome-dependent signaling for CXCL8 expression. These study results suggested that PLAG could be used for resolution of acute inflammation induced in gout lesions.

1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates chemoradiation-induced oral mucositis.

OBJECTIVE: This study was designed to investigate whether necroptosis is involved in the pathogenesis of chemoradiation-induced oral mucositis in a murine model and whether 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) ameliorates this disorder. MATERIALS AND METHODS: A chemoradiation-induced oral mucositis model was established by treating mice with concurrent 5-fluorouracil (100 mg/kg, i.p.) and head and neck X-irradiation (20 Gy). Phosphate-buffered saline or PLAG (100 mg/kg or 250 mg/kg, p.o.) was administered daily. Body weights were recorded daily, and mice were sacrificed on Day 9 for tongue tissue analysis. RESULTS: On Day 9, chemoradiotherapy-treated (ChemoRT) mice had tongue ulcerations and experienced significant weight loss (Day 0:26.18 ± 1.41 g; Day 9:19.44 ± 3.26 g). They also had elevated serum macrophage inhibitory protein 2 (MIP-2) (control: 5.57 ± 3.49 pg/ml; ChemoRT: 130.14 ± 114.54 pg/ml) and interleukin (IL)-6 (control: 198.25 ± 16.91 pg/ml; ChemoRT: 467.25 ± 108.12 pg/ml) levels. ChemoRT-treated mice who received PLAG exhibited no weight loss (Day 0:25.78 ± 1.04 g; Day 9:26.46 ± 1.68 g) and had lower serum MIP-2 (4.42 ± 4.04 pg/ml) and IL-6 (205.75 ± 30.41 pg/ml) levels than ChemoRT-treated mice who did not receive PLAG. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signalling proteins. CONCLUSION: 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigated chemoradiation-induced oral mucositis by modulating necroptosis.

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment.

Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged with an intranasal dose of lipopolysaccharide (LPS). Using this model, we found that PLAG promotes resolution of ALI through effective control of LPS-induced neutrophil infiltration, endothelial permeability, and inflammatory chemokine production. In addition, the Toll like Receptor 4 (TLR4) endocytosis/exocytosis cycle was significantly accelerated in Raw 264.7 cells co-treated with PLAG/LPS, as compared to cells treated only with LPS. During this cycle, a PLAG-induced exotoxin clearance pathway was observed to occur through the prompt assembly of nicotinamide adenine dinucleotide phosphate (NADPH) units and production of reactive oxygen species (ROS), which ultimately lead to earlier LPS clearance. We further detected reduced expression, as well as faster return to homeostatic levels, of macrophage inflammatory protein (MIP)-2, in PLAG/LPS- vs. LPS-treated cells. MIP-2 is a main inducer of neutrophil migration that is mainly controlled by interferon regulatory factor 3 (IRF3) activation and is involved in the TLR4 endosomal-signaling pathway. PLAG induced TLR4-mediated TRIF-related adaptor molecules/Toll-interleukin receptor (TIR) domain-containing adaptor protein including interferon (IFN)-ß/IRF3 endosomal signaling, leading to rapid association of TRAM/TRIF and TLR4 and earlier IRF3 phosphorylation in PLAG/LPS-treated vs. LPS-treated cells. PLAG specificity was further verified with PLAG analogs and metabolites known to control excessive neutrophil infiltration, suggesting that this acetylated diacylglycerol has a unique biological role in neutrophil motility. Thus, our data indicate that PLAG may represent a potential therapeutic agent for resolution of LPS-induced lung inflammation through effective MIP-2 modulation.

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice.

Acute radiation syndrome (ARS) occurs as a result of partial- or whole-body, high-dose exposure to radiation in a very short period of time. Survival is dependent on the severity of the hematopoietic sub-syndrome of ARS. In this study, we investigated the mitigating effects of a lipid molecule, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), on the kinetics of hematopoietic cells, including absolute neutrophil count (ANC), red blood cells (RBCs) and platelet counts, in mice after gamma-ray total-body irradiation (TBI). Male and female BALB/c mice (11 weeks old) received a LD70/30 dose of TBI. PLAG significantly and dose-dependently attenuated radiation-induced mortality (P = 0.0041 for PLAG 50 mg/kg; P < 0.0001 for PLAG 250 mg/kg) and body weight loss (P < 0.0001 for PLAG 50 and 250 mg/kg) in mice. Single-fraction TBI sharply reduced ANC within 3 days postirradiation and maintained the neutropenic state (ANC < 500 cells/µl) by approximately 26.8 ± 0.8 days. However, administration of PLAG attenuated radiation-induced severe neutropenia (ANC < 100 cells/µl) by effectively delaying the mean day of its onset and decreasing its duration. PLAG also significantly mitigated radiation-induced thrombocytopenia (P < 0.0001 for PLAG 250 mg/kg) and anemia (P = 0.0023 for PLAG 250 mg/kg) by increasing mean platelet and RBC counts, as well as hemoglobin levels, in peripheral blood. Moreover, delayed administration of PLAG, even at 48 and 72 h after gamma-ray irradiation, significantly attenuated radiation-induced mortality in a time-dependent manner. When compared to olive oil and palmitic linoleic hydroxyl (PLH), only PLAG effectively attenuated radiation-induced mortality, indicating that it has a distinctive mechanism of action. Based on these preclinical observations, we concluded that PLAG has high potential as a radiation countermeasure for the improvement of survivability and the treatment of hematopoietic injury in gamma-ray-induced ARS.

Purpose in Life Protects Against Cognitive Decline Among Older Adults.

OBJECTIVE: This study examined whether having a sense of purpose in life protects against cognitive decline among older adults and whether purpose in life moderates the relationship between selected risk factors (age, sex, and race/ethnicity) and cognitive abilities. METHODS: This was a longitudinal analysis of existing secondary data of adults (N = 11,557) aged 50 or older using the 2006-2012 waves of the Health and Retirement Study. The study measured purpose in life, cognitive functioning score, and various covariates. RESULTS: Growth curve modeling revealed that, after adjusting for covariates, purpose in life was positively associated with participants' total cognition scores. Purpose in life significantly moderated the relationship between age and race/ethnicity and cognitive decline. Further, purpose in life was a protective factor against cognitive decline for those who were older and black. There was no significant interaction between purpose in life and sex. CONCLUSION: Having a purposeful life protects against cognitive decline in older adults, and the associations varied by age and race/ethnicity, but not by sex. Potential ways to increase purpose in life are discussed in a clinical context.

Understanding the correlation between Alzheimer's Disease polygenic risk, wealth, and the composition of wealth holdings.

We investigate how the genetic risk of developing Alzheimer's Disease (AD) relates to saving behavior. Using nationally representative data from the 1996-2014 Health and Retirement Study (HRS), we find that genetic predisposition for AD correlates with, but is not causally related to how older individuals' hold wealth in different asset types. People with a higher AD polygenic risk score (PGS) hold roughly 20 per cent less wealth in IRAs and contribute about 24 percent less to IRAs between survey periods. We hypothesize that people with a high risk of AD choose different portfolios: (i) because they know their genetic risk of developing AD from parental history, (ii) because they have the lower cognitive capacity, and (iii) because they indirectly learn about their genetic predisposition for AD as they age. Our extended model results show that the first two hypotheses do not account for the observed correlation. Consistent with the third hypothesis, the interaction between age and the AD PGS accounts for the correlation between genetic traits and asset holdings. Our findings have far-reaching implications for researchers using genetic data: when indirect learning about own predispositions is possible, correlations between genes and choices must be interpreted with caution.

HX-1171 attenuates pancreatic ß-cell apoptosis and hyperglycemia-mediated oxidative stress via Nrf2 activation in streptozotocin-induced diabetic model.

Streptozotocin (STZ) acts specifically on pancreatic beta cells, inducing cell destruction and cell dysfunction, resulting in diabetes. Many studies have reported that nuclear factor-erythroid 2-related factor 2 (Nrf2), a main regulator of antioxidant expression, prevents and improves diabetes-related diseases. In this study, we investigated the antidiabetic effect of the newly discovered Nrf2 activator, HX-1171, in the STZ-induced diabetic mouse model. HX-1171 enhanced insulin secretion by reducing STZ-induced cell apoptosis, and decreased intracellular reactive oxygen species (ROS) generation by upregulating the expression of antioxidant enzymes through Nrf2 activation in INS-1 pancreatic beta cells. In STZ-induced diabetic mice, HX-1171 administration significantly lowered blood glucose levels and restored blood insulin levels. In the STZ-only injected mice, the pancreatic islets showed morphological changes and loss of function, whereas the HX-1171-treated group was similar to that of the control group. These results suggest that HX-1171 may be developed as a promising therapeutic agent for diabetes-related diseases.

Widowhood Status as a Risk Factor for Cognitive Decline among Older Adults.

OBJECTIVES: This study investigated whether widowhood status has an effect on cognitive decline among older adults in the United States. DESIGN: Longitudinal analysis of existing secondary data. SETTING: The 1996-2012 waves of the Health and Retirement Study. PARTICIPANTS: A total of 6,766 individuals (28,420 observations) aged 50 years and older who responded to all questions. MEASUREMENTS: Widow/widower status, cognitive functioning score, and various covariates. RESULTS: Growth-curve models show that after controlling for covariates, widowhood status was related to cognitive decline (95% CI: -0.8090, -0.4674). We also found a linear relationship between time since spousal loss and cognitive decline. Conditional upon spousal bereavement status, higher education and having at least one living sibling were found to be protective factors against cognitive decline. CONCLUSIONS: Widowhood status accelerated cognitive decline over time among widowed older adults. Findings suggest that extra support is needed to monitor cognitive functioning for those experiencing widowhood.