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Purpose: Low-grade inflammation, measured by circulating levels of cytokines, is a pathogenic mechanism for several chronic diseases of aging. Identifying factors related to inflammation among African-American youths may yield insights into mechanisms underlying racial disparities in health. The purpose of the study was to determine whether (1) reported racial discrimination from ages 17-19 years forecasts heightened cytokine levels at the age of 22 years and (2) this association is lower for youths with positive racial identities., Methods: A longitudinal research design was used with a community sample of 160 African-Americans who were aged 17 years at the beginning of the study. Discrimination and racial identity were measured with questionnaires, and blood was drawn to measure basal cytokine levels. Ordinary least squares regression analyses were used to examine the hypotheses., Results: After controlling for socioeconomic risk, life stress, depressive symptoms, and body mass index, racial discrimination (β = .307; p < .01), racial identity (β = -.179; p < .05), and their interaction (β = -.180; p < .05) forecast cytokine levels. Youths exposed to high levels of racial discrimination evinced elevated cytokine levels 3 years later. This association was not significant for young adults with positive racial identities., Conclusions: High levels of interpersonal racial discrimination and the development of a positive racial identity operate jointly to determine low-grade inflammation levels that have been found to forecast chronic diseases of aging, such as coronary disease and stroke., (Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective Type 1 diabetes ( T1D) results from the inflammatory destruction of pancreatic β-cells. In this study, we investigated the effect of docosahexaenoic acid ( DHA) supplementation on stimulated inflammatory cytokine production in white blood cells ( WBC) from infants with a high genetic risk for T1D. Research design and methods This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell ( RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide ( LPS), 1 µg/ mL. Results The levels of RBC DHA were increased by 61-100% in treated compared to control infants at ages 6-36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1β, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein ( hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies. Conclusions This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced. [ABSTRACT FROM AUTHOR]

Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock., Objectives: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock., Methods: We studied 394 patients in a randomized, controlled trial of vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours., Measurements and Main Results: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P < 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P = 0.037). In less severe septic shock, the difference in plasma cytokine reduction over 24 hours between survivors and nonsurvivors was less pronounced than that seen in more severe septic shock. Furthermore, vasopressin decreased interferon-inducible protein 10 and granulocyte colony-stimulating factor more than did norepinephrine in less severe septic shock, whereas vasopressin decreased granulocyte-macrophage colony-stimulating factor in patients who had more severe shock., Conclusions: Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septic shock. Vasopressin decreased 24-hour plasma cytokine levels more than did norepinephrine. The vasopressin-associated decrease of cytokines differed according to severity of shock. Clinical trial registered with www.controlled-trials.com (ISRCTN94845869).

We attempted to determine whether persons susceptible to heatstroke produced higher serum concentrations of interleukin-6, tumor necrosis factor-alpha, and interleukin-10 when subjected to heat stress. Nine patients with previous heatstroke and 21 matched controls were subjected to a heat-stress test (at 32 degrees C, 67% humidity, 900 W/m2 solar radiation, and wind speed of 2.5 m/s) for 60 minutes and rested at 24 degrees C for another 60 minutes in full battle gear. During the heat-stress test, blood was drawn at intervals of 0, 30, 60, and 120 minutes, and serum lipopolysaccharide, interleukin-6, tumor necrosis factor-alpha, and interleukin-10 concentrations were measured. Patients with previous heatstroke had a higher mean core temperature (0.6 degree C; p < 0.05) and sweated less (0.3 liters; p < 0.05). During the heat-stress test, the lipopolysaccharide levels were not increased and there was no difference in the serum cytokine concentrations between patients with previous heatstroke and controls. However, patients with previous heatstroke had higher absolute serum cytokine concentrations and poorer thermoregulatory response to heat stress in terms of core temperature and sweat loss.

Simple Summary: Current therapies are often insufficiently effective in patients with acute myeloid leukemia (AML), prompting ongoing interest in developing new drugs for this aggressive type of blood cancer. Many efforts focus on drugs that target CD33, a cell surface protein that is widely expressed on AML cells. Gemtuzumab ozogamicin (GO), which consists of a CD33 antibody linked to a small molecule toxin, benefits some AML patients but not many others, leaving room for other CD33-targeted therapeutics. Here, we examined CC-96191, a "TriNKET" protein drug that binds CD33 on AML cells at the same time it binds two different proteins, CD16a and NKG2D, on natural killer (NK) cells, thereby activating these immune cells and engaging them to kill AML cells. In preclinical studies, we found CC-96191 to be broadly active against human AML cells that express CD33. CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a protein drug that binds CD33 and CD3 on T cells. Moreover, CC-96191 eliminated AML cells but not normal CD33+ monocytes, suggesting selectivity toward leukemic cells. Together, these findings support the clinical exploration of CC-96191 as is currently ongoing. Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655. [ABSTRACT FROM AUTHOR]

Background: To assess the efficacy of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin [BDC]) and their analogs (tetrahydrocurcumin [THC], tetrahydrodemethoxycurcumin [THDC], tetrahydrobisdemethoxycurcumin) in reducing inflammatory cytokines and their toxicity to primary human corneal limbal epithelial cells, these cells were cultured and exposed to these compounds. Methods: The PrestoBlue assay assessed cell viability after treatment. Anti-inflammatory effects on hyperosmotic cells were determined using real-time polymerase chain reaction and significance was gauged using one-way analysis of variance and Tukey's tests, considering p-values < 0.05 as significant. Results: Curcuminoids and their analogs, at 1, 10, and 100 µM, exhibited no effect on cell viability compared to controls. However, cyclosporin A 1:500 significantly reduced cell viability more than most curcuminoid treatments, except 100 µM curcumin and BDC. All tested curcuminoids and analogs at these concentrations significantly decreased mRNA expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-17 A, matrix metallopeptidase-9, and intercellular adhesion molecule-1 after 90 mM NaCl stimulation compared to untreated cells. Furthermore, proinflammatory cytokine levels from hyperosmotic cells treated with 1, 10, and 100 µM curcumin, 100 µM BDC, 100 µM THC, 1 and 100 µM THDC mirrored those treated with cyclosporin A 1:500. Conclusion: The anti-inflammatory efficiency of 1 and 10 µM curcumin, 100 µM THC, 1 and 100 µM THDC was comparable to that of cyclosporin A 1:500 while maintaining cell viability. [ABSTRACT FROM AUTHOR]

Background: With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV. Methods: 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture. Results: The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p < 0.001). There was no significant difference in bleeding on probing (p = 0.17) and attachment loss (p = 0.39) between women who were HIV infected vs. HIV uninfected. Women with HIV had significantly higher RANKL expression in Gingival Crevicular Fluid (HIV + 3.80+/-3.19 pg/ul, HIV- 1.29+/-2.14 pg/ul ; p < 0.001), fewer teeth present (HIV + 17.75+/-7.62, HIV- 22.79+/-5.70; p < 0.001),), lower trabecular number (HIV + 0.08+/-0.01, HIV- 0.09+/-0.02; p = 0.004) and greater trabecular separation (HIV + 9.23+/-3.11, HIV- 7.99+/-3.23; p = 0.04) compared to women without HIV that remained significant in multivariate logistic regression analysis in a sub-cohort after adjusting for age, race/ethnicity, smoking status, and diabetes. Conclusion: Postmenopausal women with HIV have deterioration of the alveolar trabecular bone microarchitecture that may contribute to greater tooth loss. [ABSTRACT FROM AUTHOR]

Gulf War Illness (GWI) afflicts US military personnel who served in the Persian Gulf War. Suspect causal agents include exposure to pyridostigmine (PB), permethrin (PM) and N,N-diethyl-m-toluamide (DEET). Prominent symptoms include cognitive deficits, such as memory impairment. In aging animal models, we have documented the beneficial effect of the flavanol (-)-epicatechin (Epi) on hippocampus structure and related function. Using a rat model of GWI, we examined the effects of Epi on hippocampus inflammation, oxidative stress, mitochondrial dysfunction, cell death/survival pathways, and memory endpoints. Male Wistar rats underwent 3 weeks of exposure to either vehicles or DEET, PM, PB, and stress. Subgroups of GWI rats were then allocated to receive orally 15 days of either water (vehicle) or 1 mg/kg/day of Epi treatment. Object recognition tasks were performed to assess memory. Hippocampus samples were analyzed. Epi treatment yields significant improvements in short- and long-term memory versus GWI rats. Hippocampus oxidative stress and pro-inflammatory cytokine levels showed significant increases with GWI that were largely normalized with Epi becoming comparable to controls. Significant increases in markers of hippocampus neuroinflammation and cell death were noted with GWI and were also largely reduced with Epi. Neuronal survival signaling pathways were adversely impacted by GWI and were partially or fully restored by Epi. Markers of mitochondrial function were adversely impacted by GWI and were fully restored by Epi. In conclusion, in an animal model of GWI, Epi beneficially impacts recognized markers of hippocampus neuroinflammation, oxidative stress, cell survival, neurotoxicity and mitochondrial function leading to improved memory. [ABSTRACT FROM AUTHOR]

Summary: Over 200,000 individuals in the United States alone live with Down Syndrome (DS), the most common genetic disorder associated with intellectual disability. DS has a constellation of features across the body, including dysregulation of the immune system. Individuals with DS have both a higher frequency of autoimmunity and more severe infections than the general population, highlighting the importance of understanding the immune system in this population. Individuals with DS present with dysregulation of both the innate and adaptive immune systems. Elevated cytokine levels, increased type I and type II IFN signaling, a shift toward memory phenotypes in T cells, and a decrease in the size of the B‐cell compartment are observed in individuals with DS, which contribute to both autoinflammation and severe infections. Herein, we discuss the current knowledge of the immune system in individuals with Down Syndrome as well as ideas of necessary further investigations to decipher the mechanisms by which trisomy 21 leads to immune dysregulation, with the ultimate goal of identifying clinical targets to improve treatment. [ABSTRACT FROM AUTHOR]

Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009–2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50–79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines). [ABSTRACT FROM AUTHOR]

In the United States, millions of adults use electronic cigarettes (e-cigs), and a majority of these users are former or current cigarette smokers. It is unclear, whether prior smoking status affects biological responses induced by e-cigs. In this study, differentiated human nasal epithelial cells (hNECs) from nonsmokers and smokers at air-liquid interface were acutely exposed to the e-cig generated aerosols of humectants, propylene glycol (PG), and glycerol (GLY). Mucin levels were examined in the apical washes, and cytokine levels were assessed in the basolateral supernatants 24 h postexposure. The aerosol from the GLY exposure increased mucin 5, subtype AC (MUC5AC) levels in the apical wash of hNECs from nonsmokers, but not smokers. However, the aerosol from GLY induced pro-inflammatory responses in hNECs from smokers. We also exposed hNECs from nonsmokers and smokers to e-cig generated aerosol from PG:GLY with freebase nicotine or nicotine salt. The PG:GLY with freebase nicotine exposure increased MUC5AC and mucin 5, subtype B (MUC5B) levels in hNECs from nonsmokers, but the nicotine salt exposure did not. The PG:GLY with nicotine salt exposure increased pro-inflammatory cytokines in hNECs from smokers, which was not seen with the freebase nicotine exposure. Taken together, these data indicate that the e-cig generated aerosols from the humectants, mostly GLY, and the type of nicotine used cause differential effects in airway epithelial cells from nonsmokers and smokers. As e-cig use is increasing, it is important to understand that the biological effects of e-cig use are likely dependent on prior cigarette smoke exposure. [ABSTRACT FROM AUTHOR]

Objectives. Cigarette smoking is a major risk factor for RA and has been associated with increased disease severity and lower rates of disease remission. We hypothesized that inflammation and disease activity would be associated with smoking status and this would be related to levels of ACPA. Methods. RA patients from the Veterans Affairs RA registry were studied (n = 1466): 76.9% anti-CCP2 positive, 89% male, median age 63 years (interquartile range 57-72), median disease duration 8.45 years (interquartile range 2.8-18). Baseline serum samples were evaluated for levels of anti-CCP2, RF, 19 distinct ACPAs and 17 cytokines. Smoking status at baseline was recorded as current, former or never. The association of smoking status with cytokines, autoantibodies and disease activity (DAS28) was evaluated. Results. Among anti-CCP-positive RA patients, RA-associated cytokines (false-discovery rates q < 0.1%) and DAS28 (P < 0.01) were higher in current smokers compared with former or never smokers. DAS28 and cytokine levels were similar between former and never smokers. In contrast, ACPA concentrations were higher among both current and former smokers compared with never smokers, and levels of ACPA were not associated with DAS28 or cytokine levels. Conclusion. Among anti-CCP2-positive RA patients, current smoking status is associated with elevations in pro-inflammatory cytokines and increased RA disease activity. Similar levels of inflammation and disease activity among former and never smokers suggests that the detrimental effects of smoking could be ameliorated through tobacco cessation. The effect of tobacco cessation on RA disease activity should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy and aggression affect up to 90% of Alzheimer's disease (AD) patients. These symptoms significantly increase caregiver stress and institutionalization rates, and more importantly they are correlated with faster cognitive decline. However, the neuronal basis of NPS in AD remains largely unknown. Here, we review current understanding of NPS and related pathology in studies of AD patients and AD mouse models. Clinical studies indicate that NPS prevalence and severity vary across different AD stages and types. Neuroimaging and postmortem studies have suggested that pathological changes in the anterior cingulate cortex, hippocampus, prefrontal cortex, and amygdala are linked to NPS, although the precise mechanisms remain unclear. Studies of AD mouse models have indicated that amyloid-beta and tau-related neurodegeneration in the hippocampus, prefrontal cortex, and anterior cingulate cortex are correlated with NPS-like behavioral deficits. A better understanding of the NPS phenotypes and related pathological changes will pave the way for developing a better management strategy for NPS in AD patients. [ABSTRACT FROM AUTHOR]

Background: The cardiometabolic index (CMI) is a new predictor of obesity-related diseases, but its link to periodontitis is under-researched. This study aims to examine the potential association between the CMI and periodontitis. Methods: We conducted a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009–2014) to examine the potential association between CMI and periodontitis. The study utilized a weighted multivariate logistic model to assess the association between TG, HDL-C, TG/HDL-C, obesity indices (BMI, WC, WHtR, CMI), and periodontitis, employing the area under the receiver operating characteristic curves (ROC) to estimate areas under the curve (AUC). Furthermore, generalized smooth curve fitting was conducted to examine the relationship between CMI and periodontitis. Finally, the study incorporated subgroup analysis and interaction tests to examine consistency across different populations. Results: TG/HDL-C, WHtR, and CMI were positively associated with periodontitis in the fully adjusted classification model. It was observed that for each unit increase in CMI, there was a corresponding 17.8% increase in the prevalence of periodontitis [1.178 (1.049, 1.322) 0.00562] and 18.7% increase in the prevalence of moderate/severe [1.187 (1.057, 1.334) 0.00376] in the fully adjusted model. When CMI was used as a categorical variable, the adjusted OR for periodontitis prevalence increased significantly with increasing CMI after adjusting for all potential covariates (T3 vs. T1: OR, 1.28 [1.06, 1.55], p < 0.05). The ROC analysis indicated that a larger area under the curve was found in the CMI [0.554 (0.538–0.570)] than in the WC [0.544 (0.528–0.560)] and WHtR [0.544 (0.528–0.561)]. Nonetheless, the discrepancy observed did not reach statistical significance (all p > 0.05). Further generalized smooth curve fitting and threshold effect models indicated a positive linear correlation between CMI and periodontitis. Moreover, there is no interactive association between TG/HDL-C, WHtR, CMI, and periodontitis. Conclusions: This cross-sectional study revealed a positive relationship between CMI and periodontitis. Further prospective studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Alcohol-associated liver disease (ALD) poses a significant global health burden and is a leading cause of liver-related morbidity and mortality. ALD encompasses a spectrum of disease states ranging from asymptomatic steatosis to acute hepatitis and cirrhosis. Alcohol use disorder (AUD) significantly increases the risk of developing ALD, and insight into AUD can provide a more complete understanding of ALD and the patients affected by these interrelated diseases. Accurate and timely identification of AUD, even in primary care, through validated screening tools combined with blood tests and imaging techniques facilitates early detection of ALD. Although liver transplantation (LT) remains the most effective treatment for end-stage ALD, patient outcomes post-LT have evolved because of shifting perspectives on ALD transplant eligibility, comprehensive pre-LT evaluations, and advancements in post-LT ALD detection. Nonetheless, addressing disparities in LT practices for ALD is paramount for ensuring equitable access to this life-saving intervention. This article offers an updated synopsis of ALD definitions, screening methodologies, and contemporary management approaches, particularly in the context of LT. [ABSTRACT FROM AUTHOR]

Background: To explore the association between periodontitis and all-cause as well as cause-specific mortality rates in U.S. adults with hyperlipidemia. Methods: Participants were extracted from NHANES during 1988–1994, 1999–2004 and 2009–2014 periods. To assess the association between moderate-to-severe periodontitis and mortality rates for both all-cause and cause-specific mortality, hazard ratios (HRs), time ratios (TRs), and their respective 95% confidence intervals (CIs) were calculated using Cox proportional hazards and Weibull accelerated failure time (AFT) models. Results: Over a median follow-up duration of 11.83 years, 4,623 deaths of 16,848 participants were recorded. Multivariate Cox regression and AFT analyses showed moderate-to-severe periodontitis were associated with an increased risk of all-cause (HR: 1.31, 95% CI: 1.20–1.44, P < 0.001; TR: 0.85, 95% CI: 0.80–0.90, P < 0.001), cardiovascular disease (CVD)-related (HR: 1.36, 95% CI: 1.14–1.63, P = 0.001; TR: 0.83, 95% CI: 0.75–0.92, P < 0.001) and cancer-related mortality (HR: 1.35, 95% CI: 1.12–1.63, P = 0.002; TR: 0.82, 95% CI: 0.72–0.93, P = 0.002). Meanwhile, there was a significant upward trend in the risk of mortality with increasing severity of periodontitis (P for trend < 0.001). Conclusions: Our study highlights the moderate-to-severe periodontitis is associated with an increased risk of all-cause, CVD-related and cancer-related mortality among U.S. adults with hyperlipidemia. And the mortality risk increasing alongside the severity of periodontitis. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA. Purpose: (1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection. Study Design: Controlled laboratory study. Methods: A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system. Results: Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05) and similar to those in the sham group (P >.05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group (P <.05) and higher than that of the sham group (P <.05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait (P <.05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks. Conclusion: Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA. Clinical Relevance: In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA. [ABSTRACT FROM AUTHOR]

Forty percent of American women are obese and at risk for type II diabetes, impaired immune function, and altered microbiome diversity, thus impacting overall health. We investigated whether obesity induced by an excess calorie, high fat diet containing hydrogenated fats, fructose, and coconut oil (HFD) altered glucose homeostasis, peripheral immunity, and urogenital microbial dynamics. We hypothesized that HFD would cause hyperglycemia, increase peripheral inflammation, and alter urogenital microbiota to favor bacterial taxonomy associated with inflammation. We utilized female Ossabaw mini-pigs to model a ‘thrifty’ metabolic phenotype associated with increased white adipose tissue mass. Pigs were fed HFD (~4570 kcal/pig/day) or lean (~2000 kcal/pig/day) diet for a total of 9 estrous cycles (~6 months). To determine the effect of cycle stage on cytokines and the microbiome, animals had samples collected during cycles 7 and 9 on certain days of the cycle: D1, 4, 8, 12, 16, 18. Vaginal swabs or cervical flushes assessed urogenital microbiota. Systemic fatty acids, insulin, glucose, and cytokines were analyzed. Pig weights and morphometric measurements were taken weekly. Obese pigs had increased body weight, length, heart and belly girth but similar glucose concentrations. Obese pigs had decreased cytokine levels (IL-1β, TNF-α, IL-4, IL-10), arachidonic acid and plasma insulin, but increased levels of vaccenic acid. Obese pigs had greater urogenital bacterial diversity, including several taxa known for anti-inflammatory properties. Overall, induction of obesity did not induce inflammation but shifted the microbial communities within the urogenital tract to an anti-inflammatory phenotype. We postulate that the coconut oil in the HFD oil may have supported normal glucose homeostasis and modulated the immune response, possibly through regulation of microbial community dynamics and fatty acid metabolism. This animal model holds promise for the study of how different types of obesity and high fat diets may affect metabolism, immune phenotype, and microbial dynamics. [ABSTRACT FROM AUTHOR]

A large body of research demonstrates that inflammation is involved in physical health problems that cause substantial morbidity and early mortality. Given inflammation's role in the etiology of chronic diseases, pediatric scientists have begun to study childhood factors that presage elevation of inflammatory biomarkers later in life. The purpose of this study was to test hypotheses designed to determine whether early adolescent emotionally intense and low attention temperaments forecast (a) inflammation at ages 25 and 29 years and (b) worsening levels of inflammation between these two data points. Toward this end, 307 Black children from the rural southeastern United States participated in an 18-year longitudinal study (mean age at baseline, 11.2 years) to determine whether and how early adolescent's behavioral styles or emotionally intense and low attention temperaments may be associated with absolute and worsening levels of inflammation in young adulthood. When children were 11–13 years of age, different teachers at each age provided assessments of emotionally intense and low attention temperaments. Thus, multiple measures of the same temperament constructs were obtained across 3 years for each participant. At age 25, participants provided data on their self-regulation abilities. Peripheral blood was collected at ages 25 and 29 years from which inflammation was quantified, using soluble urokinase plasminogen activator (suPAR), the proinflammatory cytokines interleukin (IL) IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α). Covariates associated with inflammation in prior studies were also assessed; these included socioeconomic risk, gender, cigarette smoking, body mass index (BMI), adverse childhood experiences (ACEs), depressive symptoms, and medication use. An early adolescent emotionally intense temperament was associated directly with higher suPAR and cytokine levels at age 29, and with worsening cytokine levels between ages 25 and 29. A low attention temperament was associated with suPAR levels at age 29. Collectively, these observations highlight pathways that could underlie health risks associated with early adolescent temperaments. The findings suggest that emotionally intense and low-attention early adolescent temperaments forecast higher and worsening inflammation levels across young adulthood. • This study examined whether early adolescent temperaments forecast inflammation at ages 25 and 27 years. • The hypotheses were tested with a sample of 307 Black children who participated in an 18-year longitudinal study. • Erly adolescent temperaments forecast higher and worsening levels of inflammation across young adulthood. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), afflicts over one per thousand people in the United States. The pathology of MS typically involves lesions in several regions, including the brain and spinal cord. The manifestation of MS is variable and carries great potential to negatively impact quality of life (QOL). Evidence that inflammatory markers are related to depression in MS is accumulating. However, there are barriers in precisely identifying the biological mechanisms underlying depression and inflammation. Analysis of cytokines provides one promising approach for understanding the mechanisms that may contribute to MS symptoms. Methods: In this pilot study, we measured salivary levels of interleukin (IL)-6, IL-1beta (β), and IL-10 in 24 veterans with MS. Descriptive statistics were reported and Pearson correlation coefficients were obtained between cytokines and depression. Results: The anti-inflammatory cytokine IL-10 was significantly negatively associated with depression in veterans with MS (r = −0.47, p =.024). Conclusion: Cytokines may be useful for elucidating biological mechanisms associated with the depression and a measure for nurses caring for veterans with MS. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer can create a shield of suppressive innate immune cells that stop our body's natural defenses from tumors. VTX-0811 is a new drug that targets these cells and turns them from allies of cancer to fighters against it. Preclinical tests show that it works in the lab on human cells and tumors and is safe and efficacious in animals. The results are promising and pave the way for human trials to see if VTX-0811 can become a new powerful weapon against cancer. Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance. [ABSTRACT FROM AUTHOR]

Background: Depression is a common mental disorder with a much higher prevalence in women than in men. Although there has been a gradual increase in research on the association between reproductive health and depression, there is still some inconsistency in the evidence of the relationship between pregnancy loss and depression. This study aimed to investigate the relationship between pregnancy loss and depressive symptoms. Methods: We analyzed data from the 2007–2020 National Health and Nutrition Examination Survey (NHANES), which included female participants aged 20 to 80 years. Pregnancy loss was determined based on participants' self-reported number of pregnancies and pregnancy outcomes. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9, score ≥ 10). Multivariate logistic regression, smoothed curve fitting, and generalized additive modeling were used to examine the association between pregnancy loss and depression. We also performed sensitivity analyses and subgroup analyses to verify the robustness and specificity of the findings. Results: A total of 12,873 female participants were included in our study, of which 1,595 (12.39%) were categorized as depressed. Multivariate logistic regression results indicated that experiencing a pregnancy loss increased the risk of prevalence of depression in women (for 1 loss: OR = 1.31, 95% CI 1.15,1.50; for 2 or more losses: OR = 1.58, 95% CI 1.38, 1.81). When sensitivity analyses were performed, an association between pregnancy loss and depression was found in both multivariate linear regressions with PHQ-9 scores as a continuous variable and multivariate logistic regressions with a threshold of 5 PHQ-9 scores. The association between pregnancy loss and depression remained stable across subgroups. Conclusion: Pregnancy loss correlated with elevated PHQ-9 scores and a heightened risk of depression in adult women across the United States. Focusing on the incidence of adverse pregnancy events in the female population may help prevent or early recognize the onset of depression. Highlights: We analyzed the relationship between pregnancy loss and depression in American adult women. The sample size was large and nationally representative. Pregnancy loss was associated with higher PHQ-9 scores and an increased likelihood of depression among adult women. Our study is expected to provide more effective strategies to mitigate the impact of adverse pregnancy events on women's mental health. [ABSTRACT FROM AUTHOR]

Background: Psychiatric disorders may be a risk factor for long COVID, broadly defined as COVID-19 conditions continuing three months post-acute infection. In US Veterans with high psychiatric burden, we examined associations between psychiatric disorders and clinical diagnosis of long COVID. Methods: We conducted a retrospective cohort study using health records from VA patients with a positive SARS-CoV-2 test from February 2020 to February 2023. Generalized linear models estimated associations between any psychiatric disorder and likelihood of subsequent diagnosis with long COVID (i.e. two or more long COVID clinical codes). Models were adjusted for socio-demographic, medical, and behavioral factors. Secondary models examined individual psychiatric disorders and age-stratified associations. Results: Among 660 217 VA patients with positive SARS-CoV-2 tests, 56.3% had at least one psychiatric disorder diagnosis and 1.4% were diagnosed with long COVID. Individuals with any psychiatric disorder had higher risk for long COVID diagnosis in models adjusted for socio-demographic factors, vaccination status, smoking, and medical comorbidities (relative risk, RR = 1.28, 95% CI 1.21–1.35), with the strongest associations in younger individuals. Considering specific disorders, depressive, anxiety, and stress-related disorders were associated with increased risk for long COVID diagnoses (RRs = 1.36–1.48), but associations were in the opposite direction for substance use and psychotic disorders (RRs = 0.78–0.88). Conclusions: Psychiatric disorder diagnoses were associated with increased long COVID diagnosis risk in VA patients, with the strongest associations observed in younger individuals. Improved surveillance, treatment, and prevention for COVID-19 and its long-term sequelae should be considered for individuals with psychiatric conditions. [ABSTRACT FROM AUTHOR]

Background Studies performed to calculate metabolic rate in stroke patients have conflicting results. The indirect calorimetry is the gold standard in measuring resting energy expenditure. We compared the intensive care unit (ICU) mortality and outcome in stroke patients receiving enteral nutrition based on energy requirement calculated by either indirect calorimetry or standard weight-based formula. Methods Twenty ischemic stroke patients of older than 40 years requiring greater than 2 days of mechanical ventilation were prospectively enrolled. Demographic data, Glasgow Coma Scale (GCS), Canadian Neurological Scale, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were obtained. Patients were randomized to receive enteral nutrition based on energy requirement calculated either by indirect calorimeter (group REE IC) or by standard weight-based measurements (group REE ST). Daily ventilatory parameters, Sequential Organ Failure Assessment (SOFA) score, and blood parameters were noted. The ICU mortality/duration of stay/complication and duration of hospital stay were compared. Patient outcome at discharge was assessed using modified Rankin scale (MRS). Results Baseline characteristics were comparable. There were no ICU deaths in group REE IC. Patients in group REE IC had significantly (p < 0.01) more resting energy requirement and less maximum negative energy balance than those in group REE ST. The SOFA score at days 5, 7, and 9 and the total leukocyte count (TLC) at day 5 were higher in group REE ST. The duration of mechanical ventilation, ICU stay/complications, duration of hospital stay, and MRS at discharge were comparable. Conclusion Ischemic stroke patients receiving indirect calorimetry–guided enteral nutrition had lesser incidence of organ failure but similar ICU stay and mortality and neurological outcome as compared with those receiving standard weight-based enteral nutrition. [ABSTRACT FROM AUTHOR]

Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (pre-F) antigen were approved in the United States. We aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based protocol for the practical and large-scale evaluation of RSV vaccines. Two modified pre-F proteins (DS-Cav1 and SC-TM) were produced by genetic recombination and replication using an adenoviral vector. The protocol was established by optimizing the concentrations of the coating antigen (pre-F proteins), secondary antibodies, and blocking buffer. To validate the protocol, we examined its accuracy, precision, and specificity using serum samples from 150 participants across various age groups and the standard serum provided by the National Institute of Health. In the linear correlation analysis, coating concentrations of 5 and 2.5 μg/mL of DS-Cav1 and SC-TM showed high coefficients of determination (r > 0.90), respectively. Concentrations of secondary antibodies (alkaline phosphatase-conjugated anti-human immunoglobulin G, diluted 1:2000) and blocking reagents (5% skim milk/PBS-T) were optimized to minimize non-specific reactions. High accuracy was observed for DS-Cav1 (r = 0.90) and SC-TM (r = 0.86). Further, both antigens showed high precision (coefficient of variation < 15%). Inhibition ELISA revealed cross-reactivity of antibodies against DS-Cav1 and SC-TM, but not with the attachment (G) protein. [ABSTRACT FROM AUTHOR]

Objectives: Angiopoietins modulate endothelial permeability via endothelial cell junctions. Angiopoietin-2 blocks the angiopoietin-1/Tie-2 interaction that stabilizes these junctions, and elevated plasma angiopoietin-2 levels are associated with vascular leakage. We hypothesized that plasma angiopoietin-1 and angiopoietin-2 levels are associated with indirect markers of increased vascular permeability, organ dysfunction, mortality, and plasma proinflammatory cytokine levels in human septic shock.Design: Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).Setting: ICUs of hospitals in Canada, Australia, and the United States.Patients: Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock.Interventions: None.Measurement and Main Results: We measured plasma levels of angiopoietin-1 and angiopoietin-2 at study baseline and determined their association with percent fluid overload and acute organ dysfunction and generated a receiver operating characteristic curve for plasma angiopoietin-2 levels versus acute kidney injury. We also determined the association of angiopoietin-1 and angiopoietin-2 levels with hemodynamics, mortality, and plasma cytokine levels. Plasma angiopoietin-2 levels were directly associated with percent fluid overload at baseline (rs = 0.18; p = 0.0008) and at 6 hours (rs = 0.13; p = 0.023), but not at 24 hours (rs = 0.041; p = 0.46). Plasma angiopoietin-2 levels were associated with the development of hepatic (p < 0.0001) and coagulation (p < 0.0001) dysfunction and acute kidney injury (p < 0.0001). Receiver operating characteristic curve had an area under the curve of 0.73 for acute kidney injury. angiopoietin-2 levels were also inversely associated with days alive (r = -0.24; p = 0.010) and positively associated with increased 7-day (log-rank trend chi-square = 5.9; p = 0.015) and 28-day (log-rank chi square = 4.9; p = 0.027) mortality. A threshold of angiopoietin-2 levels above the first quartile (> 5,807 pg/mL) was observed to be associated with increased mortality risk, which aligns with prior studies. Plasma angiopoietin-2 levels were positively associated with plasma cytokine levels, including tumor necrosis factor-α and interleukin-6 at baseline (rs = 0.39; p < 0.0001 and rs = 0.51; p < 0.0001) and at 24 hours (rs = 0.29; p < 0.0001 and rs = 0.41; p < 0.0001).Conclusions: Increased plasma angiopoietin-2 levels are associated with increased fluid overload, hepatic and coagulation dysfunction, acute kidney injury, mortality, and plasma cytokines in human septic shock. angiopoietin-2 activation may increase vascular leakage leading to increased fluid requirements, organ dysfunction, and death from septic shock. [ABSTRACT FROM AUTHOR]

Purpose: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US)., Methods: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed., Findings: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available., Implications: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Rural regions of the western United States have experienced a noticeable surge in both the frequency and severity of acute wildfire events, which brings significant challenges to both public safety and environmental conservation efforts, with impacts felt globally. Identifying factors contributing to immune dysfunction, including endocrinological phenotypes, is essential to understanding how hormones may influence toxicological susceptibility. Methods: This exploratory study utilized male and female C57BL/6 mice as in vivo models to investigate distinct responses to acute woodsmoke (WS) exposure with a focus on sex-based differences. In a second set of investigations, two groups were established within the female mouse cohort. In one group, mice experienced ovariectomy (OVX) to simulate an ovarian hormone-deficient state similar to surgical menopause, while the other group received Sham surgery as controls, to investigate the mechanistic role of ovarian hormone presence in driving immune dysregulation following acute WS exposure. Each experimental cohort followed a consecutive 2-day protocol with daily 4-h exposure intervals under two conditions: control HEPA-filtered air (FA) and acute WS to simulate an acute wildfire episode. Results: Metals analysis of WS particulate matter (PM) revealed significantly increased levels of 63Cu, 182W, 208Pb, and 238U, compared to filtered air (FA) controls, providing insights into the specific metal components most impacted by the changing dynamics of wildfire occurrences in the region. Male and female mice exhibited diverse patterns in lung mRNA cytokine expression following WS exposure, with males showing downregulation and females displaying upregulation, notably for IL-1β, TNF-α, CXCL-1, CCL-5, TGF-β, and IL-6. After acute WS exposure, there were notable differences in the responses of macrophages, neutrophils, and bronchoalveolar lavage (BAL) cytokines IL-10, IL-6, IL-1β, and TNF-α. Significant diverse alterations were observed in BAL cytokines, specifically IL-1β, IL-10, IL-6, and TNF-α, as well as in the populations of immune cells, such as macrophages and polymorphonuclear leukocytes, in both Sham and OVX mice, following acute WS exposure. These findings elucidated the profound influence of hormonal changes on inflammatory outcomes, delineating substantial sex-related differences in immune activation and revealing altered immune responses in OVX mice due to ovarian hormone deficiency. In addition, the flow cytometry analysis highlighted the complex interaction between OVX surgery, acute WS exposure, and their collective impact on immune cell populations within the hematopoietic bone marrow niche. Conclusions: In summary, both male and female mice, alongside females subjected to OVX and those who had sham surgery, exhibit significant variations in the expression of proinflammatory cytokines, chemokines, lung mRNA gene expression, and related functional networks linked to signaling pathways. These differences potentially act as mediators of sex-specific and hormonal influences in the systemic inflammatory response to acute WS exposure during a wildfire event. Understanding the regulatory roles of genes expressed differentially under environmental stressors holds considerable implications, aiding in identifying sex-specific therapeutic targets for addressing acute lung inflammation and injury. [ABSTRACT FROM AUTHOR]

Hypertension is associated with increased risk of cardiovascular disease and death. Evidence suggests that Mg2+ depletion contributes to hypertension. It is estimated that 25% or more of the United States population experiences chronic, latent Mg2+ depletion. This review explores mechanisms by which Mg2+ influences blood pressure, modifying risk of hypertension and complicating its treatment. Mechanisms addressed include effects upon i) sympathetic tone, via the modulation of N-methyl-D-aspartate (NMDA) receptor and N-type Ca2+ channel activity, influencing catecholamine release from sympathetic nerve endings; ii) vascular tone, via alteration of L-type Ca2+ and endothelial nitric oxide synthase (eNOS) activity and prostacyclin release; iii) renal K+ handling, influencing systemic K+ balance and potentially indirectly influencing blood pressure; iv) aldosterone secretion from the adrenal cortex; and v) modulation of pro-hypertensive inflammatory processes in dendritic cells and macrophages, including activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and stimulation of isolevuglandin (IsoLG) production. Discovery of these mechanisms has furthered our understanding of the pathogenesis of hypertension, with implications for treatment and has highlighted the role of Mg2+ balance in hypertension and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods: Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results: Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions: Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments. Highlights: This is the first study to examine the contribution of sex on CIH-induced inflammation, steroid hormones, oxidative stress, and behavioral dysfunction in rats. CIH increased circulating inflammation and fine motor dysfunction in females, whereas CIH increased circulating oxidative stress and compulsivity in males. Inhibition of mitochondrial oxidative stress blocked sex-specific effects of CIH in males and females. CIH induced recollective memory impairments in males and females, which was not prevented by blocking mitochondrial oxidative stress. Plain language summary: Sleep apnea is a common sleeping condition in adults with a wide range of symptoms that include inflammation, oxidative stress, memory problems, anxiety, and compulsivity. Men are diagnosed with sleep apnea more often than women. Although there is limited information on how sleep apnea affects men and women differently, previous studies suggest that women may exhibit different sleep apnea symptoms than men. To examine the impact of male and female sex on common sleep apnea symptoms, we exposed adult male and female rats to a model of sleep apnea called chronic intermittent hypoxia (CIH). We found that many effects of CIH were different in males and females. CIH females had increased inflammation and motor problems, whereas CIH males had increased oxidative stress and compulsivity. To investigate the reason for these CIH sex differences, we blocked mitochondrial oxidative stress. Blocking mitochondrial oxidative stress decreased CIH associated sex differences. However, blocking mitochondrial oxidative stress had no impact on CIH-induced memory impairment that was observed in male and female rats. Our findings support previous reports that suggest that women exhibit different sleep apnea symptoms than men. Further, we extend these findings by showing that mitochondrial oxidative stress is involved in these sex differences. Clinically, patients diagnosed with sleep apnea are typically treated with continuous positive airway pressure (CPAP) machines, which have high rates of non-compliance (15–40%). Therefore, understanding why sleep apnea is causing these symptoms will be important in developing therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Image-guided stereotactic body radiation therapy (SBRT), utilizing biocompatible superparamagnetic iron oxide nanoparticles (SPION), like ferumoxytol, has emerged as a non-invasive, safe, and effective therapy for liver tumors. However, the radiomodulating properties of ferumoxytol on hepatic macrophages have never been directly investigated. We showed that ferumoxytol affected human monocytes increasing their resistance to radiation-induced cell death. These findings provide the basis for mechanism-based optimization of SPION-enhanced image-guided functional treatment planning platform for reducing hepatotoxicity in patients with advanced hepatic cirrhosis undergoing liver SBRT for liver cancer before liver transplant. Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, while it persists as the fourth most prevalent cause of cancer-related death in the United States of America. Although there are several novel therapeutic strategies for the approach of this intensely aggressive tumor, it remains a clinical challenge, as it is hard to identify in early stages, due to its asymptomatic course. A diagnosis is usually established when the disease is already in its late stages, while its chemoresistance constitutes an obstacle to the optimal management of this malignancy. The discovery of novel diagnostic and therapeutic tools is considered a necessity for this tumor, due to its low survival rates and treatment failures. One of the most extensively investigated potential diagnostic and therapeutic modalities is extracellular vesicles (EVs). These vesicles constitute nanosized double-lipid membraned particles that are characterized by a high heterogeneity that emerges from their distinct biogenesis route, their multi-variable sizes, and the particular cargoes that are embedded into these particles. Their pivotal role in cell-to-cell communication via their cargo and their implication in the pathophysiology of several diseases, including pancreatic cancer, opens new horizons in the management of this malignancy. Meanwhile, the interplay between pancreatic carcinogenesis and short non-coding RNA molecules (micro-RNAs or miRs) is in the spotlight of current studies, as they can have either a role as tumor suppressors or promoters. The deregulation of both of the aforementioned molecules leads to several aberrations in the function of pancreatic cells, leading to carcinogenesis. In this review, we will explore the role of extracellular vesicles and miRNAs in pancreatic cancer, as well as their potent utilization as diagnostic and therapeutic tools. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains. In this review, we summarized the phenotypes of a few commonly used as well as newly developed mouse models in translational research laboratories including the presence or absence of key pathological features of AD such as amyloid and tau pathology, synaptic and neuronal degeneration as well as cognitive and behavior deficits. In addition, advantages and limitations of these AD mouse models have been elaborated along with discussions of any sex-specific features. More importantly, the omics data from available AD mouse models have been analyzed to categorize molecular signatures of each model reminiscent of human AD brain changes, with the hope to guide future selection of most suitable models for specific research questions to be addressed in the AD field. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences, which result in the specific destruction of insulin‐producing pancreatic β‐cells. Currently, there are over 1.6 million cases of T1D in the United States with a worldwide incidence rate that has been increasing since 1990. Here, we examined the effect of Cornus officinalis (CO), a well‐known ethnopharmacological agent, on a T1D model of the non‐obese diabetic (NOD) mouse. A measured dose of CO extract was delivered into 10‐week‐old NOD mice by oral gavage for 15 weeks. T1D incidence and hyperglycemia were significantly lower in the CO‐treated group as compared to the water gavage (WT) and a no handling or treatment control group (NHT) following treatment. T1D onset per group was 30%, 60% and 86% for the CO, WT and NHT groups, respectively. Circulating C‐peptide was higher, and pancreatic insulitis was decreased in non‐T1D CO‐treated mice. Our findings suggest that CO may have therapeutic potential as both a safe and effective interventional agent to slow early stage T1D progression. [ABSTRACT FROM AUTHOR]

The aim of this study is to enhance comprehension of the different types and features of dementia, including their symptoms, diagnosis and medical treatment, and to propose various evidence-based exercise interventions and their clinical applications tailored to each specific type of dementia. The theoretical review includes the analysis of publications in the scientific databases PubMed/Medline, Ebsco, Scielo, and Google. A total of 177 articles were found, of which 84 were studied in depth. With the prevalence of all forms of dementia projected to increase from 57.4 million in 2019 to 152.8 million in 2050, personalized treatment strategies are needed. This review discusses various forms of dementia, including their pathologies, diagnostic criteria, and prevalence rates. The importance of accurate diagnosis and tailored care is emphasized, as well as the effectiveness of physical exercise in improving cognitive function in dementia patients. For Alzheimer's, a combination of drug therapies and exercises is recommended to enhance cerebral blood flow and neurotransmitter activity. To improve cognitive and motor functions in Lewy body dementia, a combination of pharmacological and physical therapies is recommended. For managing frontotemporal dementia, a mix of medication and exercises aimed at emotion regulation, including aerobic exercises, and a unified protocol, is suggested. For mild cognitive impairment, aerobic and functional exercises are important in delaying cognitive decline and enhancing cognitive performance. In conclusion, individualized care and treatment plans tailored to the specific characteristics of each disease type can improve the quality of life for individuals with this condition and effectively manage this growing global health issue. [ABSTRACT FROM AUTHOR]

Background. Methicillin-resistant Staphylococcus aureus (MRSA) has become a major health threat in the United States. Staphylococcal enterotoxin B (SEB) is a potent superantigen that contributes to its virulence. High mortality and frequent failure of therapy despite available antibiotics have stimulated research efforts to develop adjunctive therapies.Methods. Treatment benefits of SEB-specific monoclonal antibody (mAb) 20B1 were investigated in mice in sepsis, superficial skin, and deep-tissue infection models.Results. Mice challenged with a SEB-producing MRSA strain developed fatal sepsis, extensive tissue skin infection, and abscess-forming deep-seeded thigh muscle infection. Animals preimmunized against SEB or treated passively with mAb 20B1 exhibited enhanced survival in the sepsis model, whereas decrease of bacterial burden was observed in the superficial skin and deep-tissue models. mAb 20B1 bound to SEB in the infected tissue and decreased abscess formation and proinflammatory cytokine levels, lymphocyte proliferation, and neutrophil recruitment.Conclusions. mAb 20B1, an SEB-neutralizing mAb, is effective against MRSA infection. mAb 20B1 protects against lethal sepsis and reduces skin tissue invasion and deep-abscess formation. The mAb penetrates well into the abscess and binds to SEB. It affects the outcome of S. aureus infection by modulating the host's proinflammatory immune response. [ABSTRACT FROM PUBLISHER]

Salmonella infections are reported as the second most common pathogen caused foodborne disease in the United States, and several Salmonella serovars can colonize in the intestinal tracts of poultry. Reducing Salmonella in poultry is crucial to decrease the incidence of salmonellosis in humans. In this study, we evaluated the immune response of chicken macrophage cells ( HD-11) and effects of bacteriophage P22 against the extra- and intracellular S. Typhimurium LT2. Four treatments, (1) HD-11 cells as control, (2) HD-11 cells with LT2, (3) HD-11 cells with LT2 and P22, and (4) HD-11 cells with P22, were administered, and IL-8 responses of HD-11 cells were measured using an ELISA. Also, four cytokine ( IL-4, IL-8, IL-10, and IFN-γ) gene expression levels in the presence of LT2 and/or P22 were quantified by qRT- PCR. We found that P22 lysed the extra- and intracellular LT2, which adhered and were taken up by the HD-11 cells. The ELISA indicated that HD-11 cells produced significantly higher IL-8 cytokine levels in the supernatant during the intracellular lyses of LT2 by P22 ( P < 0.05). The IL-8 expression levels measured by qRT- PCR also exhibited similar results with the IL-8 production based on ELISA measurements. [ABSTRACT FROM AUTHOR]

Abstract: Despite vaccine efforts, influenza outbreaks pose a significant threat to global public health. There are two commercially available seasonal influenza vaccines in the United States: the trivalent inactivated vaccine (TIV), delivered parenterally, and the live attenuated influenza vaccine (LAIV), delivered intranasally. Although both vaccines are generally efficacious, the immunologic mechanisms which contribute to protective immunity are incompletely understood. Thus, we investigated the protracted effects of TIV and LAIV on serum cytokine profiles at 14 and 28days post-vaccination (when antibody titers are peak) in healthy adults over two influenza seasons. Vaccination with TIV was associated with a small, yet significant, decrease in the levels of both IL-8 and TNF-α at 14 and 28days post-vaccination. LAIV, however, had no impact on serum cytokine levels. Similarly, analysis of serum antibody titers indicated that TIV recipients had a significantly higher sero-response rate compared to LAIV recipients, as has been previously shown. Finally, we examined the relationship between baseline serum cytokine levels and antibody responses to TIV (LAIV recipients were excluded due to the poor sero-response rate). Interestingly, in TIV recipients pre-vaccination levels of IL-8 were higher in sero-responders compared to non-responders. Collectively, these data suggest that cytokines may influence vaccine outcomes and indicate that parenteral immunization with TIV induces a sustained, systemic cytokine response which lasts for weeks. [Copyright &y& Elsevier]

Summary: A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms. Introduction: Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins' potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion. Methods: Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass ( N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset. Results: Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h. Conclusions: Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. [ABSTRACT FROM AUTHOR]

The article presents a comparative study of low white blood cell counts (WBC) and absolute neutrophil counts (ANC) from six ethnic groups in the U.S. and the Caribbean Area. The methodology of the study made use of 261 healthy women blood samples and is analyzed based on the growth factor levels and cytokine levels. The study concludes that there is a strong association of neutropenia in a certain ethnic group.

Differences in incidence and outcome of cancer among ethnic groups may be explained by biological and/or socio-economic factors. Genetic variations that affect chronic inflammation, a potentially important risk factor for carcinogenesis, may differ across ethnic groups. Such differences may help explain cancer disparities among these groups. Single nucleotide polymorphisms (SNPs) within cytokine genes can affect cytokine levels and the degree of inflammation. Associations between cancer and some cytokine SNPs have been suggested. However, these have not been consistently replicated among populations, suggesting that SNP function may differ according to ethnicity, or that SNPs alone do not completely account for regulation of inflammation. We examined seven polymorphisms in African-American ( n = 294) and Caucasian ( n = 299) newborns in Louisiana: IL1B-511C > T, IL1B-31T > C, IL1B + 3954C > T, IL1RN*2, IL10-1082G > A, IL10-592C > A, and TNF-308G > A. African-American newborns had significantly higher frequencies of IL1B-511T, IL1B-31C, IL10-1082A and IL10-592A alleles and complete linkage equilibrium between IL1B + 3954 and IL1B-31. In contrast, IL1B + 3954T, IL1RN*2, and TNF-308A were more frequent in Caucasian newborns and exhibited strong linkage disequilibrium between IL1B + 3954 and IL1B-31. All allelic frequencies were significantly different between groups. We hypothesize that these dissimilarities may contribute to differences in the inflammatory response and cancer incidence and mortality between African-Americans and Caucasians in Louisiana. [ABSTRACT FROM AUTHOR]

The study describes cytokine response to pneumonia in association with severe sepsis and death. It involved 1,886 patients with community-acquired pneumonia (CAP) from 28 hospitals in the United States. Proinflammatory interleukin 6 (IL-6) and the anti-inflammatory interleukin 10 (IL 10) levels in the plasma were measured and the development of severe sepsis and 90-day mortality were monitored. It was found that 82 percent of the CAP patients had elevated cytokine response. A total of 583 patients developed severe sepsis, of whom 149 died. Highest mortality risks were found with increased IL-6 and IL-10 cytokine activity. It was concluded that cytokine response to pneumonia is varied, whether or not severe sepsis develops, and that elevated cytokine levels result in increased mortality.

The association between the systemic immune-inflammation index (SII) and the risk of sarcopenia has not yet been revealed. The purpose of this study was to investigate the relationship between the SII and sarcopenia in individuals aged 18–59 years. All data for this study are from the National Health and Nutrition Examination Survey (NHANES) database, including 7258 participants (age range: 18–59 years). We divided SII values by quartiles (quartiles 1–4: 0.3–3.1, 3.2–4.4, 4.4–6.2, and 6.2–58.5). We constructed a multivariate logistic regression model to assess the association between the SII and the risk of sarcopenia, and an interaction test was run to test the stability of the model and identify high-risk individuals with sarcopenia. Compared to nonsarcopenia participants, sarcopenia patients had a significantly higher SII value (weighted average: 6.65 vs. 5.16) (P = 0.002). Multivariate logistic regression results showed a positive linear relationship between the SII and sarcopenia (OR [odds ratio] = 1.12, 95% CI [confidence interval] 1.03–1.21). Compared to the quartile 1 group, the quartile 4 group was associated with a higher risk of sarcopenia (OR = 3.94, 95% CI 1.42–10.94). Compared with the quartile 1 group, the OR value of the quartile 2 to quartile 4 groups showed an upwards trend (Ptrend < 0.001) as the level of SII increased. Subgroup analysis also indicate that the correlation between higher SII values and the risk of sarcopenia was stable. There was a significant positive linear relationship between SII and sarcopenia, indicating that higher SII values can increase the risk of sarcopenia in individuals aged 18–59 in the United States. The findings of this study will be beneficial in promoting the use of SII alone or in combination with other tools for the risk screening of sarcopenia in communities or large populations. [ABSTRACT FROM AUTHOR]

Background: Little is known regarding the impact of serum carotenoids, a class of compounds having anti-inflammatory and antioxidant properties, on migraine. This study aimed to examine the association between serum carotenoid levels and migraine risk among United States adults., Methods: This cross-sectional study recruited 7744 individuals aged 20 years or older from the National Health and Nutrition Examination Survey conducted between 2001 and 2004. The concentrations of five serum carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin) and retinol were measured using high-performance liquid chromatography. Migraine was diagnosed when participants reported that they had severe headaches or migraines during the past three months. Weighted multivariable logistic regression and restricted cubic spline models were used to determine the association between serum carotenoid levels and migraine risk., Results: Among the 7744 participants enrolled in the study, 1595 (20.6%) had migraine. Compared with the lowest quartiles, the highest quartiles of the three serum carotenoids were associated with a lower risk of migraine, with a multivariable-adjusted odds ratio (OR) of 0.74 (95% confidence interval [CI], 0.57-0.97) for α-carotene, 0.64 (95% CI, 0.49-0.83) for β-carotene, and 0.64 (95% CI, 0.53-0.78) for lutein + zeaxanthin, while the third quartile of serum β-cryptoxanthin had lower odds of migraine (OR, 0.70; 95% CI, 0.54-0.90). The U-shaped patterns of nonlinear relationships between serum β-cryptoxanthin and lutein + zeaxanthin levels and migraine risk were represented by restricted cubic splines. No association was observed between serum lycopene and retinol levels and migraine., Conclusions: Low serum carotenoid levels were associated with an increased risk of migraine. Further prospective investigations are warranted to clarify the causative relationship and explore the possible prevention and treatment of migraine using carotenoid supplementation., Competing Interests: Declarations. Ethical approval and consent to participate: Ethical approval was obtained from the National Center for Health Statistics Ethics Review Board, and all participants signed the informed consent. Conflict of interest: None., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We investigated the association of female reproductive factors with periodontitis., Materials and Methods: This cross-sectional study analyzed data from the US National Health and Nutrition Examination Survey 2009-2014 on 2321 women aged 45-80 years who had full-mouth periodontal examination and reproductive questionnaire. The 2018 World Workshop Classification of Periodontal and Peri-implant Diseases was used to classify periodontitis stages., Results: After adjustment, > 3 pregnancies or live births were associated with increased stage III/IV periodontitis but age at first birth (AFB) > 23 years and female hormone use were associated with decreased stage III/IV periodontitis, while there were no associations of oral contraceptive use or menopause status with stage III/IV periodontitis. Stage III/IV periodontitis was more common in women with > 3 pregnancies or live births and AFB ≤ 23 years or never using female hormones but less common in women with ≥ 3 pregnancies or > 3 live births and AFB > 23 years or using female hormones. >3 pregnancies or live births were related with increased stage III/IV periodontitis and increased AFB was related with lowered stage III/IV periodontitis in overweight and smoking subgroups but using female hormone was related with reduced stage III/IV periodontitis in nonsmoking, non-overweight and black subgroups., Conclusions: >3 pregnancies/live births were related with severe periodontitis but AFB > 23 years and female hormone use were related with ameliorating periodontitis., Clinical Relevance: Women with > 3 pregnancies/live births should receive intensive periodontal interventions. Female hormone therapy or AFB > 23 years may be beneficial for periodontal health of > 3 pregnancies/live births women., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Natural products have always served as an important source of drugs for treating various diseases. Among various privileged natural product scaffolds, the benzopyrone class of compounds has a substantial presence among biologically active compounds. One of the pioneering anticoagulant drugs, warfarin approved in 1954 bears a benzo-α-pyrone (coumarin) nucleus. The widely investigated psoriasis drugs, methoxsalen, and trioxsalen, also contain a benzo-α-pyrone nucleus. Benzo-γ-pyrone (chromone) containing drugs, cromoglic acid, and pranlukast were approved as treatments for asthma in 1982 and 2007, respectively. Numerous other small molecules with a benzopyrone core are under clinical investigation. The present review discusses the discovery, absorption, distribution, metabolism, excretion properties, and synthetic approaches for the Food and Drug Administration-approved and clinical-stage benzopyrone class of compounds. The role of the pyrone core in biological activity has also been discussed. The present review unravels the potential of benzopyrone core in medicinal chemistry and drug development., (© 2024 Wiley Periodicals LLC.)

Prostate cancer is a leading cause of cancer-related deaths in men in the United States. Although treatable when detected early, prostate cancer commonly transitions to an aggressive castration-resistant metastatic state. While taxane chemotherapeutics such as docetaxel are mainstay treatment options for prostate cancer, taxane resistance often develops. Fatty acid binding protein 5 (FABP5) is an intracellular lipid chaperone that is upregulated in advanced prostate cancer and is implicated as a key driver of its progression. The recent demonstration that FABP5 inhibitors produce synergistic inhibition of tumor growth when combined with taxane chemotherapeutics highlights the possibility that FABP5 may regulate other features of taxane function, including resistance. Employing taxane-resistant DU145-TXR cells and a combination of cytotoxicity, apoptosis, and cell cycle assays, our findings demonstrate that FABP5 knockdown sensitizes the cells to docetaxel. In contrast, docetaxel potency was unaffected by FABP5 knockdown in taxane-sensitive DU145 cells. Taxane-resistance in DU145-TXR cells stems from upregulation of the P-glycoprotein ATP binding cassette subfamily B member 1 (ABCB1). Expression analyses and functional assays confirmed that FABP5 knockdown in DU145-TXR cells markedly reduced ABCB1 expression and activity, respectively. Our study demonstrates a potential new function for FABP5 in regulating taxane sensitivity and the expression of a major P-glycoprotein efflux pump in prostate cancer cells. [ABSTRACT FROM AUTHOR]

For a searchable version of these abstracts, please visit www.acrabstracts.org. [ABSTRACT FROM AUTHOR]

Background: Mood disorders are very common among adolescents and include mainly bipolar disorder (BD) and major depressive disorder (MDD), with overlapping depressive symptoms that pose a significant challenge to realizing a rapid and accurate differential diagnosis in clinical practice. Misdiagnosis of BD as MDD can lead to inappropriate treatment and detrimental outcomes, including a poorer ultimate clinical and functional prognosis and even an increased risk of suicide. Therefore, it is of great significance for clinical management to identify clinical symptoms or features and biological markers that can accurately distinguish BD from MDD. With the aid of bibliometric analysis, we explore, visualize, and conclude the important directions of differential diagnostic studies of BD and MDD in adolescents. Materials and methods: A literature search was performed for studies on differential diagnostic studies of BD and MDD among adolescents in the Web of Science Core Collection database. All studies considered for this article were published between 2004 and 2023. Bibliometric analysis and visualization were performed using the VOSviewer and CiteSpace software. Results: In total, 148 publications were retrieved. The number of publications on differential diagnostic studies of BD and MDD among adolescents has been generally increasing since 2012, with the United States being an emerging hub with a growing influence in the field. Boris Birmaher is the top author in terms of the number of publications, and the Journal of Affective Disorders is the most published journal in the field. Co-occurrence analysis of keywords showed that clinical characteristics, genetic factors, and neuroimaging are current research hotspots. Ultimately, we comprehensively sorted out the current state of research in this area and proposed possible research directions in future. Conclusion: This is the first-ever study of bibliometric and visual analyses of differential diagnostic studies of BD and MDD in adolescents to reveal the current research status and important directions in the field. Our research and analysis results might provide some practical sources for academic scholars and clinical practice. [ABSTRACT FROM AUTHOR]