Evaluating age-associated phenotypes in a mouse model of protein dyshomeostasis

Proteotoxicity caused by an imbalanced protein quality control surveillance system is believed to contribute to the phenotypes associated with aging as well as many neurodegenerative diseases. Understanding and monitoring the impact of proteotoxicity in these processes offers researchers keen insight into the biology of aging, as well as other conditions that share similar pathological etiologies. In this methods review we present various technical approaches that can be used to calculate and characterize the phenotypes associated with aging that are linked to increased proteotoxicity. Methods such as the measurement of oligomer protein expression and the capacity of proteasome function are useful tools in observing both aging phenotypes and neurodegenerative diseases, both of which share the phenomenon of impaired protein homeostasis

Endothelial toll-like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a.

We previously reported that the canonical innate immune receptor toll-like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic-specific, lung- and cell-targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4-/- mice. Lung Ec-silencing of TLR4 in wild-type mice induced emphysema, highlighting the specific and distinct role of Ec-expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16INK4a , a senescence-associated gene. Lung Ec-p16INK4a -silencing prevented TLR4-/- induced emphysema, revealing a new functional role for p16INK4a in lungs. TLR4 suppressed endogenous p16INK4a expression via HDAC2-mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence-related gene expression

Bis(4-cyano-1-methyl­pyridinium) bis­(1,2-dicyano­ethene-1,2-dithiol­ato-κ2 S,S′)cuprate(II)

The title ion-pair compound, (C7H7N2)2[Cu(C4N2S2)2], was obtained by the direct reaction of CuCl2·2H2O, disodium maleonitrile­dithiol­ate (Na2mnt) and 4-cyano-1-methyl­pyridinium iodide. The anion and one pyridinium cation lie entirely on a mirror plane, whereas for the other cation, a crystallographic mirror plane runs through the N and para-C atoms of the pyridine ring, the methyl C atom, and the cyano group. In the crystal, ions are linked into a three-dimensional network by C—H⋯N hydrogen bonds

Association between frequency of muscle-strengthening exercise and depression symptoms among middle and high school students: cross-sectional survey study

Background: Existing literature on the association between the frequency of muscle-strengthening exercise (MSE) and depression among adolescents is limited and contradictory. Objective: This study aimed to elucidate the association of MSE frequency with depression symptoms among middle and high school students in China. Methods: A total of 27,070 students in grades 7-12 from 376 middle and high schools were surveyed using an anonymous self-administered questionnaire between April and June 2022. Information on engaging in MSE was self-reported, and depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Poisson regression was used to examine the association between MSE frequency and depression symptoms. Results: Among the 27,006 eligible students, 51.6% (n=13,933) were boys, and the mean age was 15.6 (SD 1.7) years. The overall prevalence of meeting MSE recommendations (ie, engaging in MSE ≥3 days/week) was 34.6% (95% CI 32.6%-36.6%; n=9145); the prevalence was higher in boys (43.8%, 95% CI 41.8%-45.8%; 6067/13,933) than in girls (24.3%, 95% CI 22%-26.6%; 3078/13,073; P Conclusions: The overall prevalence of meeting MSE recommendations among Chinese adolescents is low. The frequency of MSE was inversely associated with depression symptoms

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus

Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

TRPM7 is a potential therapeutic target for treatment of prostate cancer. In this study, we investigated the effects of nonselective TRPM7 inhibitor carvacrol on cell proliferation, migration, and invasion of prostate cancer PC-3 and DU145 cells. Our results showed that carvacrol blocked TRPM7-like currents in PC-3 and DU145 cells and reduced their proliferation, migration, and invasion. Moreover, carvacrol treatment significantly decreased MMP-2, p-Akt, and p-ERK1/2 protein expression and inhibited F-actin reorganization. Furthermore, consistently, TRPM7 knockdown reduced prostate cancer cell proliferation, migration, and invasion as well. Our study suggests that carvacrol may have therapeutic potential for the treatment of prostate cancer through its inhibition of TRPM7 channels and suppression of PI3K/Akt and MAPK signaling pathways

A role of sodium bicarbonate cotransporter(NBC) in HCO3- formation in human salivary gland acinar cells

The sodium bicarbonate cotransporter (NBC) protein is functionally expressed in salivary glands. In this experiment, we examined the role of NBC in HCO3- formation in human parotid gland acinar cells. Intracellular pH (pHi) was measured in 2'-7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) -loaded cells. Acetazolamide (0.1 mM) and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS, 0.5 mM) were used as specific inhibitors of carbonic anhydrase and NBC, respectively. The degree of inhibition was assessed by measuring the pHi recovery rate (△pHi/min) after cell acidification using an ammonium prepulse technique. In control experiments, △pHi/min was 1.40 ± 0.06. Treatment of cells with 0.5 mM DIDS or 0.1 mM acetazolamide significantly reduced △pH/min to 1.14 ± 0.14 and 0.74 ± 0.15, respectively. Simultaneous application of DIDS and acetazolamide further reduced △ pHi/min to 0.47 ± 0.10. Therefore, DIDS and acetazolamide reduced △pHi/min by 19 % and 47 %, respectively, while simultaneous application of both DIDS and acetazolamide caused a reduction in △pHi/min of 67 %. These results suggest that in addition to carbonic anhydrase, NBC also partially contributes to HCO3- formation in human parotid gland acinar cells.This work was supported by the Korea Science & Engineering Foundation (KOSEF) grant funded by Korea government (R13-2008-008-01001-0) through the Oromaxillofacial Dysfunction Research Center for the Elderly(ODRCE) at Seoul National University

Long-Term Bidirectional Association Between Asthma and Attention Deficit Hyperactivity Disorder: A Big Data Cohort Study

BACKGROUND: Previous studies have argued that attention deficit hyperactivity disorder (ADHD) is associated with asthma. However, reliable evidence to verify this association has not yet been reported. OBJECTIVES: To investigate the bidirectional association between asthma and ADHD through a 12-year big data cohort study. METHODS: The independent variable group was extracted from 3.5 million individuals randomly sampled by the National Health Insurance Service (NHIS). In Study 1, the incidence of ADHD according to asthma was evaluated, while in Study 2, the incidence of asthma according to ADHD was analyzed. Propensity score (PS) matching with several variables was used to obtain a control group. MEASUREMENTS AND MAIN RESULTS: In Study 1, the asthma group included 131,937 individuals and the non-asthma group included 131,937 individuals. The adjusted hazard ratio (aHR) for ADHD in the asthma group was 1.17 [95% confidence interval (CI): 1.11-1.23]. In subgroup analysis, the aHRs for ADHD of individuals in the subgroups male sex, 0-5 years old, 6-10 years old, atopic dermatitis, allergic rhinitis, Charlson comorbidity index (CCI) 1, and CCI \u3e 2 were significant (aHR: 2.83, 1.70, 1.79, 1.09, 1.15, 1.06, and 1.49, respectively). In Study 2, ADHD was found to significantly affect asthma in all age groups (aHRs of the subgroups 0∼60 and 0∼17 years old were 1.10 and 1.09, respectively). In the 0∼17 years old subgroup, the association of ADHD with asthma was greater with younger age (aHRs of the subgroups 0∼5 and 6∼10 years old were 2.53 and 1.54, respectively). CONCLUSION: From long-term follow-up, the incidence of ADHD was 1.17 times higher in the asthma group than in the control group. The incidence of asthma was 1.10 times higher in the ADHD group than in the control group. Asthma and ADHD have a bidirectional relationship, and childhood asthma and ADHD should be rigorously managed

17β-estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells

Background/Aims: Estrogen is known to have protective effect in colorectal cancer development. The aims of this study are to investigate whether estradiol treatment reduces inflammation in CCD841CoN, a female human colonic epithelial cell line and to uncover underlying mechanisms of estradiol effects. Methods: 17 beta-Estradiol (E2) effect was measured by Western blot after inducing inflammation of CCD841CoN by tumor necrosis factor alpha (TNF-alpha). Expression levels of estrogen receptor alpha (ER alpha) and beta (ER beta), cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-kappa B), heme oxygenase-1 (HO-1), and NAD(P)H-quinone oxidoreductase-1 (NQO-1) were also evaluated. Results: E2 treatment induced expression of ERO but did not increase that of ER alpha. E2 treatment for 48 hours significantly elevated the expression of anti-oxidant enzymes, HO-1 and NQO-1. TNF-alpha treatment significantly increased the level of activated NF-kappa B (p < 0.05), and this increase was significantly suppressed by treatment of to nM of E2 (p < 0.05). E2 treatment ameliorated TNF-alpha-induced COX-2 expression and decrease of HO-1 expression. 4-(2-phenyl-5,7-bis(trifluoromethyl) pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), antagonist of ER beta, removed the inhibitory effect of E2 in the TNF-alpha-induced COX-2 expression (p = 0.05). Conclusions: Estrogen seems to inhibit inflammation in female human colonic epithelial cell lines, through down-regulation of NF-kappa B and COX-2 expression and induction of anti-oxidant enzymes such as HO-1 and NQO-1.

Inhaled corticosteroid use and risks of lung cancer and laryngeal cancer

SummaryBackgroundChronic inflammation has been implicated in the pathogenesis of several cancers, including lung and laryngeal cancer. The objective of the study is to elucidate the association between ICS use and diagnosis of lung and laryngeal cancer.MethodsA nested case–control study based on the Korean national claims database included new adult users of inhaled medications between January 1, 2007, and December 31, 2010. Patients diagnosed with lung cancer or laryngeal cancer after enrollment were identified as cases and up to five control individuals matched for age, sex, diagnosis of asthma or COPD, Charlson Comorbidity Index scores, number of health care visits, and initiation date were selected.ResultsFrom the 792,687 eligible cohort, 9177 individuals diagnosed with lung cancer were matched with 37,048 controls. Additionally, 408 laryngeal cancer patients and 1651 controls were matched. ICS use was associated with a decreased rate of lung cancer diagnosis [adjusted odds ratio (aOR), 0.79; 95% confidence interval (CI), 0.69–0.90]. The inverse association between ICS use and lung cancer risk was dose dependent (P < 0.0001 for the trend). However, no reduction in the risk of laryngeal cancer among ICS users was identified (aOR, 1.06; 95% CI, 0.62–1.18).ConclusionThe use of ICS is associated with a reduced risk of lung cancer but not of laryngeal cancer