APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Analysis of factors influencing fall risk among elderly people in rural of China.

Falls can cause serious health problems in the elderly. China is gradually entering a moderately aging society. In rural areas of China, the elderly are at a higher risk of falling. This study aims to explore and analyze the factors affecting the fall risk of elderly people in rural areas of China, and provide theoretical basis for reducing the fall risk of elderly people. M County, Anhui Province, China was selected as the survey site by the typical field sampling method, and the elderly people in rural areas were selected as the research objects. A total of 1187 people were investigated. Mann-Whitney U test and Kruskal-Wallis H test were used for univariate analysis, and multiple linear regression was used for multivariate analysis. Chronic diseases, multimorbidity, daily living ability, mental health, working status and family doctors are the factors that influence falls among elderly people in rural areas of China (P < 0.05, Adjusted R2 = 0.395). The falls risk of the elderly in rural areas of China is influenced by multiple factors. Therefore, comprehensive measures should be taken to reduce the fall risk by comprehensively evaluating the influencing factors.

The Norepinephrine-QseC Axis Aggravates F. nucleatum-associated Colitis Through Interkingdom Signaling.

AIMS: Inflammatory bowel disease (IBD) is associated with F. nucleatum, and chronic stress can increase the risk of aggravation. However, whether norepinephrine (NE) can enhance the pathogenicity of F. nucleatum to aggravate dextran sulfate sodium salt (DSS)-induced colitis is unclear. METHODS: Transcriptome sequencing was used to identify differentially expressed genes in bacteria treated with NE. Affinity testing and molecular docking were applied to calculate and predict the binding of NE and Quorum sensing  regulators C (QseC). The pathogenicity of Fusobacterium nucleatum treated with NE and QseC inhibitors was examined in vitro and further verified using the IBD mouse model induced by DSS. RESULTS: Norepinephrine could bind to QseC directly to upregulate the quorum sensing pathway of F. nucleatum and enhance its virulence gene expression (FadA, FomA, Fap2) and invasiveness in vitro. Meanwhile, it promoted the invasion of F. nucleatum into the intestine and increased the expression of host inflammatory cytokines (IL-6, IL-1ß) to aggravate colonic inflammation in IBD mice. The QseC inhibitor LED209 inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid (SCFA)-producing bacteria (Prevotellaceae, Lactobacillaceae) to attenuate colonic inflammation in IBD mice. CONCLUSIONS: Generally, the NE-QseC axis enhanced the pathogenicity of F. nucleatum through interkingdom signaling to aggravate colonic inflammation in IBD mice. We see that QseC may be a potential target for microbiota management of IBD under chronic pressure.

Norepinephrine could bind to QseC directly to enhance the pathogenicity of F. nucleatum to aggravate colonic inflammation. The QseC inhibitor inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid­producing bacteria to attenuate colonic inflammation.

Physical activity attenuates the association of long-term exposure to nitrogen dioxide with sleep quality and its dimensions in Chinese rural older adults.

BACKGROUND: Joint impacts of air pollution and physical activity (PA) on sleep quality remain unaddressed. We aimed to investigate whether PA attenuates the association of long-term exposure to nitrogen dioxide (NO2) with sleep quality and its dimensions in older adults. METHODS: This study included 3408 Chinese rural older adults. Annual NO2 was estimated using the Space-Time Extra-Trees model. PA was assessed by International Physical Activity Questionnaire. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI) scale. Linear regression models were used to assess the associations of long-term NO2 exposure and PA with sleep quality and its dimensions, and interaction plots were used to depict the attenuating effect of PA on associations of NO2 with sleep quality and its dimensions. RESULTS: Three-year (3-y) average NO2 (per 0.64-µg/m3 increment) was positively associated with global PSQI (ß = 0.41, 95 % CI: 0.23, 0.59), sleep duration (ß = 0.16, 95 % CI: 0.11, 0.21), and habitual sleep efficiency (ß = 0.22, 95 % CI: 0.17, 0.27), while PA was negatively associated with global PSQI (ß = -0.33, 95 % CI: -0.46, -0.20) and five domains of PSQI other than sleep duration and sleep disturbances. The associations of NO2 with global PSQI, sleep duration, and habitual sleep efficiency were attenuated with increased PA (Pinteraction were 0.037, 0.020, and 0.079, respectively). CONCLUSIONS: PA attenuates the adverse impacts of long-term NO2 exposure on sleep quality, especially on sleep duration, and habitual sleep efficiency, in Chinese rural elderly people. Participating in PA should be encouraged in this population, and continued efforts are still needed to reduce air pollution.

Associations of CKIP-1 and LOX-1 polymorphisms with the risk of type 2 diabetes mellitus with hypertension among Chinese adults.

AIMS: Type 2 diabetes mellitus (T2DM) and hypertension are common high-incidence diseases, closely related, and have common pathogenic basis such as oxidative stress. Casein kinase 2 interacting protein-1 (CKIP-1) and low-density lipoprotein receptor (LOX-1) are considered to be important factors affect the level of oxidative stress in the body. The main purpose of this study was to explore the relationship between CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 (rs1050283 G > A, rs11053646 C > G) polymorphisms and the risk of hypertension and diabetes, and try to find new candidate genes for diabetes and diabetes with hypertension etiology in Chinese population. METHODS: 574 T2DM patients and 597 controls frequently matched by age and sex were selected for genotyping of CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 gene (rs1050283 G > A, rs11053646 C > G). Logistic regression was used to analyze the correlation between different genotypes and the risk of T2DM and T2DM with hypertension, and the results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: We found that the risk of T2DM in the AA + AT genotype of rs6693817 was higher than that in the TT genotype in Chinese population (OR = 1.318, 95%CI: 1.011-1.717, P = 0.041), and the difference was still significant after adjustment (OR = 1.370, 95%CI: 1.043-1.799, Padjusted = 0.024), the difference of heterozygotes (AT vs TT: OR = 1.374, 95%CI: 1.026-1.840, Padjusted = 0.033) was statistically significant. But after Bonferroni correction, the significance of the above sites disappeared. And rs6693817 was associated with the risk of T2DM combined with hypertension before and after adjustment in dominant model (OR = 1.424, 95% CI: 1.038-1.954, P = 0.028; OR = 1.460, 95% CI: 1.057-2.015, Padjusted = 0.021, respectively) and in heterozygote model (OR = 1.499, 95% CI: 1.069-2.102, P = 0.019; OR = 1.562, 95% CI: 1.106-2.207, Padjusted = 0.011, respectively). However, only the statistical significance of the heterozygous model remained after Bonferroni correction. rs2306235, rs1050283 and rs11053646 were not significantly correlated with T2DM and T2DM combined with hypertension risk (P > 0.05). CONCLUSIONS: The results suggest that CKIP-1 rs6693817 is related to the susceptibility of Chinese people to T2DM with hypertension, providing a new genetic target for the treatment of diabetes with hypertension with in the future.

The Association Between Essential Metal Element Mixture and Sleep Quality in Chinese Community-Dwelling Older Adults.

Previous studies have related single essential metal elements (EMEs) to sleep quality among older adults, however, the association of the EME mixture with sleep quality remained poorly understood. This study aimed to investigate the relationships between single EMEs and the EME mixture and sleep quality in older adults living in Chinese communities. This study consisted of 3957 older adults aged 60 years or over. Urinary concentrations of cobalt (Co), vanadium (V), selenium (Se), molybdenum (Mo), strontium (Sr), calcium (Ca), and magnesium (Mg) were detected using inductively coupled plasma mass spectrometry. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI). The associations of single EMEs and EME mixture with sleep quality were assessed using logistic regression and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted single-element logistic regression models showed that Mo (OR = 0.927, 95%CI:0.867-0.990), Sr (OR = 0.927, 95%CI:0.864-0.994), and Mg (OR = 0.934, 95%CI:0.873-0.997) were negatively related to poor sleep quality. BKMR models exhibited similar results. Also, higher levels of the EME mixture in urine were inversely related to the odds of poor sleep quality after adjustment for covariates, and Mo had the largest conditional posterior inclusion probability (condPIP) value in the mixture. Mo, Sr, and Mg were negatively related to poor sleep quality, separately and as the mixture. The EME mixture in urine was associated with decreased odds of poor sleep quality in older adults, and Mo was the greatest contributor within the mixture. Additional cohort research is warranted to clarify the relationship of multiple EMEs with sleep quality.

The association between influenza vaccination and the perception of COVID-19 as well as COVID-19 vaccination behavior among community residents in Anhui province, China.

Influenza is a significant public health threat associated with high morbidity and mortality globally. This study investigated the influenza vaccination rate (IVR) among community residents in Anhui province, China, and explored the association between participants' influenza vaccination and their key sociodemographic characteristics, perception of COVID-19 as well as COVID-19 vaccination behavior. We found that the IVR among respondents in Anhui province was 27.85% in 2020. Regression analyses revealed that males (OR = 1.41, 95% CI: 1.01 ~ 1.96), residents with above middle school education (OR = 1.88, 95% CI: 1.04 ~ 3.39), considered themselves likely to be infected with COVID-19 (OR = 1.53, 95% CI: 1.04 ~ 2.24), had received the COVID-19 vaccine (OR = 9.85, 95% CI: 3.49 ~ 27.78), did not plan to receive COVID-19 vaccine in the future (OR = 1.70, 95% CI: 1.17 ~ 2.47), and had no adverse reactions after COVID-19 vaccination (OR = 1.54, 95% CI: 1.04 ~ 2.27) were associated with a higher IVR. The acceptance of influenza vaccination was mainly associated with respondents' gender, education, perception of COVID-19, history of COVID-19 vaccination in city and countryside community residents in Anhui province.

Short-term effects of ambient PM1, PM2.5, and PM10 on internal metal/metalloid profiles in older adults: A distributed lag analysis in China.

There is limited evidence linking exposure to ambient particulate matter (PM) with internal doses of metals and metalloids (metal(loid)s). This study aimed to evaluate the effects of short-term exposure to ambient PM on urine metal(loid)s among Chinese older adults. Biological monitoring data of 15 urine metal(loid)s collected in 3, 970 community-dwelling older adults in Fuyang city, Anhui Province, China, from July to September 2018, were utilized. PMs with an aerodynamic diameter ≤ 1 µm (PM1), ≤ 2.5 µm (PM2.5), and ≤ 10 µm (PM10) up to eight days before urine collection were estimated by space-time extremely randomized trees (STET) model. Residential greenness was reflected by Normalized Difference Vegetation Index (NDVI). We used generalized additive model (GAM) combined with distributed lag linear/non-linear models (DLMs/DLNMs) to estimate the associations between short-term PM exposure and urine metal(loid)s. The results suggested that the cumulative exposures to PM1, PM2.5, or PM10 over two days (lag0-1 days) before urine collection were associated with elevated urine metal(loid)s in DLMs, while exhibited linear or "inverted U-shaped" relationships with seven urine metal(loid)s in DLNMs, including Gallium (Ga), Arsenic (As), Aluminum (Al), Magnesium (Mg), Calcium (Ca), Uranium (U), and Barium (Ba). Aforementioned results indicated robust rather than spurious associations between PMs and these seven metal(loid)s. After standardizations for three PMs, PM1 was the greatest contributor to U, PM2.5 made the greatest contributions to Ga, As, Al, and Ba, and PM10 contributed the most to Mg and Ca. Furthermore, the effects of three PMs on urine Ga, As, Al, Mg, Ca, and Ba were reduced when exposed to higher levels of NDVI. Overall, short-term exposures to ambient PMs contribute to elevated urinary metal(loid) levels in older adults, and three PMs exhibit various contributions to different urine metal(loid)s. Moreover, residential greenness may attenuate the effects of PMs on urine metal(loid)s.

Comparative analysis of microbial communities and volatile flavor components in the brewing of Hongqu rice wines fermented with different starters.

As one of the quintessential representatives of Chinese rice wine, Hongqu rice wine is brewed with glutinous rice as the main raw material and Hongqu (Gutian Qu or Wuyi Qu) as the fermentation starter. The present study aimed to investigate the impact of Hongqu on the volatile compositions and the microbial communities in the traditional production of Gutian Hongqu rice wine (GT) and Wuyi Hongqu rice wine (WY). Through the OPLS-DA analysis, 3-methylbutan-1-ol, isobutanol, ethyl lactate, ethyl acetate, octanoic acid, diethyl succinate, phenylethyl alcohol, hexanoic acid and n-decanoic acid were identified as the characteristic volatile flavor components between GT and WY. Microbiome analysis revealed significant enrichments of Lactobacillus, Pediococcus, Aspergillus and Hyphopichia in WY brewing, whereas Monascus, Saccharomyces, Pantoea, and Burkholderia-Caballeronia-Paraburkholderia were significantly enriched in GT brewing. Additionally, correlation analysis showed that Saccharomyces, Lactobacillus, Weissella and Pediococcus were significantly positively correlated wih most characteristic volatile components. Conversely, Picha, Monascus, Franconibacter and Kosakonia showed significant negative correlations with most of the characteristic volatile components. Furthermore, bioinformatical analysis indicated that the gene abundances for enzymes including glucan 1,4-alpha-glucosidase, carboxylesterase, alcohol dehydrogenase, dihydroxy-acid dehydratase and branched-chain-amino-acid transaminase were significantly higher in WY compared to GT. This finding explains the higher content of higher alcohols and characteristic esters in WY relative to GT. Collectively, this study provides a theoretical basis for improving the flavor profile of Hongqu rice wine and establishing a solid scientific foundation for the sustainable development of Hongqu rice wine industry.

Insights into microbial communities and metabolic profiles in the traditional production of the two representative Hongqu rice wines fermented with Gutian Qu and Wuyi Qu based on single-molecule real-time sequencing.

Hongqu rice wine, a famous traditional fermented alcoholic beverage, is brewed with traditional Hongqu (mainly including Gutian Qu and Wuyi Qu). This study aimed to compare the microbial communities and metabolic profiles in the traditional brewing of Hongqu rice wines fermented with Gutian Qu and Wuyi Qu. Compared with Hongqu rice wine fermented with Wuyi Qu (WY), Hongqu rice wine fermented with Gutian Qu (GT) exhibited higher levels of biogenic amines. The composition of volatile flavor components of Hongqu rice wine brewed by different fermentation starters (Gutian Qu and Wuyi Qu) was obviously different. Among them, ethyl acetate, isobutanol, 3-methylbutan-1-ol, ethyl decanoate, ethyl palmitate, ethyl oleate, nonanoic acid, 4-ethylguaiacol, 5-pentyldihydro-2(3H)-furanone, ethyl acetate, n-decanoic acid etc. were identified as the characteristic aroma-active compounds between GT and WY. Microbiome analysis based on high-throughput sequencing of full-length 16S rDNA/ITS-5.8S rDNA amplicons revealed that Lactococcus, Leuconostoc, Pseudomonas, Serratia, Enterobacter, Weissella, Saccharomyces, Monascus and Candida were the predominant microbial genera during the traditional production of GT, while Lactococcus, Lactobacillus, Leuconostoc, Enterobacter, Kozakia, Weissella, Klebsiella, Cronobacter, Saccharomyces, Millerozyma, Monascus, Talaromyces and Meyerozyma were the predominant microbial genera in the traditional fermentation of WY. Correlation analysis revealed that Lactobacillus showed significant positive correlations with most of the characteristic volatile flavor components and biogenic amines. Furthermore, bioinformatical analysis based on PICRUSt revealed that microbial enzymes related to biogenic amines synthesis were more abundant in GT than those in WY, and the enzymes responsible for the degradation of biogenic amines were less abundant in GT than those in WY. Collectively, this study provides important scientific data for enhancing the flavor quality of Hongqu rice wine, and lays a solid foundation for the healthy and sustainable development of Hongqu rice wine industry.

An acid-responsive MOF nanomedicine for augmented anti-tumor immunotherapy via a metal ion interference-mediated pyroptotic pathway.

Pyroptosis is an inflammatory form of programmed cell death (PCD) that is regulated by the Gasdermin protein family in response to various stimuli, playing a critical role in the development of tumor therapy strategies. However, cancers are generally known to escape from PCD via immunosuppressive pathways or other resistant mechanisms. In this study, an acid-responsive Fe/Mn bimetal-organic framework nanosystem carrying metal ions and immune adjuvant R848 (FeMn@R@H) was designed for combining pyroptosis and augmented immunotherapy. The FeMn@R@H would be triggered to disintegrate and release Fe3+ and Mn2+ ions in response to the acidic tumor microenvironment (TME), thereby initiating Fenton-like reactions for ROS-mediated pyroptosis. On the one hand, the pyroptosis-caused cell rupture would induce the release of proinflammatory cytokines and immunogenic constituents from tumor cells, further resulting in immunogenic cell death (ICD) to promote antitumor immune responses. On the other hand, the co-delivered R848 could reverse suppressive tumor immune microenvironment (TIME) and induce inflammatory responses by activating the TLR7/8 pathway. In conclusion, this tumor-specific therapy system can co-deliver metal ions and R848 to tumor tissues to perform pyroptosis-mediated PCD and augmented anti-tumor immunotherapy.

Gut microbiota-derived autoinducer-2 regulates lung inflammation through the gut-lung axis.

OBJECTIVE: This study aimed to determine whether autoinducer-2 (AI-2), a crucial bacterial metabolite and quorum sensing molecule, is involved in lung immunity through the gut-lung axis. METHODS: The level of AI-2 and the gut microbiome composition were analysed in the stools from pneumonic patients and the mouse model of acute lung injury. The effect of AI-2 on lung inflammation was further investigated in the mouse model. RESULTS: The diversity of the faecal microbiota was reduced in pneumonic patients treated with antibiotics compared with healthy volunteers. The AI-2 level in the stool was positively correlated with inflammatory molecules in the serum of pneumonic patients. Intraperitoneal injection of AI-2 reinforced lung inflammation in the acute lung injury mouse model, characterized by increased secretion of inflammatory molecules, including IL-6, IL-1ß, C-C chemokines, and CXCL chemokines, which were alleviated by the AI-2 inhibitor D-ribose. CONCLUSIONS: Our results suggested that gut microbiota-derived AI-2 could modulate lung inflammation through the gut-lung axis.

The associations of non-essential metal mixture with fasting plasma glucose among Chinese older adults without diabetes.

The evidence about the effect of non-essential metal mixture on fasting plasma glucose (FPG) levels among older adults without diabetes is limited. This study aims to estimate the individual and joint relationship between five non-essential metals and FPG levels in Chinese older adults without diabetes. This study included 2362 older adults without diabetes. Urinary concentrations of five non-essential metals, i.e., cesium (Cs), aluminum (Al), thallium (Tl), cadmium (Cd), and arsenic (As), were detected by inductively coupled plasma mass spectrometry (ICP-MS). The associations of single metals and the metal mixture with FPG levels were assessed using linear regression and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted single-metal linear regression models showed positive associations of urinary Al (ß = 0.016, 95%CI: 0.001-0.030) and Cs (ß = 0.018, 95%CI: 0.006-0.031) with FPG levels. When comparing the 2th, 3th, and 4th quartiles of urine Cs to its 1th quartile, the significant associations between Cs and FPG levels were found and presented as an "inverted U" trend (ßQ2 vs. Q1: 0.034; ßQ3 vs. Q1:0.054; ßQ4 vs. Q1: 0.040; all P<0.05). BKMR analyses showed urinary level of Cs exhibited an "inverted U" shape association with FPG levels. Moreover, the FPG levels increased linearly with the raised levels of the non-essential metal mixture, and the posterior inclusion probability (PIP) of Cs was the highest (0.92). Potential positive interaction of As and Cs on FPG levels was found in BKMR model. Stratified analysis displayed significant interactions of hyperlipidemia and urine Cs or Tl on FPG levels. An inverse U-shaped association between Cs and FPG was found, individually and as mixture. The FPG levels increased with the raised levels of the non-essential metal mixture, and Cs was the most contributor to FPG levels. Further research is required to confirm the correlation between non-essential metals and FPG levels and to clarify the underlying mechanisms.

The association between the essential metal mixture and fasting plasma glucose in Chinese community-dwelling elderly people.

BACKGROUND: Epidemiological studies about the effect of essential metal mixture on fasting plasma glucose (FPG) levels among elderly people are sparse. The object of this study was to examine the associations of single essential metals and essential metal mixture with FPG levels in Chinese community-dwelling elderly people. METHODS: The study recruited 2348 community-dwelling elderly people in total. Inductively coupled plasma-mass spectrometry was adopted to detect the levels of vanadium (V), selenium (Se), magnesium (Mg), cobalt (Co), calcium (Ca), and molybdenum (Mo) in urine. The relationships between single essential metals and essential metal mixture and FPG levels were evaluated by linear regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: In multiple-metal linear regression models, urine V and Mg were negatively related to the FPG levels (ß = - 0.016, 95 % CI: - 0.030 to - 0.003 for V; ß = - 0.021, 95 % CI: - 0.033 to - 0.009 for Mg), and urine Se was positively related to the FPG levels (ß = 0.024, 95 % CI: 0.014-0.034). In BKMR model, the significant relationships of Se and Mg with the FPG levels were also found. The essential metal mixture was negatively associated with FPG levels in a dose-response pattern, and Mg had the maximum posterior inclusion probability (PIP) value (PIP = 1.0000), followed by Se (PIP = 0.9968). Besides, Co showed a significant association with decreased FPG levels in older adults without hyperlipemia and in women. CONCLUSIONS: Both Mg and Se were associated with FPG levels, individually and as a mixture. The essential metal mixture displayed a linear dose-response relationship with reduced FPG levels, with Mg having the largest contribution to FPG levels, followed by Se. Further prospective investigations are necessary to validate these exploratory findings.

ROS-Triggered Self-Assembled Nanoparticles Based on a Chemo-Sonodynamic Combinational Therapy Strategy for the Noninvasive Elimination of Hypoxic Tumors.

The hypopermeability and hypoxia in the tumor milieu are important factors that limit multiple treatments. Herein, the reactive oxygen species (ROS)-triggered self-assembled nanoparticles (RP-NPs) was constructed. The natural small molecule Rhein (Rh) was encapsulated into RP-NPs as a sonosensitizer highly accumulated at the tumor site. Then highly tissue-permeable ultrasound (US) irradiation induced apoptosis of tumor cells through the excitation of Rh and acoustic cavitation, which prompted the rapid production of large amounts of ROS in the hypoxic tumor microenvironment. In addition, the thioketal bond structures in the innovatively designed prodrug LA-GEM were triggered and broken by ROS to achieve rapid targeted release of the gemcitabine (GEM). Sonodynamic therapy (SDT) increased the tissue permeability of solid tumors and actively disrupted redox homeostasis via mitochondrial pathways to kill hypoxic tumor cells, and the triggered response mechanism to GEM synergistically amplified the effect of chemotherapy. The chemo-sonodynamic combinational treatment approach is highly effective and noninvasive, with promising applications for hypoxic tumor elimination, such as in cervical cancer (CCa) patients who want to maintain their reproductive function.

The Associations between Multiple Essential Metal(loid)s and Gut Microbiota in Chinese Community-Dwelling Older Adults.

Several experimental studies have suggested that individual essential metal(loid)s (EMs) could regulate the gut microbiota. However, human studies assessing the associations between EMs and gut microbiota are limited. This study aimed to examine the associations of individual and multiple EMs with the compositions of the gut microbiota in older adults. A total of 270 Chinese community-dwelling people over 60 years old were included in this study. Urinary concentrations of selected EMs, including vanadium (V), cobalt (Co), selenium (Se), strontium (Sr), magnesium (Mg), calcium (Ca), and molybdenum (Mo), were examined by inductively coupled plasma mass spectrometry. The gut microbiome was assessed using the 16S rRNA gene sequencing analysis. The zero-inflated probabilistic principal components analysis PCA (ZIPPCA) model was performed to denoise substantial noise in microbiome data. Linear regression and the Bayesian Kernel Machine Regression (BKMR) models were utilized to determine the associations between urine EMs and gut microbiota. No significant association between urine EMs and gut microbiota was found in the total sample, whereas some significant associations were found in subgroup analyses: Co was negatively associated with the microbial Shannon (ß = -0.072, p < 0.05) and the inverse-Simpson (ß = -0.045, p < 0.05) indices among urban older adults; Ca (R2 = 0.035) and Sr (R2 = 0.023) exhibited significant associations with the altercations of beta diversity in females, while V (R2 = 0.095) showed a significant association with altercations of beta diversity in those who often drank. Furthermore, the associations between partial EMs and specific bacterial taxa were also found: the negative and linear associations of Mo with Tenericutes, Sr with Bacteroidales, and Ca with Enterobacteriaceae and Lachnospiraceae, and a positive and linear association of Sr with Bifidobacteriales were found. Our findings suggested that EMs may play an important role in maintaining the steady status of gut microbiota. Prospective studies are needed to replicate these findings.

Urinary antibiotic exposure and low grip strength risk in community-dwelling elderly Chinese by gender and age.

Emerging studies have shown that environmental contaminants were related to decreased handgrip strength. Nevertheless, no prior research has investigated the relationship of exposure to environmental antibiotics with grip strength. Thus, we explored the relationship between urinary antibiotic burden and grip strength among the elderly in China. This study consisted of 451 men and 539 women from the baseline survey of a cohort study. Commonly used antibiotics for humans and animals were detected in 990 urine samples through a biomonitoring method. Grip strength was measured by an electronic dynamometer. We examined the associations of antibiotic exposure with low grip strength (LGS), grip strength, and grip strength index, respectively. Results suggested that 34.9% of participants developed LGS, and 93.0% of individuals were exposed to 1-10 antibiotics. Among women, oxytetracycline (Quartile 2: odds ratio: 2.97, 95% confidence interval: 1.36-6.50), florfenicol (Quartile 3: 2.60 [1.28-5.27]), fluoroquinolones (Quartile 4: 1.88 [1.07-3.30]), and chloramphenicols (Quartile 3: 2.73 [1.35-5.51]) could enhance LGS risk. Among men, ofloxacin (Quartile 2: 3.32 [1.45-7.59]) increased LGS risk, whereas tetracycline (Quartile 2: 0.31 [0.11-0.88]) was implicated in reduced LGS risk. In participants < 70 years, ofloxacin (Quartile 2: 3.00 [1.40-6.42]) could increase LGS risk. For participants who were 70 years of age or older, veterinary antibiotics (Quartile 3: 1.73 [1.02-2.94]) were linked to a 73% increased risk of LGS. Our findings suggested that antibiotics mainly pertained to LGS, and there were gender and age disparities in associations between antibiotic exposure and muscle strength indicators in the elderly Chinese population.

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.

The immunotherapeutic effect elicited by photodynamic therapy (PDT) is attenuated by tumor defense mechanisms associated with glutamine metabolism, including the metabolic regulation of redox homeostasis and the limitation of the immunosuppressive tumor microenvironment (ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with dual synergistic effects was constructed by the self-assembly of glutaminase (GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6. C968-mediated GSH deprivation through inhibiting glutamine metabolism prevented PDT-generated reactive oxygen species from being annihilated by GSH, amplifying intracellular oxidative stress, which caused severe cell death and also enhanced the immunogenic cell death (ICD) effect. In addition, genome-wide analysis was carried out using RNA-sequencing to evaluate the changes in cell transcriptome induced by amplifying oxidative stress. Thereafter, neoantigens generated by the enhanced ICD effect promoted the maturation of dendritic cells, thereby recruiting and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which further recruited and activated the CTLs. Ultimately, this immunotherapeutic nanobooster suppressed primary and distant tumors. This "kill two birds with one stone" strategy would shed light on enhancing tumor immunogenicity and alleviating tumor immunosuppression to improve the immunotherapeutic effect of PDT.

Association of tag single nucleotide polymorphisms (SNPs) at lncRNA MALAT1 with type 2 diabetes mellitus susceptibility in the Chinese Han population: A case-control study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic, lifelong disease. The molecular mechanisms and pathophysiology of T2DM have not yet been fully elucidated. Dysregulation of the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) is considered one of the main contributing factors of the dysfunction found in many diseases, including those of the endocrine system. The aim of this study was to investigate the association between lncRNA MALAT1 single nucleotide polymorphisms (SNPs) and T2DM in the Chinese Han population. METHODS: We genotyped three SNPs (rs3200401 C > T, rs619586 A > G, rs11227209 C > G) of the MALAT1 gene, including 571 T2DM patients and 526 controls. The association between different genotypes and the risk of T2DM was analyzed using logistic regression, and the results were expressed by odds ratio (OR) and its 95% confidence interval (95%CI), and then stratified by age, sex, and BMI. P < 0.05 on both sides was considered as statistically significant. RESULTS: We found that the CT + TT genotypes of the rs3200401 polymorphism were significantly associated with an increased risk of T2DM in Chinese Han population (OR = 1.77; 95% CI:1.35-2.33; Padjusted < 0.001), whereas MALAT1 rs619586 AG + GG genotypes were associated with a reduced risk of T2DM (OR = 0.67; 95% CI:0.48-0.94; Padjusted = 0.021). Subsequent stratified analysis showed that compared with the rs3200401 CC genotype, CT + TT genotypes were associated with an increased risk of T2DM in the male, female, age ≥ 65 years, and BMI ≥ 24 subgroups (OR = 1.68, 95% CI:1.10-2.56, Padjusted = 0.016; OR = 1.83, 95% CI:1.27-2.62, Padjusted = 0.001; OR = 1.86, 95% CI:1.38-2.52, Padjusted < 0.001; OR = 2.13, 95% CI:1.45-3.15, Padjusted < 0.001; respectively). Haplotype analysis showed that T-A-C haplotype had a 1.533-fold increased risk of T2DM (95% CI, 1.208-1.945, P < 0.001) and C-G-G was associated with a decreased risk of T2DM. No significant association was found between rs11227209 and T2DM risk (P > 0.05). CONCLUSION: The results suggest that MALAT1 rs619586 and rs3200401 confer susceptibility for T2DM in the Chinese Han population and provide new genetic targets for the treatment of diabetes and its complications in the future.

Selenium attenuates the association of co-exposure to arsenic, cadmium, and lead with cognitive function among Chinese community-dwelling older adults.

The effects of interactions between the toxic and essential metal mixtures on cognitive function are poorly understood. This study aims to identify the joint association of arsenic (As), cadmium (Cd), and lead (Pb) with cognitive function in older adults and the moderating role of selenium (Se), zinc (Zn), and copper (Cu) in this association. This study included 1000 community-dwelling older adults. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). Blood concentrations of As, Cd, Pb, Se, Zn, and Cu were measured using inductively coupled plasma mass spectrometry. Linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess the individual and joint associations of As, Cd, and Pb with cognitive function and to examine whether Se, Zn, and Cu (individually and as a mixture) modified these associations. In the adjusted single-metal models, both Cd (ß = - 0.37, 95% CI: - 0.73 to - 0.01) and Pb (ß = - 0.44, 95% CI: - 0.86 to - 0.02) were associated with MMSE scores, while Se (ß = 0.71, 95% CI: 0.30 to 1.13) exhibited a positive relationship with MMSE scores. Univariate exposure-response functions from BKMR models showed similar results. Moreover, the toxic metal mixture (As, Cd, and Pb) exhibited a significant negative association with MMSE scores in a dose-response pattern, with Pb being the greatest contributor within the mixture. The negative association of Pb alone or the toxic metal mixture with MMSE scores became weaker at higher concentrations of Se within its normal range, especially when Se levels were greater than the median (89.18 µg/L). Our findings support that Se can attenuate the negative associations of exposure to single Pb or the As, Cd, and Pb mixtures with cognitive function. Future prospective studies are needed to replicate our findings.