The exopolysaccharides produced by Leuconostoc mesenteroides XR1 and its effect on silk drawing phenomenon of yoghurt.

Yoghurt fermented by Leuconostoc mesenteroides XR1 from Kefir grains was found to produce a unique silk drawing phenomenon. This property was found to be associated with the exopolysaccharides (EPS), X-EPS, produced by strain XR1. In order to better understand the mechanism that produced this phenomenon, the X-EPS was extracted, purified and characterized. The molecular weight and monosaccharide composition were determined by size exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS) and ion chromatography (IC) analysis, respectively. The results showed that its molecular weight was 4.183 × 106 g/mol and its monosaccharide composition was glucose, and glucuronic acid, with the contents of 567.6148 and 0.2096 µg/mg, respectively. FT-IR and NMR analyses showed that X-EPS was an α-pyranose polysaccharide and was composed of 92.22 % α-(1 â†’ 6) linked d-glucopyranose units and 7.77 % α-(1 â†’ 3) branching. Furthermore, it showed a chain-like microstructure with branches in atomic force microscopy (AFM) and scanning electron microscopy (SEM) experiments. These results suggested that the unique structure of X-EPS, gave the yoghurt a strong viscosity and cohesiveness, which resulted in the silk drawing phenomenon. This work suggested that X-EPS holds the potential for food and industrial applications.

Association between social isolation and depression: Evidence from longitudinal and Mendelian randomization analyses.

BACKGROUND: Increasing evidence shows that social isolation and depression are likely to interact with each other, yet the direction and causality of the association are not clear. This study aims to examine the possible reciprocity in the relationship between social isolation and depression. METHODS: This study fitted a cross-lagged panel model (CLPM) by using data from the English Longitudinal Study of Aging (ELSA, 2014-2019, n = 6787) to examine the temporal relationship between social isolation and depressive symptoms in older adults. We then conducted two-sample bidirectional Mendelian randomization (MR) analyses by using independent genetic variants associated with multiple social isolation phenotypes (n = 448,858-487,647) and with depression (n = 215,644-2,113,907) as genetic instruments from genome-wide association studies to assess the causality between social isolation and onset of depression. RESULTS: The CLPM in the ELSA cohort showed a significant and positive lagged effect of social isolation on depressive symptoms (ß = 0.037, P < .001). The reverse cross-lagged path from depressive symptoms to social isolation was also statistically significant (ß = 0.039, P < .001). In two-sample bidirectional MR, the genetically predicted loneliness and social isolation combined phenotype (LNL-ISO) was positively associated with occurrence of depression (OR = 1.88, 95 % CI: 1.41-2.50, P < .001), vice versa (OR = 1.16, 95 % CI:1.13-1.20, P < .001). LIMITATIONS: The self-report nature of the assessments and missing data are study limitations. CONCLUSIONS: These findings suggest a bidirectional relationship between social isolation and depression. It is important to develop interventions that highlight the reciprocal consequences of improving either mental health or social connection in older adults.

Are immune checkpoint inhibitors ineffective in treating patients with head and neck squamous cell carcinoma aged 75 years or Older? A Meta-Analysis.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) is unclear in patients aged ≥ 75 years with head and neck squamous cell carcinoma (HNSCC). We conducted a systematic review and meta-analysis of randomized trials that compared ICIs with standard-of-care (SOC) therapy for recurrent/metastatic HNSCC. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched for eligible trials. We evaluated the overall survival (OS) benefit of ICIs versus SOC according to patient age (<75 versus ≥ 75 years). The OS benefit was evaluated and compared between the age subgroups using hazard ratios (HRs). Data were pooled using a random-effects model. RESULTS: Five phase 3 trials involving 3437 patients were included. In patients aged ≥ 75 years (n = 207), ICIs did not improve OS compared to SOC (HR = 1.30, 95 % confidence interval [CI]: 0.93-1.81, P = 0.127). However, an improvement in OS was observed in patients aged < 75 years (n = 3230, HR = 0.90, 95 % CI: 0.83-0.99, P = 0.025). There is a significant difference in OS benefit between patients aged < 75 and ≥ 75 years (ratio of HR = 0.69, 95 % CI: 0.49-0.98, P = 0.036). Subgroup, meta-regression, and sensitivity analyses supported the reliability of the results. CONCLUSIONS: Given the small sample size, our findings showing no improvement in OS suggest a lack of evidence to support the use of ICIs in patients with recurrent/metastatic HNSCC aged ≥ 75 years. Therefore, prospective studies are needed to clarify their efficacy among this age group.

A Hierarchical Mechanotransduction System: From Macro to Micro.

Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole-body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

Sonosensitizer Nanoplatforms Augmented Sonodynamic Therapy-Sensitizing Shikonin-Induced Necroptosis Against Hepatocellular Carcinoma.

Background: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance. Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis. Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group. Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.

Sono-Immunotherapy Mediated Controllable Composite Nano Fluorescent Probes Reprogram the Immune Microenvironment of Hepatocellular Carcinoma.

Background: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy. Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety. Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype. Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.

IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy.

Purpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer. Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used. Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly. Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.

Intra- and interspecific ecophysiological responses to waterlogging stress in two contrasting waterlogging-tolerant arbor species.

At present, establishing planted forests, typically composed of not more than two tree species, to avoid forest losses has received increasing attention. In addition, investigating the impact of environmental stress such as waterlogging on different planting patterns is essential for improving wetland ecosystem resilience. Knowledge about the impact of waterlogging on planted forests is crucial for developing strategies to mitigate its adverse effects. Here, we conducted experimentally a simulated pure and mixed planting system composed of two contrasting WL-tolerant species (Cleistocalyx operculatus and Syzygium cumini) to determine their ecophysiological responses based on the type of interaction. Results showed that the aboveground growth performance of S. cumini was better than that of C. operculatus under well-watered conditions regardless of the planting model, which is contrary to the belowground accumulation that was significantly improved in C. operculatus. Intra- and interspecific interactions in different planting models facilitated the growth performance of C. operculatus while provoking a significant competition in S. cumini under waterlogging. Such phenomenon was explained through the remarkable ability of C. operculatus to naturally increase its root network under stress on non-stress conditions compared with S. cumini. In this study, two main factors are proposed to play key roles in the remarkable performance of C. operculatus compared with S. cumini following the planting model under waterlogging. The high level of nitrogen and phosphor absorption through C. operculatus primary roots and the significant starch biosynthesis constituted the key element that characterized the facilitation or competition within the intra- or interspecific interactions shown in C. operculatus compared with S. cumini. Furthermore, the intraspecific competition is more pronounced in S. cumini than in C. operculatus when grown in a pure planting pattern, particularly when subjected to waterlogging. However, when the two species are planted together, this competition is alleviated, resulting in enhanced waterlogging tolerance.

Effects of dietary PUFA patterns and FADS genotype on breast milk PUFAs in Chinese lactating mothers.

BACKGROUND: Breastfeeding affects the growth and development of infants, and polyunsaturated fatty acids (PUFAs) play a crucial role in this process. To explore the factors influencing the PUFA concentration in breast milk, we conducted research on two aspects: dietary fatty acid patterns and single nucleotide polymorphisms (SNPs) in maternal fatty acid desaturase genes. METHODS: Three hundred seventy Chinese Han lactating mothers were recruited. A dietary semi-quantitative food frequency questionnaire (FFQ) was used to investigate the dietary intake of lactating mothers from 22 to 25 days postpartum for 1 year. Meanwhile, breast milk samples were collected from the participants and tested for the concentrations of 8 PUFAs and 10 SNP genotypes. We sought to determine the effect of dietary PUFA patterns and SNPs on breast milk PUFAs. We used SPSS 24.0 statistical software for data analysis. Statistical tests were all bilateral tests, with P < 0.05 as statistically significant. RESULTS: Under the same dietary background, PUFA contents in breast milk expressed by most major allele homozygote mothers tended to be higher than that expressed by their counterparts who carried minor allele genes. Moreover, under the same gene background, PUFA contents in breast milk expressed by the mother's intake of essential PUFA pattern tended to be higher than that expressed by their counterparts who took the other two kinds of dietary. CONCLUSIONS: Our study suggests that different genotypes and dietary PUFA patterns affect PUFA levels in breast milk. We recommend that lactating mothers consume enough essential fatty acids to ensure that their infants ingest sufficient PUFAs.

Liver Iron Overload Drives COVID-19 Mortality: a Two-Sample Mendelian Randomization Study.

Iron overload has been associated with an increased risk of COVID-19 severity and mortality in observational studies, but it remains unclear whether these associations represent causal effects. We performed a two-sample Mendelian randomization (MR) to determine associations between genetic liability to iron overload and the risk of COVID-19 severity and mortality. From genome-wide association studies of European ancestry, single-nucleotide polymorphisms associated with liver iron (n = 32,858) and ferritin (n = 23,986) were selected as exposure instruments, and summary statistics of the hospitalization (n = 16,551) and mortality (n = 15,815) of COVID-19 were utilized as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis to estimate causal effects, and other alternative approaches as well as comprehensive sensitivity analysis were conducted for estimating the robustness of identified associations. Genetically predicted high liver iron levels were associated with an increased risk of COVID-19 mortality based on the results of IVW analysis (OR = 1.38, 95% CI: 1.05-1.82, P = 0.02). Likewise, sensitivity analyses showed consistent and robust results in general (all P > 0.05). A higher risk of COVID-19 hospitalization trend was also observed in patients with high liver iron levels without statistical significance. This study suggests that COVID-19 mortality might be partially driven by the iron accumulation in the liver, supporting the classification of iron overload as one of the independent death risk factors. Therefore, avoiding iron overload and maintaining normal iron levels may be a powerful measure to reduce COVID-19 mortality.

Association of dietary inflammatory potential and non-alcoholic fatty liver disease in US adults.

OBJECTIVES: Long-term inflammatory effects of diet may elevate the risk of non-alcoholic fatty liver disease (NAFLD). The present study aims to investigate dietary patterns associated with inflammation and whether such diets were associated with the risk of NAFLD. METHODS: Data were collected from the 2017-2018 National Health and Nutrition Examination Survey. Dietary intake was obtained through two 24-hour dietary recall interviews, and levels of inflammatory biomarkers were assessed in blood samples. NAFLD was defined as a controlled attenuation parameter (CAP) ≥ 274 dB/m. Reduced-rank regression (RRR) analysis was used to derive sex-specific inflammatory dietary patterns (IDPs). Logistic regression analysis was used to examine the association between IDPs and NAFLD. RESULTS: A total of 3570 participants were included in this study. We identified the IDP characterized by higher intake of added sugars, and lower intake of fruits, vegetables, whole grains, seafood high in n -3 fatty acids, soybean products, nuts, seeds, yogurt, and oils. After multivariate adjustment, the highest tertile of the IDP scores had a significantly higher risk of NAFLD than the lowest tertile [odds ratio (OR) = 1.884, 95% confidence interval (CI) = 1.003-3.539, P for trend = 0.044 for males; OR = 1.597, 95% CI = 1.129-2.257, P for trend = 0.010 for females]. CONCLUSION: Overall, the IDP was positively associated with the prevalence of NAFLD. The findings may provide dietary prevention strategies for controlling chronic inflammation and further preventing NAFLD.

Genome-wide DNA methylation analysis of body composition in Chinese monozygotic twins.

BACKGROUND: Little is currently known about epigenetic alterations associated with body composition in obesity. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and three common traits of body composition as measured by body fat percentage (BF%), fat mass (FM) and lean body mass (LBM) among Chinese monozygotic twins. METHODS: Generalized estimated equation model was used to regress the methylation level of CpG sites on body composition. Inference about Causation Through Examination Of Familial Confounding was used to explore the evidence of a causal relationship. Gene expression analysis was further performed to validate the results of differentially methylated genes. RESULTS: We identified 32, 22 and 28 differentially methylated CpG sites (p < 10-5 ) as well as 20, 17 and eight differentially methylated regions (slk-corrected p < 0.05) significantly associated with BF%, FM and LBM which were annotated to 65 genes, showing partially overlapping. Causal inference demonstrated bidirectional causality between DNA methylation and body composition (p < 0.05). Gene expression analysis revealed significant correlations between expression levels of five differentially methylated genes and body composition (p < 0.05). CONCLUSIONS: These DNA methylation signatures will contribute to increased knowledge about the epigenetic basis of body composition and provide new strategies for early prevention and treatment of obesity and its related diseases.

Predictive Value of Malnutrition, Identified via Different Nutritional Screening or Assessment Tools, for Functional Outcomes in Patients with Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Malnutrition affects more than half of patients with stroke. Although malnutrition leads to more deaths, a longer hospital stay, and higher costs, there is still a lack of consensus regarding the impact of malnutrition on physical functional outcomes in patients with stroke, and there are large differences in the diagnostic effects of nutritional screening or assessment tools for malnutrition. This study aimed to explore the impact of malnutrition in patients with stroke and assess the significance of current nutritional screening and assessment tools for these patients. METHODS: Six databases were systematically searched until October 2022. Cohort studies meeting the eligibility criteria were included. Pooled effects were calculated using random-effects models. RESULTS: Twenty-six studies with 21,115 participants were included. The pooled effects of malnutrition on poor functional outcome, FIM points, and dysphagia were OR = 2.72 (95% CI = 1.84-4.06), WMD = -19.42(95% CI = -32.87--5.96), and OR = 2.80 (95% CI = 1.67-4.67), respectively. CONCLUSION: Malnutrition adversely affects the recovery of physical and swallowing functions in patients with stroke. Nutritional assessments consistently predict the outcomes of physical function in patients with stroke.

Signaling pathways and intervention for therapy of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic ß cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and ß cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

Cellular immunotherapy combined with platinum-based chemotherapy prolongs survival for non-small cell lung cancer patients.

Platinum-based chemotherapy is the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients without a driver gene mutation, but its efficacy is still modest. Through a potential synergistic effect, autologous cellular immunotherapy (CIT) composed of cytokine-induced killer (CIK), natural killer (NK), and T cells might enhance it. NK cells exhibited in vitro cytotoxicity toward lung cancer cells (A549 cells) following platinum therapy. Using flow cytometry, the expression of MICA, MICB, DR4, DR5, CD112, and CD155 on lung cancer cells was assessed. In this retrospective cohort study, there were included 102 previously untreated stage IIIB/IV NSCLC patients ineligible for tyrosine kinase inhibitor (TKI) target therapy who received either chemotherapy alone (n=75) or combination therapy (n=27). The cytotoxicity of NK cells for A549 cells was increased obviously and a time-dependent enhancement of this effect was also observed. After platinum therapy, the levels of MICA, MICB, DR4, DR5, CD112, and CD155 on the surface of A549 cells were increased. In the combination group, the median PFS was 8.3 months, compared to 5.5 months in the control group (p=0.042); the median overall survival was 18.00 months, compared to 13.67 months in the combined group (p=0.003). The combination group had no obvious immune-related adverse effects. The combination of NK cells with platinum showed synergistic anticancer effects. Combining the two strategies increased survival with minor adverse effects. Incorporating CIT into conventional chemotherapy regimens may improve NSCLC treatment. However, additional evidence will require multicenter randomized controlled trials.

Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study.

AIMS: Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good alignment with in vivo rat studies showing cardioprotection by limb RIPC, we performed a systematic review and meta-analysis. In addition, we investigated the importance of different study parameters. METHODS AND RESULTS: Male Wistar rats were subjected to 20-45 min cardiac ischaemia followed by 120 min reperfusion with or without preceding RIPC by 3 or 4 × 5-5 min occlusion/reperfusion of one or two femoral vessels by clamping, tourniquet, or pressure cuff. RIPC did not reduce infarct size (IS), microvascular obstruction, or arrhythmias at any study centres. Systematic review and meta-analysis focusing on in vivo rat models of myocardial ischaemia/reperfusion injury with limb RIPC showed that RIPC reduces IS by 21.28% on average. In addition, the systematic review showed methodological heterogeneity and insufficient reporting of study parameters in a high proportion of studies. CONCLUSION: We report for the first time the lack of cardioprotection by RIPC in rats, assessed in individually randomized, blinded in vivo studies, involving three study centres, using different RIPC protocols. These results are in discrepancy with the meta-analysis of similar in vivo rat studies; however, no specific methodological reason could be identified by the systematic review, probably due to the overall insufficient reporting of several study parameters that did not improve over the past two decades. These results urge for publication of more well-designed and well-reported studies, irrespective of the outcome, which are required for preclinical reproducibility, and the development of clinically translatable cardioprotective interventions.

Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity.

Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart.

The association of pulse pressure change with memory decline in middle-aged and older adults.

BACKGROUND: Less is known regarding the association of pulse pressure (PP) with memory function. This study aimed to characterize long-term patterns of PP in middle-aged and older adults and explore their impact on subsequent change in memory function. METHODS: Data from the English Longitudinal Study of Ageing (ELSA, 2004-2018), were analyzed. Totally, 3587 dementia-free participants with three measurements of BP were included. All three visits of PP (2004-2012) were used to characterize longitudinal patterns of PP by group-based trajectory modeling (GBTM). Generalized estimating equation (GEE) models were fitted to explore the impact of PP trajectories on change in memory over a subsequent 6-year period (2012-2018). RESULTS: Using GBTM, three distinct trajectories of PP were identified: low-stable (38.1%), moderate-stable (48.6%), and elevated-increasing group (13.3%). GEE model suggested that memory declined over a 6-year period in all PP trajectories (all Ptime <0.001). The overall interactions between patterns of PP changes and time with memory were statistically significant (χ2 interaction  = 20.69, p = 0.002). Compared to participants in the low-stable group, those in the moderate-stable and elevated-increasing group exhibited a faster decline in memory. CONCLUSIONS: Longitudinal patterns of moderate-stable and elevated-increasing PP were associated with an accelerated decrease in memory. Controlling BP instability may be a promising interventional strategy for preventing cognitive decline among older adults.

Genome-wide DNA methylation analysis of middle-aged and elderly monozygotic twins with age-related hearing loss in Qingdao, China.

OBJECTIVE: To explore the differences in DNA methylation associated with age-related hearing loss in a study of 57 twin pairs from China. DESIGN: Monozygotic twins were identified through the Qingdao Twin Registration system. The median age of participants was > 50 years. Their hearing thresholds were measured using a multilevel pure-tone audiometry assessment. The pure-tone audiometry was calculated at low frequencies (0.5, 1.0, and 2.0 kHz), speech frequencies (0.5, 1.0, 2.0, and 4.0 kHz), and high frequencies (4.0 and 8 kHz). The CpG sites were tested using a linear mixed-effects model, and the function of the cis-regulatory regions and ontological enrichments were predicted using the online Genomic Regions Enrichment of Annotations Tool. The differentially methylated regions were identified using a comb-p python library approach. RESULTS: In each of the PTA categories (low-, speech-, high-frequency), age-related hearing loss was detected in 25.9%, 19.3%, and 52.8% of participants. In the low-, speech- and high-frequency categories we identified 18, 42, and 12 individual CpG sites and 6, 11, and 6 differentially methylated regions. The CpG site located near DUSP4 had the strongest association with low- and speech-frequency, while the strongest association with high-frequency was near C21orf58. We identified associations of ALG10 with high-frequency hearing, C3 and LCK with low- and speech-frequency hearing, and GBX2 with low-frequency hearing. Top pathways that may be related to hearing, such as the Notch signaling pathway, were also identified. CONCLUSION: Our study is the first of its kind to identify these genes and their associated with DNA methylation may play essential roles in the hearing process. The results of our epigenome-wide association study on twins clarify the complex mechanisms underlying age-related hearing loss.

Human growth hormone supplement promotes human lymphohematopoietic cell reconstitution in immunodeficient mice.

Aim: To investigate the potential of human growth hormone (hGH) to improve human hematopoietic reconstitution in humanized mice. Materials & methods: Immunodeficient mice were conditioned by total body irradiation and transplanted with human CD34+ fetal liver cells. Peripheral blood, spleen and bone marrow were harvested, and levels of human lymphohematopoietic cells were determined by flow cytometry. Results: Supplementation with hGH elevated human lymphohematopoietic chimerism by more than twofold. Treatment with hGH resulted in significantly increased reconstitution of human B cells and myeloid cells in lymphoid organs, enhanced human erythropoiesis in the bone morrow, and improved engraftment of human hematopoietic stem cells. Conclusion: hGH supplementation promotes human lymphohematopoietic reconstitution in humanized mice.

Humanized mice generated by human hematopoietic stem cell transplantation play crucial roles in biomedical investigations. One of the factors hindering the efficacy of their construction is the lack of or insufficient interaction of human cells to mouse cytokines and growth hormones (GHs) that are crucial for hematopoiesis and immune cell differentiation. In this study, we show that injection of human GH significantly improved human hematopoietic stem cell engraftment and function, as well as immune cell reconstitution in humanized mice. Our findings indicate that human cells may not efficiently respond to mouse GH, and generation of immunodeficient mice producing human GH may improve the efficacy of humanized mouse construction.