Expression of BAG1 is associated with prognosis in kidney renal clear cell carcinoma based on bioinformatics.

BACKGROUND: BCL2 associated Athano-Gene 1 (BAG1) has been described to be involved in the development and progression of cancer. But the role of BAG1 in kidney renal clear cell carcinoma (KIRC) has remained largely unknown. METHODS: We performed bioinformatic analysis of data from TCGA and GEO dataset. The role of BAG1 in KIRC was explored by Logistic and Cox regression model. The molecular mechanisms of BAG1 was revealed by GSEA. RESULTS: The current study found that the KIRC tumor samples have a low level of BAG1 mRNA expression compared to the matched normal tissues based on TCGA data and GEO databases. Low expression of BAG1 in KIRC was significantly associated with Sex, clinical pathological stage, tumor-node-metastasis (TNM) stage, hemoglobin levels, cancer status and history of neoadjuvant treatment. Kaplan-Meier survival analysis indicated that KIRC patients with BAG1 high expression have a longer survival time than those with BAG1 low expression (p < 0.000). Cox regression analysis showed that BAG1 remained independently associated with overall survival, with a hazard ratio (HR) of 1.75(CI:1.05-2.90; p = 0.029). GSEA indicated that the signaling pathways including fatty acid metabolism and oxidative phosphorylation were differentially enriched in high BAG1 expression phenotype. CONCLUSIONS: These findings suggested that BAG1 expression may act as a potential favorable prognostic marker and challenging therapeutic target.

N-terminal mutation of apoA-I and interaction with ABCA1 reveal mechanisms of nascent HDL biogenesis.

ApoA-I and ABCA1 play important roles in nascent HDL (nHDL) biogenesis, the first step in the pathway of reverse cholesterol transport that protects against cardiovascular disease. On the basis of the crystal structure of a C-terminally truncated form of apoA-I[Δ(185-243)] determined in our laboratory, we hypothesized that opening the N-terminal helix bundle would facilitate lipid binding. To that end, we structurally designed a mutant (L38G/K40G) to destabilize the N-terminal helical bundle at the first hinge region. Conformational characterization of this mutant in solution revealed minimally reduced α-helical content, a less-compact overall structure, and increased lipid-binding ability. In solution-binding studies, apoA-I and purified ABCA1 also showed direct binding between them. In ABCA1-transfected HEK293 cells, L38G/K40G had a significantly enhanced ability to form nHDL, which suggests that a destabilized N-terminal bundle facilitates nHDL formation. The total cholesterol efflux from ABCA1-transfected HEK293 cells was unchanged in mutant versus WT apoA-I, though, which suggests that cholesterol efflux and nHDL particle formation might be uncoupled events. Analysis of the particles in the efflux media revealed a population of apoA-I-free lipid particles along with nHDL. This model improves knowledge of nHDL formation for future research.

Probing the C-terminal domain of lipid-free apoA-I demonstrates the vital role of the H10B sequence repeat in HDL formation.

apoA-I plays important structural and functional roles in reverse cholesterol transport. We have described the molecular structure of the N-terminal domain, Δ(185-243) by X-ray crystallography. To understand the role of the C-terminal domain, constructs with sequential elongation of Δ(185-243), by increments of 11-residue sequence repeats were studied and compared with Δ(185-243) and WT apoA-I. Constructs up to residue 230 showed progressively decreased percent α-helix with similar numbers of helical residues, similar detergent and lipid binding affinity, and exposed hydrophobic surface. These observations suggest that the C-terminal domain is unstructured with the exception of the last 11-residue repeat (H10B). Similar monomer-dimer equilibrium suggests that the H10B region is responsible for nonspecific aggregation. Cholesterol efflux progressively increased with elongation up to ∼60% of full-length apoA-I in the absence of the H10B. In summary, the sequential repeats in the C-terminal domain are probably unstructured with the exception of H10B. This segment appears to be responsible for initiation of lipid binding and aggregation, as well as cholesterol efflux, and thus plays a vital role during HDL formation. Based on these observations and the Δ(185-243) crystal structure, we propose a lipid-free apoA-I structural model in solution and update the mechanism of HDL biogenesis.

Surfactant-Induced Artifacts during Proteomic Sample Preparation.

Bottom-up proteomics is a powerful tool for characterization of protein post-translational modifications (PTMs), where PTMs are identified at the peptide level by mass spectrometry (MS) following protein digestion. However, enzymatic digestion is associated with additional sample processing steps that may potentially introduce artifactual modifications. Here, during an MS study of the PTMs of the regulator of G-protein signaling 4, we discovered that the use of ProteaseMAX, which is an acid-labile surfactant commonly used to improve protein solubilization and digestion efficiency, can lead to in vitro modifications on cysteine residues. These hydrophobic modifications resemble S-palmitoylation and hydroxyfarnesylation, thus discouraging the use of ProteaseMAX in studies of lipid modifications of proteins. Furthermore, since they target the cysteine thiol group, the presence of these artifacts will inevitably lead to inaccuracies in quantitative analysis of cysteine modifications.

Graded Progressive Home-Based Resistance Combined with Aerobic Exercise in Community-Dwelling Older Adults with Sarcopenia: A Randomized Controlled Trial.

Purpose: This randomized parallel controlled trial aimed to determine the effectiveness of graded progressive home-based resistance combined with aerobic exercise in improving physical fitness in community-dwelling older adults with sarcopenia. Patients and Methods: Community-dwelling older adults (≥60 years) with sarcopenia were randomly assigned to the intervention group (IG), receiving 12 weeks of graded progressive home-based resistance and aerobic exercise training, and the control group (CG), maintaining lifestyle unchanged. The primary outcomes were knee extensor muscle strength and the six-minute walk distance (6MWD). Intention-to-treat analysis was applied to the data from all participants in the CG and IG. Post-intervention differences between the intervention and control groups were determined using a generalized estimated equation model with pre-values adjusted. Results: Data from all the participants in the IG (n=41) and CG (n=45) were analyzed. After the intervention, knee extensor muscle strength (95% CI: 0.140-3.460, P=0.036), 6MWD (95% CI: 35.350-80.010, P<0.001), flexor muscle strength and the results of 30s bicep curls, 30s chair stand, the chair sit and reach test and back stretch test in the IG were larger and value of the timed up-and-go test was smaller than those in the CG (P<0.05). The body composition, quality of life and their changes showed no group differences. The attendance rates were 82.9% and 85.4% for resistance and aerobic exercise, respectively. Conclusion: The 12-week graded progressive home-based resistance and aerobic exercise intervention improved muscle strength, balance, flexibility, and cardiorespiratory fitness in community-dwelling older adults with sarcopenia, whereas body composition and quality of life remained unchanged. The research was approved by the Ethics Committee of Soochow University (ECSU-2019000161) and registered at the Chinese Clinical Trial Registry (ChiCTR1900027960, http://www.chictr.org.cn/showproj.aspx?proj=45968).

Effect of "maccog" TCM tea on improving glucolipid metabolism and gut microbiota in patients with type 2 diabetes in community.

Objectives: This work aimed to observe the effect of consuming Chinese herb tea on glucolipid metabolism and gut microbiota in patients with type 2 diabetes mellitus (T2DM). Methods: Ninety patients with T2DM were recruited from a community and randomly divided into the control group (CG) and intervention group (IG). CG maintained conventional treatment and lifestyle, and IG accepted additional "maccog" traditional Chinese medicine (TCM) tea (mulberry leaf, radix astragali, corn stigma, cortex lycii, radix ophiopogonis, and gynostemma) for 12 weeks. Glucolipid metabolism, hepatorenal function, and gut microbiota were then measured. Results: After the intervention, the decreases in fasting plasma glucose (FPG) and total cholesterol (TC) were greater (P<0.05) in IG than in CG, and those in glycosylated serum protein (GSP) were almost significantly greater (P=0.066) in IG than in CG. The total protein (TP), albumin (ALB), and creatinine (CREA) levels in IG were significantly lower and their decreases were larger in IG than in CG (P<0.05) after the intervention. The Ace and Chao1 indices in IG were slightly higher after the intervention (P=0.056 and 0.052, respectively) than at baselines. The abundance of Actinobacteria, Lachnospiraceae, Bifidobacteriaceae, and Phascolarctobacterium increased significantly after the intervention in IG (P<0.05), and the abundance was higher in IG than in CG (P<0.05 or P<0.1). The abundance of Clostridiales and Lactobacillales was negatively correlated with FPG (P<0.05), Clostridiales and Lachnospiraceae was negatively correlated with GSP (P<0.05), and Bacteroides/Firmicutes was positively correlated with both (P<0.05). No adverse event was observed during the intervention. Conclusions: Administration of "maccog" TCM tea for 12 weeks slightly improved glucolipid metabolism and significantly increased the abundance of beneficial gut microbiota in community patients with T2DM. The increase in beneficial bacteria abundance may be involved in the improvement of glucose metabolism indicators. In addition, this intervention is safe and feasible. Clinical trial registration: https://www.chictr.org.cn/showproj.aspx?proj=31281, identifier ChiCTR1800018566.

Exercise Combined with a Chinese Medicine Herbal Tea for Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

Objectives: Exercise and Traditional Chinese Medicine (TCM) herbal tea may improve glucose metabolism through quite different mechanisms while sharing some common effects. The purpose of this study was to discover whether the intervention of exercise combined with TCM herbal tea intervention could produce advanced improvement in glucose metabolism than exercise alone in community patients with type 2 diabetes mellitus (T2DM). Materials and Methods: This was a 12-week, randomized controlled trial in which 75 community patients with T2DM were randomly assigned to the single group (n = 39) receiving intervention of aerobic and resistance exercise three times per week and the combined group (n = 36) receiving intervention of TCM herbal tea (consisted of six substances) taken once daily besides the exercise. The change of glycated hemoglobin A1 (HbA1c), tested before and after intervention, served as the primary outcome. Other measurements include fasting plasma glucose (FPG), glycated serum protein (GSP), lipid profile, and physical fitness profile. Results: HbA1c and FPG levels and their changes showed no group difference. The level of GSP was lower, and its decrease was also larger after exercise combined with TCM herbal tea than after single exercise intervention (p < 0.05). Lipid profile and physical fitness parameters were similar in the two groups except the larger six-minute walk test (6MWT) power after the combined intervention (p < 0.05). Patients showed good compliance with the intervention and had similar exercise days or amount in the two groups. No patient reported serious adverse events or significant changes in other lifestyles. Conclusions: A 12-week of exercise combined with TCM herbal tea could not enhance the hypoglycemic effects by exercise alone in community patients with type 2 diabetes. However, the lower GSP level and larger 6MWT work brought by combined intervention suggest its potential benefits, and further studies are needed to explore the effects of longer period and larger dosage of intervention. Clinical Trial Registration Number: Chinese Clinical Trial Registry: ChiCTR1800018721.

Immune Effect of T Lymphocytes Infiltrated by Tumors on Non-Small-Cell Lung Cancer.

Lung cancer is increasing every year and it has high morbidity and mortality. Antitumor immunotherapy is a new method for the treatment of lung cancer. Currently, tumor immunotherapy mainly includes classical immunotherapy and immune-targeted therapy To explore the influence of tumor T-lymphocyte (T-cell) infiltration in non-small-cell lung cancer (NSCLC) patients, 100 NSCLC patients diagnosed and treated in Changde Second People's hospital were recruited. Patients were followed up for 3 years. The subjects were divided into a survival group (group S) and a death group (group D). The patient's pathological tissue sections were made, and the degree of T-cell infiltration was counted by H&E (Hematoxylin and eosin) staining. The infiltration degree was graded, and the positive rate of T-cell subsets was calculated by immunohistochemical staining. The 3-year positive rate was 48%, with 48 cases in group S and 52 cases in group D. The positive rate of H&E staining of group S was 100%, including 0 cases of grade 0, 5 cases of grade 1 (10.42%), 16 cases of grade 2 (33.33%), and 27 cases of grade 3 (56.25%). The positive rate of group D was 86.54%, including 4 cases of grade 0 (8.89%), 10 cases of grade 1 (22.22%), 25 cases of grade 2 (55.56%), and 6 cases of grade 3 (13.33%). The total number of T-cell infiltrates in group S was much higher than that in group D (P < 0.05). Immunohistochemical results showed that the mean positive rate of CD8+ T-cell infiltration was 72.1% in group S and 47.6% in group D, with a considerable difference (P < 0.05). No remarkable difference was found in CD4+ and CD25+ (P < 0.05). CD8+ + CD4+, CD8+/CD4+, CD25+/CD8+, CD25+/CD4+, and CD25+/(CD8+ + CD4+) positive rates were calculated, and the difference between group S and group D was substantial in CD8+ + CD4+ (P < 0.05). The results showed that T cells infiltrated by tumors had an immunosuppressive effect on tumor cells.

Frailty in elderly inpatients with cardiovascular disease: an exploration of associated factors.

AIMS: Older patients with cardiovascular diseases (CVDs) are more likely to develop frailty. Few studies have investigated frailty status, and its multiple associated factors, in this population. The aim of the present study was to explore frailty status, and its multidimensional associated factors, in elderly inpatients with CVDs. METHODS AND RESULTS: In this cross-sectional study, 1021 inpatients with CVDs aged ≥60 years old were recruited through convenience sampling from multiple hospitals in Suzhou, China. The FRAIL scale was used to assess frailty. A self-designed questionnaire gathered sociodemographic, clinical, and health-related information related to the physiological, psychological, and social dimensions of frailty. Among the 629 elderly inpatients with CVDs (73.64 ± 7.93 years old) who met inclusion criteria and completed the assessments, 176 (28.0%) were classified as frail. Univariate analyses demonstrated that the proportion of frailty was significantly associated with multiple factors. Logistic regression analysis indicated that, compared to their counterparts, the risk of frailty was higher in participants with cardiac function classes II, III, and IV [odds ratio (OR) = 1.866, 3.393, and 6.351, respectively]; average and bad mastication function (OR = 2.534 and 2.945, respectively); and often or always using walking aids (OR = 2.713). Conversely, the risk of frailty was lower in participants with good nutritional status (OR = 0.879) and regular exercise habits (OR = 0.573), as compared with their counterparts. CONCLUSION: Frailty in elderly inpatients with CVDs is common and associated with multiple physiological factors including cardiac function, mastication function, nutritional status, use of walking aids, and regular exercise habits.