Self-Aggregation, Antimicrobial Activity and Cytotoxicity of Ester-Bonded Gemini Quaternary Ammonium Salts: The Role of the Spacer.

Five ester-bonded gemini quaternary ammonium surfactants C12-En-C12 (n = 2, 4, 6), with a flexible spacer group, and C12-Bm-C12 (m = 1, 2), with rigid benzene spacers, were synthesized via a two-step reaction and analyzed. Furthermore, the effects of the spacer structure, spacer length and polymerization degree on the self-aggregation, antimicrobial activity and cytotoxicity of C12-En-C12 and C12-Bm-C12 and their corresponding monomer N-dodecyl-N,N,N-trimethyl ammonium chloride DTAC were investigated. The results showed that C12-En-C12 and C12-Bm-C12 had markedly lower critical micellar concentration (CMC) values and lower surface tension than DTAC. Moreover, the CMC values of C12-En-C12 and C12-Bm-C12 decreased with increasing spacer length. In the case of equivalent chain length, the rigidity and steric hindrance of phenylene and 1,4-benzenediyl resulted in larger CMC values for C12-Bm-C12 than for C12-En-C12. The antibacterial ability of C12-En-C12 and C12-Bm-C12 was assessed using Escherichia coli (E. coli) and Staphylococcus albus (S. aureus) based on minimum inhibitory concentrations (MICs). Furthermore, C12-En-C12 and C12-Bm-C12 exhibited higher antimicrobial activity than DTAC and had stronger function toward S. aureus than E. coli. The antimicrobial activity was enhanced by increasing the spacer chain length and decreased with the increased rigidity of the spacers. The cytotoxic effects of C12-En-C12 and C12-Bm-C12 in cultured Hela cells were evaluated by the standard CCK8 method based on half-maximal inhibitory concentration (IC50). The cytotoxicity of C12-En-C12 and C12-Bm-C12 was significantly lower than alkanediyl-α,ω-bis(dimethyldodecylammonium) bromide surfactants and DTAC. The spacer structure and the spacer length could induce significant cytotoxic effects on Hela cells. These findings indicate that the five ester-bonded GQASs have stronger antibacterial activity and lower toxicity profile, and thus can be used in the pharmaceutical industry.

[Clinical phenotype and genetic analysis of a child with 3p26.3p25.3 deletion].

OBJECTIVE: To explore the genetic basis for a child with facial dysmorphism and multiple malformations. METHODS: The child, born at 34+6 weeks' gestation due to premature rupture of amniotic membrane, dichorionic diamniotic twinning and gestational diabetes, was subjected to chromosomal karyotyping analysis and copy number variations sequencing (CNV-seq). RESULTS: The child was found to have facial dysmorphism, hypospadia, cryptorchidism and hypotonia. He was found to have a 46,XY,del(3)(p26) karyotype in addition with a 9.80 Mb deletion (chr3: 60 000-9 860 000) encompassing 33 protein coding genes. CONCLUSION: The 3p26.3p25.3 deletion probably underlay the multiple malformations in this child. Continuous follow-up is required to improve his quality of life.

The Effect of Resourcefulness Training on Depression and Coping Styles of Patients With Coronary Heart Disease in China [RETRACTED].

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of mortality worldwide. Previous research has demonstrated that resourcefulness interventions can help individuals identify effective coping strategies to manage their conditions, reduce the incidence of depression, and improve their quality of life. However, little is known about such interventions for people with CHD in China. OBJECTIVE: This study aimed to investigate the effects of a resourcefulness training intervention on depression and coping style of patients with CHD in China. METHODS: A cluster randomized controlled trial design was used. A convenience sample of 72 patients in community settings took part in the study. Participants in the intervention group (n = 36) received an 8-week intervention based on the concept of resourcefulness, plus routine health education. Participants in the control group (n = 36) received routine health education only. Three outcomes (resourcefulness, depression, and coping styles) were measured using the Resourcefulness Scale, Center for Epidemiological Studies Depression Scale, and Medical Coping Mode Questionnaire. Data were collected at baseline and post intervention, and analyzed using frequencies, percentages, means, standard deviations, independent sample t tests, and χ tests. RESULTS: After the intervention, participants in the intervention group had significantly higher scores on resourcefulness and coping styles, and lower scores on depression than those in the control group (both Ps < .001). CONCLUSIONS: It is suggested that a well-developed resourcefulness intervention could help patients with CHD in China and beyond to be more resourceful, improve their level of depression, and choose more effective strategies to cope with stress.

Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.

Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.

Exposure to Vinyl Chloride and Its Influence on Western Diet-Induced Cardiac Remodeling.

Obesity, usually caused by high fat diets (HFD), is a major public health issue worldwide, causing obesity associated cardiomyopathy. Moreover, the environmental toxicant vinyl chloride (VC) can exacerbate HFD-induced fatty liver disease. However, whether VC serves to enhance obesity-associated cardiomyopathy remains unclear. This study aims to investigate the interaction of western diet (WD) containing relatively low fat (42%) with VC on cardiac remodeling and its underling mechanisms. Adult male C57BL/6J mice were exposed to WD coinhalation of low-dose VC (<1 ppm/d) for 12 weeks. Results showed that WD feeding for 12 weeks caused slight cardiac systolic dysfunction without significant hypertrophy or fibrosis, even with VC. Nevertheless, WD upregulated NF-κB function and expression of IL-1ß and PAI-1, while VC showed no significant impact on these effects. In contrast, WD together with VC significantly increased the expression of CHOP and TGF-ß1, key markers for endoplasmic reticulum stress and profibrotic cytokine, respectively. In summary, exposure to low-dose of environmental toxicant VC while a WD is consumed for a relatively short time does not have significant impact on cardiac remodeling except for a mild systolic dysfunction of the heart.

Metabolic and senescence characteristics associated with the immune microenvironment in non-small cell lung cancer: insights from single-cell RNA sequencing.

Non-small lung cancer (NSCLC) has been defined as a highly life-threatening heterogeneous disease, with high mortality and occurrence. Recent research has indicated that tumor-infiltrating lymphocytes play a key determinant role in cancer progression. Emerging single-cell RNA sequencing (also termed scRNA-seq) has been extensively applied to depict the baseline landscape of the cell composition and function phenotype in the tumor environment (TME). Herein, we dissected the cell types in NSCLC samples (including tissue and blood) and identified three types of cell marker genes including cancer cells, T cells, and macrophages by integrating two NSCLC-associated scRNA-seq datasets in GEO. Survival analysis indicated that 17 marker genes were related to tumor prognosis. Function annotation was used to scrutinize the molecular mechanism of these marker genes in different cells. Besides, we investigated the developmental trajectory and T cell receptor repertoire diversity of tumor-infiltrating T cells. Our analysis will help further understand the complexity of cell components and the heterogeneity of TME in NSCLC.

Effects of Teaching Resourcefulness in Patients with Coronary Heart Disease.

This cluster randomized controlled trial aimed to investigate the effects of an intervention to teach resourcefulness on depression and coping style of patients with coronary heart disease (CHD). A convenience sample of 72 patients in community settings took part. Participants in the intervention group (n = 36) received an 8-week intervention based on the concept of resourcefulness, plus routine health education. Participants in the control group (n = 36) received routine health education only. After the intervention, participants in the intervention group had significantly higher scores on resourcefulness and coping styles, and lower scores on depression than those in the control group (both ps < .001). The findings suggest that a well-developed intervention to teach resourcefulness could help patients with CHD to be more resourceful, improve their level of depression, and choose more effective strategies to cope with stress.

Mutational status of main driver genes influences the prognosis of stage I-III lung adenocarcinoma patients underwent radical surgery.

BACKGROUND: The therapeutic strategies and prognosis of local advanced and metastatic lung cancer have been extensively investigated. However, the prognosis of early-stage lung cancer patients undergoing radical surgery has not been fully studied due to the difficulties in follow-up and assessment. METHODS: We recruited 447 stage I-III lung adenocarcinoma (LUAD) patients who underwent radical surgery and investigated the influence of main driver gene mutations and clinicopathological factors on patient overall survival (OS). Cancer tissue samples were collected retrospectively and mutational status and tumor mutational burden (TMB) were determined by whole-exome sequencing (WES). RESULTS: Distinct stage-dependent mutational frequency was revealed in main driver genes including EGFR, TP53, KRAS, STK11, ATM and NF1. Patients with TP53 mutations exhibited a trend of better survival than those with wild type TP53 (P=0.066), and STK11 mutations exhibited worse survival in stage III patients (P=0.031). EGFR mutations eliminated the across-stage difference in survival, which was still present in other wild type and mutant driver genes. Furthermore, patients with wild type TP53 appeared to have significantly worse survival than patients with other wild type driver genes in stage I (P<0.001). TMB cannot stratify the survival of LUAD patients in stage I-III. Age, gender, smoking status, smoking years, prior cancer history and cancer location had no stratification effect on patient survival, while T grading (P<0.001) and N grading (P<0.001) had significant stratification on survival. CONCLUSIONS: TP53, EGFR and STK11 mutational status influenced the prognosis of stage I-III LUAD. T and N grading also stratified the patient survival. T grading was an independent risk factor.

miR­454­3p inhibits non­small cell lung cancer cell proliferation and metastasis by targeting TGFB2.

Accumulating studies have suggested that microRNAs (miRs) play a significant role in lung cancer development and progression, especially in non­small cell lung cancer (NSCLC). The present study aimed to investigate the associations between miR­454­3p and NSCLC progression. qPCR assay was applied to examine the expression of miR­454­3p and transforming growth factor­ß2 (TGFB2) in tissues and cell lines. CCK­8 and EdU assays were used to detect cell proliferation. Wound­healing and Transwell assays were conducted to assess cell migration and invasion. Western blotting assay was performed to explore the protein levels of epithelial­mesenchymal transition (EMT) markers. The interaction between miR­454­3p and TGFB2 was investigated with a luciferase reporter assay. miR­454­3p was downregulated in NSCLC tissues and NSCLC cell lines. miR­454­3p overexpression led to the suppression of proliferation, migration, and invasion in A549 and NCI­H1650 cells. In addition, the overexpression of miR­454­3p in A549 and NCI­H1650 cells significantly inhibited EMT. TGFB2 was revealed to be a direct target of miR­454­3p by using TargetScan database and luciferase reporter assay. TGFB2 was observed to be upregulated in NSCLC tissues and cell lines. Further mechanistic studies revealed that the inhibitory effects of miR­454­3p on NSCLC were reversed upon overexpression of TGFB2. These findings provided strong evidence that miR­454­3p suppressed NSCLC cell proliferation and metastasis by targeting TGFB2. The study suggests that targeting miR­454­3p could be a promising strategy for treating NSCLC.

Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis.

Elevated tumor suppressor p53 expression has been associated with heart diseases, including the diabetic heart. However, its precise role in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. We hypothesized that the development of DCM is attributed to up-regulated p53-mediated both early cardiac cell death and persistent cell senescence, glycolytic and angiogenetic dysfunctions. The present study investigated the effect of p53 inhibition with its specific inhibitor pifithrin-α (PFT-α) on the pathogenesis of DCM and its associated mechanisms. Type 1 diabetes was induced with multiple low doses of streptozotocin. Both hyperglycemic and age-matched control mice were treated with and without PFT-α five times a week for 2 months and then sacrificed at 3 and 6 months post-diabetes. Treatment with PFT-α significantly prevented the progression of diabetes-induced cardiac remodeling and dysfunction (i.e., DCM). Mechanistically, the inhibition of p53 prevented the cardiac apoptosis during early-stage diabetes (0.5 month), attenuated diabetes-induced cell senescence (3 and 6 months), and improved both glycolytic and angiogenic defects by increasing hypoxia-induced factor (HIF)-1α protein stability and upregulating HIF-1α transcription of specific target genes at 3 and 6 months after diabetes. Therefore, the targeted inhibition of p53 in diabetic individuals may provide a novel approach for the prevention of DCM.

Lipoprotein lipase: Biosynthesis, regulatory factors, and its role in atherosclerosis and other diseases.

Lipoprotein lipase (LPL) is a rate-limiting enzyme that catalyzes hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins including chylomicrons (CM), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). A variety of parenchymal cells can synthesize and secrete LPL. Recent studies have demonstrated that complicated processes are involved in LPL biosynthesis, secretion and transport. The enzyme activity of LPL is regulated by many factors, such as apolipoproteins, angiopoietins, hormones and miRNAs. In this article, we also reviewed the roles of LPL in atherosclerosis, coronary heart disease, cerebrovascular accident, Alzheimer disease and chronic lymphocytic leukemia. LPL in different tissues exerts differential physiological functions. The role of LPL in atherosclerosis is still controversial as reported in the literature. Here, we focused on the properties of LPL derived from macrophages, endothelial cells and smooth muscle cells in the vascular wall. We also explore the existence of crosstalk between LPL and those cells when the molecule mainly plays a proatherogenic role. This review will provide insightful knowledge of LPL and open new therapeutic perspectives.

Synthesis, characterization, and sustained release property of Fe3O4@(enrofloxacin-layered double hydroxides) nanocomposite.

A novel magnetic nanocomposite with enrofloxacin (ENR) intercalated MgAl layered double hydroxides (LDH) coated on Fe3O4 particles, denoted as Fe3O4@(ENR-LDH), was assembled via a delamination-reassembling process. Fe3O4@(ENR-LDH) was characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, element chemical analysis, transmission electron microscopy, differential scanning calorimetry, and room-temperature magnetic measurements. Results showed the following: ① Fe3O4@(ENR-LDH) consisted of both ENR-LDH nanocrystallite and Fe3O4 phases; ② Fe3O4@(ENR-LDH) presented well-defined core-shell structure with diameter in the range of 15-20nm; ③ the thermal stability of ENR was enhanced after intercalation; and ④ Fe3O4@(ENR-LDH) exhibited good superparamagnetism. The release kinetics of ENR was investigated in buffer solutions at pH4.6 and 7.2, and the release process fitted Bhaskar model indicating diffusion-controlled mechanism. In addition, ENR release rate from Fe3O4@(ENR-LDH) was remarkably lower than that from the corresponding physical mixture, showing that Fe3O4@(ENR-LDH) can be considered as a potential magnetic targeting drug delivery-controlled-release system.

Exacerbation of diabetic cardiac hypertrophy in OVE26 mice by angiotensin II is associated with JNK/c-Jun/miR-221-mediated autophagy inhibition.

Both diabetes and angiotensin II (Ang II) excess trigger cardiac remodeling and dysfunction, and diabetic cardiomyopathy. We hypothesized that cardiac hypertrophy associated with the development of diabetic cardiomyopathy is worsened by increased Ang II. Male type 1 diabetic OVE26 and wild-type mice were given Ang II (sc., 1.15 mg/kg, twice a day) for 14 days. Diabetes-induced cardiac dysfunction and hypertrophy was exacerbated by Ang II treatment as determined by echocardiography, wheat germ agglutinin staining and atrial natriuretic peptide. Ang II treatment dramatically exacerbated diabetes-caused decreased LC3-II, a marker of autophagy, and increased p62, an indicator of cytosolic protein clearance. Ang II treatment also augmented diabetes-associated increased phosphorylated levels of c-Jun, JNK, mTOR, and miR-221, and decreased of p27 expression, a direct target of miR-221. Chromatin immunoprecipitation assay showed that Ang II elevated c-Jun binding to the promoter of miR-221 in diabetic mice. These results suggest that Ang II accelerates cardiac hypertrophy in the early stage of murine diabetes, probably through activation of the JKN/c-Jun/miR-221 axis and inhibition of downstream autophagy. Therefore, inhibition of Ang II or miR-221 in diabetic individuals may be a potential approach for delaying the onset and/or reducing the severity of diabetic cardiomyopathy.

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury.

In the present study, we investigated the effect of classic PDE4 inhibitor rolipram and novel PDE4 inhibitor ZL-n-91 on LPS-induced acute lung injury (ALI) in mice and its mechanism. ALI was induced in ICR mice by instilling intratracheally with LPS, and mice were divided into seven groups: control (Saline), LPS group, ZL-n-91 (3 microg, 10 microg, and 30 microg kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6h of instilling intratracheally with LPS in mice, total leukocyte number, neutrophil number and protein content in BALF increased rapidly, a large number of neutrophil infiltration around the pulmonary vessel and airway, the lung wet weight/dry weight (w/d)ratio raised significantly. MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P(a)O(2), P(a)CO(2) and PH value in peripheral arterial blood also changed obviously, P(a)O(2) and PH value dropped slightly and P(a)CO(2) increased significantly in LPS group. ZL-n-91 (3 microg, 10 microg, 30 microg kg(-1)) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate, but the effect of ZL-n-91 in pathological changes and lung wet w/d ratio is slight; Rol and Dex significantly reduced lung wet w/d ratio and improved pathological changes, neutrophil around the pulmonary vessel and airway significantly reduced, symptoms of lung edema relieved; The PH value, P(a)O(2) and P(a)CO(2) in ZL-n-91 high dosage group and Rol group had changes, but there was no significant difference compared with LPS group or saline group; After the administration, the righting reflex recovery time significantly shorten in every group of ZL-n-91. the righting reflex recovery time of Rol group was similar with ZL-n-91 30 microg kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 microg kg(-1)) on the inflammatory reactivity, including inhibition of inflammatory cell and protein exudation, MPO and PDE4 activity, improvement of the blood gas, those effects were equivalent with rolipram 1 mg kg(-1), and suggested that ZL-n-91 was stronger than rolipram in PDE4 inhibition. So we speculated that ZL-n-91 may have stronger therapeutic potential for treatment of inflammatory disease than rolipram, meantime have stronger nervous system effect than rolipram.