Atherosclerosis is a chronic inflammatory disease that commonly affects the elderly and is characterized by vascular damage, macrophage infiltration, and plaque formation. Moreover, it increases the risk of cardiovascular disease. The pathogenesis of atherosclerosis involves an interplay between macrophage autophagy and apoptosis. A recently discovered transcription factor, transcription factor EB (TFEB) is known to activate autophagy in macrophages. Sirtuin deacetylase 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, activates several transcription factors, including TFEB. We studied the effects of berberine on the NAD+ synthesis pathway and interactions between SIRT1 and TFEB. We also studied the effects of berberine-induced TFEB activation via SIRT1 on autophagy and apoptosis of peritoneal macrophages. We found that berberine promoted autophagy of peritoneal macrophages by activating SIRT1 via the NAD+ synthesis pathway and, in turn, promoting TFEB nuclear translocation and deacetylation. The functional regulation of SIRT1 and TFEB by berberine could be exploited as a potential therapeutic strategy for atherosclerosis.
The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both in vitro and in vivo. IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.
BACKGROUND: To study the role of nm23-H1 and CD44v6 gene in non-small cell lung cancer (NSCLC). METHODS: Expressions of nm23-H1 and CD44v6 genes were analyzed in 147 cases of NSCLC by SP immunohistochemistry method. RESULTS: The overall positive rate of nm23-H1 staining was 62.6% (92/147). Significant differences in the positive rate of nm23-H1 were found between well and poor differentiated groups [68.6% (83/121) [WTBX]vs 34.6% (9/26)], and between adenocarcinoma and squamous cell carcinoma , and between adenocarcinoma and squamous cell carcinoma [78.8% (52/66) [WTBX]vs 50.8% (32/63) ] ( (P 0.05). The positive rate of nm23-H1 of patients who survived for more than 3 years was 71.4% (55/77), which was significantly higher than 52.9% (37/70) of patients who survived for less than 3 years (Chi-square=5.4, P 0.05). The positive rate of CD44v6 of patients who survived for more than 3 years was much lower than that of patients who survived for less than 3 years (43/74 vs 51/70, P < 0.01 ). The 3-year survival rate in patients with nm23-H1(+)CD4v6(-) was significantly higher than those with nm23-H1(-)CV44v6(+) (22/32 vs 11/34, P < 0.01). CONCLUSIONS: There are some relationships among expressions of nm23-H1 and CD44v6 in NSCLC and cell differentiation, histological classification and prognosis, and no relation in stage and lymph node metastasis.
Currently, only a limited numbers of tumor markers for non small lung cancer (NSCLC) diagnosis, new biomarker, such as serum autoantibody may improve the early detection of lung cancer. Our objective is construction human lung squamous carcinoma and adenocarcinoma T7 phage display cDNA library from the tissues of NSCLC patients. mRNA was isolated from a pool of total RNA extract from NSCLC tissues obtained from 5 adenocarcinomas and 5 squamous carcinomas, and then mRNA was reverse transcribed into double stranded cDNA. After digestion, the cDNA was inserted into T7Select 10-3 vector. The phage display cDNA library was constructed by package reaction in vitro and plate proliferation. Plaque assay and PCR were used to evaluate the library. Two T7 phage display cDNA library were established. Plaque assay show the titer of lung squamas carcinoma library was 1.8*10(6) pfu, and the adenocarcinoma library was 5*10(6) pfu. The phage titer of the amplified library were 3.2*10(10) pfu/mL and 2.5*10(10) pfu/mL. PCR amplification of random plaque show insert ratio were 100% (24/24) in adenocarcinoma library and 95.8% in human lung squamas carcinoma library (23/24). Insert range from 300 bp to 1 500 bp. Two phage display cDNA library from NSCLC were constructed.
To date, there has been limited information on phytoestrogen (PE) exposure and metabolism in breastfed infants. In the present work, 50 sample pairs of Chinese breastfed infants' urine and the corresponding breast milk were collected. The contents of the relevant PE metabolites in the biosamples were detected via liquid chromatography–tandem mass spectrometry. The correlations between the PE metabolite contents in breastfed infants' urine and those in the corresponding breast milk were analyzed. The average concentrations of total PE metabolites in breast milk and urine were 0.27 and 0.23 nmol/mL, respectively. Genistein and enterolactone levels in the infant urine were positively correlated with their concentrations in the corresponding breast milk samples, which implies that urine excretion can be utilized as a noninvasive parameter for precise genistein and enterolactone intake assessment. Additionally, the efficiency of PE urine excretion showed significant differences across infants with different ages, genders, and durations of pregnancy.
Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ∆Exon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.
This study evaluated the association between body composition and clinical parameters and prognosis in patients with colorectal cancer (CRC) treated by radical resection.Baseline data on patient age, body mass index (BMI), bowel obstruction and tumor-related factors were collected retrospectively. Body composition parameters such as visceral fat area (VFA), total abdominal muscle area (TAMA), muscle attenuation (MA), posterior renal fat thickness (PPNF) and intermuscular fat area (IMF) are measured using Computed tomography (CT) scans. We also propose a new predictor of linear skeletal muscle index (LSMI) that can be easily measured clinically at CT. Follow-up endpoints were disease-free survival and all-cause death. We follow up with patients in hospital or by telephone. Univariate and multifactorial Cox proportional hazards analyses were performed to identify risk factors associated with prognosis. Survival analysis was performed using the Kaplan-Meier method and a nomogram was established to predict survival.A total of 1761 patients (median age 62 years) with CRC were enrolled in our study, of whom 201 had intestinal obstruction and 673 had a BMI > 24.0. Among all patients, the 3- and 5-year disease-free survival rates were 84.55% and 68.60% respectively, and the overall survival rates were 88.87% and 76.38%. Overall survival was significantly correlated with MA, LSMI, SMI, Tumor size, N stage, metastasis and adjuvant therapy by Cox regression analysis (p < 0.05). The risk of tumor progression was significantly associated with MA, VFA, LSMI, SMI, Male, N stage, metastasis and adjuvant therapy (p < 0.05). In addition, based on the Chinese population, we found that female patients with MA < 30.0 HU, LSMI < 18.2, and SMI < 38.0 had a worse prognosis, male patients with MA < 37.6 HU, LSMI < 21.9, and SMI < 40.3 had a poorer prognosis.Our findings suggest that linear skeletal muscle index and MA can be used as new independent predictors for colorectal cancer patients treated with radical surgery, and that baseline data such as body composition parameters, LSMI and tumor-related factors can collectively predict patient prognosis. These results could help us to optimize the management and treatment of patients after surgery.
SARS-CoV-2 infection induces severe disease in a subpopulation of patients, but the underlying mechanisms remain unclear. We demonstrate robust IgM autoantibodies that recognize angiotensin converting enzyme-2 (ACE2) in 18/66 (27%) patients with severe COVID-19, which are rare (2/52; 3.8%) in hospitalized patients who are not ventilated. The antibodies do not undergo class-switching to IgG, suggesting a T-independent antibody response. Purified IgM from anti-ACE2 patients activates complement. Pathological analysis of lung obtained at autopsy shows endothelial cell staining for IgM in blood vessels in some patients. We propose that vascular endothelial ACE2 expression focuses the pathogenic effects of these autoantibodies on blood vessels, and contributes to the angiocentric pathology observed in some severe COVID-19 patients. These findings may have predictive and therapeutic implications.
Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro . Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo . Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway.
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