Parishin treatment alleviates cardiac aging in naturally aged mice.

Background: Cardiac aging progressively decreases physiological function and drives chronic/degenerative aging-related heart diseases. Therefore, it is crucial to postpone the aging process of heart and create products that combat aging. Aims & methods: The objective of this study is to examine the effects of parishin, a phenolic glucoside isolated from traditional Chinese medicine Gastrodia elata, on anti-aging and its underlying mechanism. To assess the senescent biomarkers, cardiac function, cardiac weight/body weight ratio, cardiac transcriptomic changes, and cardiac histopathological features, heart tissue samples were obtained from young mice (12 weeks), aged mice (19 months) treated with parishin, and aged mice that were not treated. Results: Parishin treatment improved cardiac function, ameliorated aging-induced cardiac injury, hypertrophy, and fibrosis, decreased cardiac senescence biomarkers p16Ink4a, p21Cip1, and IL-6, and increased the "longevity factor" SIRT1 expression in heart tissue. Furthermore, the transcriptomic analysis demonstrated that parishin treatment alleviated the cardiac aging-related Gja1 downregulation and Cyp2e1, Ccna2, Cdca3, and Fgf12 upregulation in the heart tissues. The correlation analysis suggested a strong connection between the anti-aging effect of parishin and its regulation of gut microbiota and metabolism in the aged intestine. Conclusion: The present study demonstrates the protective role and underlying mechanism of parishin against cardiac aging in naturally aged mice.

Genetic predisposition to white blood cells in relation to the risk of frailty.

BACKGROUND: Observational studies have suggested an association between white blood cells (WBCs) and frailty, but considering the susceptibility to reverse causality and confounding, the causal direction and magnitude of this association remain ambiguous. Our aim was to investigate the causal effect of WBCs on frailty by means of a Mendelian randomization (MR) analysis. METHODS: Based on the genome-wide association study (GWAS) summary statistics data provided by the European Bioinformatics Institute (EBI), we carried out a two-sample MR study. We applied the genetically predicted independent WBCs from GWAS as a measure of exposure data. The Rockwood Frailty Index (FI) was used as outcome measure, which was derived from a meta-analysis from GWAS in UK Biobank European ancestry participants and Swedish TwinGene participants. Our study applied inverse variance weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger) and outlier test (MR-PRESSO) methods to explore relationships between various WBCs and frailty. RESULTS: In our study, a possible causal relationship between eosinophil levels and frailty was demonstrated by two-sample MR analysis. Eosinophils were associated with FI (beta:0.0609; 95% CI 0.0382, 0.0836; P = 1.38E-07). Our results suggest that as the level of eosinophils increases, so does the risk of frailty. No meaningful causal relationship between neutrophils, lymphocytes, monocytes or basophils and FI was found in the MR results (P > 0.05). CONCLUSIONS: According to this MR study, higher eosinophil counts are related to an increased risk of frailty. To validate these findings and investigate the mechanisms underlying these connections, future studies are warranted.

Serum IGF-1 levels are associated with sarcopenia in elderly men but not in elderly women.

BACKGROUND: Sarcopenia is an age-associated decline in muscle mass that negatively affects the metabolic rate, strength, and function of the body and ultimately leads to a decrease in quality of life. Insulin-like growth factor 1 (IGF-1) is a modulator of muscle mass and muscle function. There is evidence that IGF-1 is related to the appendicular skeletal muscle mass index (ASMI) and grip strength. The aim of this study was to explore the relationship between serum IGF-1 levels and sarcopenia in older people. METHODS: In this cross-sectional survey of 984 people older than 60 years old, we used the 2019 criteria of the Asian Working Group for Sarcopenia (AWGS) to define sarcopenia. We collected demographic variables, measured ASMI and grip strength, and detected serum IGF-1 data. The levels of serum IGF-1 were separated into quintiles (Q1-Q5). RESULTS: Adjusted for age, education level, smoking, number of diseases and BMI, the multivariable linear regression analysis revealed that serum IGF-1 levels were related to ASMI in elderly men (coefficient = 0.03, 95% CI = 0.02-0.05, P < 0.001) but were not related to their grip strength. There was no significant relationship between serum IGF-1 levels and ASMI or grip strength in elderly women. The multivariable log-binomial regression analysis showed that higher serum IGF-1 levels were associated with a lower prevalence of sarcopenia in elderly men (prevalence ratio (PR) = 0.99, 95% CI = 0.98-1.00, P < 0.05) but not in elderly women. CONCLUSION: Serum IGF-1 levels were highly correlated with sarcopenia in older men. Further studies are needed to further explore the possible reasons for the observed difference between genders. Serum IGF-1 might predict sarcopenia prevalence in elderly men.

TLR3 inhibitor and tyrosine kinase inhibitor attenuate cigarette smoke/poly I:C-induced airway inflammation and remodeling by the EGFR/TLR3/MAPK signaling pathway.

Tobacco smoke is the major risk factor for developing chronic obstructive pulmonary disease (COPD). Viral infection is a major cause of COPD exacerbation, which lacks effective drug treatments. In the present study, to mimic the pathogenesis of COPD, we employed a TLR3 ligand [Poly (I:C), PIC] to mimic viral infection to determine whether it enhances the effects of cigarette smoke (CS)-induced airway inflammation and remodeling. Our results showed that PIC enhanced the effects of cigarette smoke extract (CSE)-induced inflammatory cytokine IL-1ß, TNF-α and IL-8 mRNA expression and remodeling factor E-cadherin, α-SMA and TGF-ß1 mRNA expression with TLR3 upregulation and EGFR phosphorylation in pulmonary epithelial NCI-H292 cells. These responses were inhibited by a TLR3/dsRNA complex inhibitor (TLR3i) or a tyrosine kinase inhibitor icotinib (Ico). Similarly, in the PIC-enhanced CS-induced airway inflammation and remodeling mouse model, treatment with TLR3i or Ico reduced the mRNA and protein expression of the inflammatory cytokines IL-1ß and TNF-α and keratinocyte chemoattractant (KC) and the remodeling factors α-SMA, TGF-ß1, MMP-9 and MUC5AC, while increasing E-cadherin mRNA and protein expression. Furthermore, we found that TLRi and Ico can attenuate the airway hyperreactivity induced by PIC, which is enhanced by CS. Finally, PIC enhanced the effects of CS on TLR3 upregulation and EGFR phosphorylation and significantly increased Erk1/2 and P38 phosphorylation, whereas TLR3i and Ico markedly suppressed TLR3 upregulation and EGFR, Erk1/2 and P38 phosphorylation in the model. Our findings suggest that TLR3/EGFR may be a potential target for the treatment of airway inflammation and remodeling in COPD.

Knockdown of miR-25 increases the sensitivity of liver cancer stem cells to TRAIL-induced apoptosis via PTEN/PI3K/Akt/Bad signaling pathway.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is considered as a promising anticancer agent, it induced apoptosis in cancer cells selectively without damaging the normal tissue cells. However, the resistance of cancer cells to TRAIL limits its application. Since the cancer stem cells (CSCs) are believed to be responsible for the treatment failure in multiple cancers including hepatocellular carcinoma (HCC), the aim of this study was to investigate the strategies to increase the sensitivity of liver cancer stem cells (LCSCs) to TRAIL. In the present study, we observed significant upregulation of miR-25 in LCSCs compared with the non-CSCs. Furthermore, we found that knockdown of miR-25 by its antisense oligonucleotide (anti­miR-25) significantly increased the sensitivity of LCSCs to TRAIL-induced apoptosis. The gene of phosphatase and tensin homologue (PTEN), which is a natural inhibitor of PI3K, was found to be directly regulated by miR-25 in HepG2­CSCs. We demonstrated that knockdown of miR-25 increased the expression of PTEN. Mechanistically, inhibition of Bad phosphorylation, which is regulated by the PTEN/PI3K/AKT pathway, is essential for the functional roles of anti-miR-25 in HepG2-CSCs. In conclusion, our findings indicate that overexpression of miR-25 is associated with the low-sensitivity to TRAIL in LCSCs. Knockdown of miR-25 may represent a potential strategy for increasing the efficacy of TRAIL by targeting the PTEN/PI3K/Akt/Bad signaling pathway.

MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway.

Gefitinib is a first line anti-tumor drug used for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, the drug resistance to gefitinib limits its clinical application. Here, we observed the CSCs of PC9 are obviously resistant to gefitinib compared with the non-CSCs. Furthermore, we found the gefitinib failed to suppress the PI3K/AKT pathway in the PC9-CSCs. Mechanically, we showed significant down-regulation of miR-128 in the PC9-CSCs compared with the non-CSCs. Overexpression of miR-128 significantly increased the sensitivity of PC9-CSCs to gefitinib-induced apoptosis. In addition, the gene of c-met was proved to be directly inhibited by miR-128. Enforced expression of c-met could "rescue" the miR-128 promoted apoptosis and cleavage of caspases in PC9-CSCs treated with gefitinib. Thus, these results indicate that the miR-128/c-met pathway enhances the gefitinib sensitivity of the lung cancer stem cells by suppressing the PI3K/AKT pathway.

Primary pulmonary chondrosarcoma and a fast-growing mass that accidentally mimicked teratoma.

Primary pulmonary chondrosarcoma is a rare neoplasm that usually grows slowly, metastasizes late, and responds well to excision when localized. Herein, we present a 59-year-old man who manifested with hemoptysis, cough and dyspnea with a hemithorax mass. A chest computed tomography scan demonstrated a fast-growing mass in the right upper lobe, and the enhancement was partially heterogeneous. Bronchoscopy revealed a hemorrhagic neoplasm in the right upper bronchus. A bronchoscopy biopsy specimen revealed a variety of tissues, including mucoid cartilage, fibers, respiratory epithelium and squamous epithelium. Because malignancy was suspected, the patient underwent a right upper sleeve lobectomy with mediastinal lymphadenectomy. Macroscopically, we observed a firm white mass 9.5 cm in diameter with a central area of necrosis. Histopathology revealed neoplastic chondrocytes with enlarged and hyperchromatic nuclei in the myxoid matrix. The tumors were positive for S-100. The patient was diagnosed with tracheobronchial myxoid chondrosarcoma. Lymph node dissection indicated no metastasis. The tumor grows slowly in the initial symptom-free phase when localized. Then, a symptomatic phase ensues, during which the tumor progresses rapidly. The patient displayed pulmonary and subcutaneous skull metastases eight months after operation and was treated with adriamycin and ifosfamide chemotherapy.

Regulation of Viral Infection-induced Airway Remodeling Cytokine Production by the TLR3-EGFR Signaling Pathway in Human Bronchial Epithelial Cells.

Toll-like receptor 3 (TLR3) is involved in the virus-induced pulmonary inflammatory response, but its role in airway remodeling after viral infection is unclear. We explored the role of TLR3 in poly(I:C)-induced inflammatory cytokines and mucin 5AC (MUC5AC) production in human bronchial epithelial cells by Western blotting, RT-PCR and ELISA. The expression of TLR3, MUC5AC, Matrixmetalloproteinase (MMP9), Transforming growth factor (TGF-ß1) and Vascular endothelial growth factor (VEGF) in human bronchial epithelial cells increased in a dose-dependent manner after exposure to poly(I:C), and this effect was inhibited by treatment with TLR3 siRNA. The phosphorylation of epithelial growth factor receptor (EGFR)/ERK/P38 Mitogen-activated protein kinases (MAPK) proteins increased after poly(I:C) treatment, and inhibition of this signaling pathway decreased TLR3 expression and MUC5AC and TGF-ß1 production in human bronchial epithelial cells. The TLR3-EGFR signaling pathway is involved in the production of airway remodeling cytokines after virus infection. Inhibiting EGFR and its signaling pathway may be a therapeutic strategy for modifying airway remodeling.

Characterization of a novel plasmid type and various genetic contexts of bla OXA-58 in Acinetobacter spp. from multiple cities in China.

BACKGROUND/OBJECTIVE: Several studies have described the epidemiological distribution of blaOXA-58-harboring Acinetobacter baumannii in China. However, there is limited data concerning the replicon types of blaOXA-58-carrying plasmids and the genetic context surrounding blaOXA-58 in Acinetobacter spp. in China. METHODOLOGY/PRINCIPAL FINDINGS: Twelve non-duplicated blaOXA-58-harboring Acinetobacter spp. isolates were collected from six hospitals in five different cities between 2005 and 2010. The molecular epidemiology of the isolates was carried out using PFGE and multilocus sequence typing. Carbapenemase-encoding genes and plasmid replicase genes were identified by PCR. The genetic location of blaOXA-58 was analyzed using S1-nuclease method. Plasmid conjugation and electrotransformation were performed to evaluate the transferability of blaOXA-58-harboring plasmids. The genetic structure surrounding blaOXA-58 was determined by cloning experiments. The twelve isolates included two Acinetobacter pittii isolates (belong to one pulsotype), three Acinetobacter nosocomialis isolates (belong to two pulsotypes) and seven Acinetobacter baumannii isolates (belong to two pulsotypes/sequence types). A. baumannii ST91 was found to be a potential multidrug resistant risk clone carrying both blaOXA-58 and blaOXA-23. blaOXA-58 located on plasmids varied from ca. 52 kb to ca. 143 kb. All plasmids can be electrotransformed to A. baumannii recipient, but were untypeable by the current replicon typing scheme. A novel plasmid replicase named repAci10 was identified in blaOXA-58-harboring plasmids of two A. pittii isolates, three A. nosocomialis isolates and two A. baumannii isolates. Four kinds of genetic contexts of blaOXA-58 were identified. The transformants of plasmids with structure of IS6 family insertion sequence (ISOur1, IS1008 or IS15)-ΔISAba3-like element-blaOXA-58 displayed carbapenem nonsusceptible, while others with structure of intact ISAba3-like element-blaOXA-58 were carbapenem susceptible. CONCLUSION: The study revealed the unique features of blaOXA-58-carrying plasmids in Acinetobacter spp. in China, which were different from that of Acinetobacter spp. found in European countries. The diversity of the genetic contexts of blaOXA-58 contributed to various antibiotics resistance profiles.

[Thoracic involvement of Castleman's disease: report of 10 cases].

OBJECTIVE: To improve the recognition of thoracic involvement of Castleman' s disease. METHODS: Ten patients with thoracic involvement of Castleman' s disease were retrospectively studied by review of the clinical manifestations, radiology, pathology, differential diagnosis, therapy and prognosis. RESULTS: The 10 patients were all females. Five of the patients, aged from 29 to 49 years, presented with multicentric lesions, manifested by interstitial pneumonia and mediastinal lymphadenopathy on radiology, as well as extrathoracic involvement including peripheral lymphadenopathy, and multiple organ impairment. The pathology was the plasma cell type. Treatment with corticosteroids and chemotherapy achieved partial remission in 4 cases, but 1 died of cardiac and respiratory failure. Localized lesions were found in the other 5 patients, aged from 13 to 49 years. No specific manifestations were revealed in these patients. The major radiological sign was right mediastinal masses, 6-9 cm in diameter, uniformly enhanced by contrast radiology. The pathology revealed vascular hyaline degeneration. Early surgical resection achieved good prognosis. The 5 patients were all alive. CONCLUSIONS: Diagnosis of thoracic involvement of Castleman' s disease is not easy. Early, repeated and multiple biopsy of lymph nodes is recommended, especially when the disease is multicentric or when the lymph nodes are massive. Synchronous enhancement with the vessels on contrast radiology is suggestive of the diagnosis.

Primary pulmonary synovial sarcoma, a rare primary lung neoplasm: two case reports and review of the current literature.

This report describes the clinical, histological and immunohistochemical features of two patients with primary pulmonary synovial sarcoma in the context of the literature. Chest pain, cough, haemoptysis and an enlarging pleural-based mass are the main clinical manifestations. Diagnosis depends on identifying epithelioid or spindle cells microscopically and on immunohistochemistry showing positivity for cytokeratin and vimentin and epithelial membrane antigen stains. Surgical excision is the main treatment approach.