- Orexin-A protects against oxygen-glucose deprivation/reoxygenation-induced cell damage by inhibiting endoplasmic reticulum stress-mediated apoptosis via the Gi and PI3K signaling pathways. [Journal Article]
- CSCell Signal 2019 Jun 21; :109348
- The neuropeptide orexin-A (OXA) has a neuroprotective effect, acting as an anti-apoptotic factor in response to multiple stimuli. Apoptosis induced by endoplasmic reticulum stress (ERS) underlies oxy…
The neuropeptide orexin-A (OXA) has a neuroprotective effect, acting as an anti-apoptotic factor in response to multiple stimuli. Apoptosis induced by endoplasmic reticulum stress (ERS) underlies oxygen-glucose deprivation and reoxygenation (OGD/R)-induced cell damage, an in vitro model of ischemia/reperfusion injury. However, that OXA inhibits ERS-induced apoptosis in the OGD/R model has not been reported. In the present study, we investigated the neuroprotective effect of OXA (0.1 μM) on OGD/R-induced damage in the human neuroblastoma cell line SH-SY5Y. After OXA treatment following 4 h oxygen-glucose deprivation (OGD) and then 4 h reoxygenation (R), cell morphology, viability, and apoptosis were analyzed by histology, Cell Counting Kit-8 assay, and flow cytometry, respectively. Western blotting was used to measure expression levels of ERS- and apoptosis-related proteins. To determine signaling pathways involved in OXA-mediated neuroprotection, the Gi pathway inhibitor pertussis toxin (PTX; 100 ng/mL) and PI3K inhibitor LY294002 (LY; 10 μM) were added. In addition, in order to prove the specificity of these characteristics, the OXA antagonist Suvorexant (DORA; Ki of 0.55 nM and 0.35 nM for OX1R and OX2R) was used for intervention. Our results showed that OGD/R induced cell damage, manifested as morphological changes and a significant decrease in viability. Furthermore, Western blotting detected an increase in ERS-related proteins GRP78, p-IRE1α, p-JNK, and Cleaved caspase-12, as well as apoptosis-related proteins Cleaved caspase-3 and Bax, and a decrease in the anti-apoptosis factor Bcl-2. OXA intervention alleviated the degree of cellular damage, and protein expression was also reversed. In addition, the protective effect of OXA was reduced by adding PTX and LY. Meanwhile, after the use of DORA, changes in the expression of related proteins were detected, and it was found that the protective effect of OXA was weakened. Collectively, our results indicate that OXA has a neuroprotective effect on OGD/R-induced cell damage by inhibiting ERS-induced apoptosis through the combined action of Gi and PI3K signaling pathways. These findings help to clarify the mechanism underlying the neuroprotective action of OXA, which should aid the development of further candidate drugs, and provide a new therapeutic direction for the treatment of ischemic stroke.
- Anti-colorectal cancer biotargets and biological mechanisms of puerarin: Study of molecular networks. [Journal Article]
- EJEur J Pharmacol 2019 Jun 21; :172483
- Based on network pharmacology analysis, this study was to uncover the anti-colorectal cancer (CRC) targets and molecular mechanisms exerted by puerarin. Pathological genes of CRC and therapeutic gene…
Based on network pharmacology analysis, this study was to uncover the anti-colorectal cancer (CRC) targets and molecular mechanisms exerted by puerarin. Pathological genes of CRC and therapeutic genes of puerarin were collected through well-established databases. The crucial targets of puerarin against CRC were further used for function and pathway enrichment assays to elucidate the biological processes and signaling pathways, followed by experiment-based verification. In network data, the most significant targets of tyrosyl-DNA phosphodiesterase-1 (TDP1), aldehyde dehydrogenase 1 family member A-1 (ALDH1A1), muscleblind like splicing regulator 1 (MBNL1), aldehyde dehydrogenase-2 (ALDH2), and nicotinamide adenine dinucleotide (HPGD) were screened and defined in anti-CRC effects exerted by puerarin. In further enrichment assays, the functional processes of puerarin against CRC were associated with energy pathways, metabolism, cell communication, signal transduction, aldehyde metabolism, DNA repair. Meanwhile, key ten signaling pathways from bioinformatic findings were ascertained respectively. As revealed in human data, CRC patients showed up-regulated expressions of endogenous TDP1, ALDH1A1, accompanied with visible hematoxylin-eosin (HE) and Ki-67 stains and elevated blood tumor marker expressions. In further study in vitro, puerarin-treated human CRC cells resulted in inhibited cell growth, increased cell apoptosis in a dose-dependent way. Further, down-regulated expressions of TDP1, ALDH1A1 and proliferating cell nuclear antigen (PCNA) were detected in puerarin-treated CRC cells. In conclusion, the molecular network data manifest the biotargets and signaling pathways of puerarin against CRC, followed by verification of both human and cell line studies. Furthermore, the pharmacological molecules of TDP1, ALDH1A1 seem to be the possible targets for managing CRC.
- Distribution of Keratoconus Indices in Normal Children 6 to 12 Years of Age. [Journal Article]
- ECEye Contact Lens 2019 Jun 20
- CONCLUSIONS: The results provide valuable information about normal distribution of keratoconus indices in children aged 6 to 12 years. These findings can be used in future research and detection of abnormal cases in the clinical setting.
- Eruption of Metastatic Paraganglioma After Successful Therapy with 177Lu/90Y-DOTATOC and 177Lu-DOTATATE. [Case Reports]
- NMNucl Med Mol Imaging 2019; 53(3):223-230
- Metastatic paraganglioma treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been introduced as a novel management option for metastatic neuroendocrine tumors demonstratin…
Metastatic paraganglioma treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been introduced as a novel management option for metastatic neuroendocrine tumors demonstrating safety, efficacy, and increased quality of life. We present two cases of marked progression of metastatic paraganglioma following initial partial response to PRRT. Given their positivity on 68Ga-DOTATATE PET/CT and 111In-octreotide SPECT, they underwent PRRT. Imaging following treatment revealed significant improvement in size and intensity, with some foci nearly completely resolved in one patient, and disease regression with a decrease in the number and size of bone and liver lesions in the second patient. Within months, repeat imaging in both patients revealed extensive metastatic disease with new lesions, which eventually lead to their deaths. The mechanism for rapid disease progression after partial response is not well understood, although it could be related to initially high Ki-67 levels or 18F-FDG PET/CT SUVmax values. However, naturally rapid disease progression despite PRRT response cannot be excluded. This finding warrants the importance of proper patient counseling along with early and accurate pre-PRRT assessment, taking into consideration the above potential risk factors for therapy response in order to personalize treatment regimens and achieve maximum patient benefit.
- Single-Cell RNA Sequencing of the T Helper Cell Response to House Dust Mites Defines a Distinct Gene Expression Signature in Airway Th2 Cells. [Journal Article]
- IImmunity 2019 Jun 14
- Naive CD4+ T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We …
Naive CD4+ T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We performed single-cell RNA sequencing (scRNA-seq) of T helper cells from lymph node, lung, and airways in the house dust mite (HDM) model of allergic airway disease. scRNA-seq resolved transcriptional profiles of naive CD4+ T, Th1, Th2, regulatory T (Treg) cells, and a CD4+ T cell population responsive to type I interferons. Th2 cells in the airways were enriched for transcription of many genes, including Cd200r1, Il6, Plac8, and Igfbp7, and their mRNA profile was supported by analysis of chromatin accessibility and flow cytometry. Pathways associated with lipid metabolism were enriched in Th2 cells, and experiments with inhibitors of key metabolic pathways supported roles for glucose and lipid metabolism. These findings provide insight into the differentiation of pathogenic Th2 cells in the context of allergy.
- Mitotic Chromosome Mechanics: How Cells Segregate Their Genome. [Review]
- TCTrends Cell Biol 2019 Jun 20
- During mitosis, replicated chromosomes segregate such that each daughter cell receives one copy of the genome. Faithful mechanical transport during mitosis requires that chromosomes undergo extensive…
During mitosis, replicated chromosomes segregate such that each daughter cell receives one copy of the genome. Faithful mechanical transport during mitosis requires that chromosomes undergo extensive structural changes as the cell cycle progresses, resulting in the formation of compact, cylindrical bodies. Such structural changes encompass a range of different activities, including longitudinal condensation of the chromosome axis, global chromatin compaction, resolution of sister chromatids, and individualisation of chromosomes into separate bodies. After mitosis, chromosomes undergo further reorganisation to rebuild interphase cell nuclei. Here we review the requirements for mitotic chromosomes to successfully transmit genetic information to daughter cells and the biophysical principles that underpin such requirements.
- Incidence, determinants and impact of acute kidney injury in patients with diabetes mellitus and multivessel disease undergoing coronary revascularization: Results from the FREEDOM trial. [Journal Article]
- IJInt J Cardiol 2019 Jun 13
- CONCLUSIONS: Although risk for AKI was higher in patients undergoing CABG, the impact of AKI on MACE was substantial irrespective of revascularization strategy. Preventive strategies to identify patients at risk for AKI are warranted to mitigate the long-term effects of this complication.
- Effectiveness of the herpes zoster vaccine Zostavax® in Stockholm County, Sweden. [Journal Article]
- VVaccine 2019 Jun 20
- CONCLUSIONS: This is the first population-based study in Sweden studying the effectiveness of HZ vaccination. Our findings are well in-line with previous studies, however studies addressing the longitudinal efficacy and effectiveness of Zostavax are still required.
- Prognostic value of cyclin A2 and B1 expression in lung carcinoids. [Journal Article]
- PPathology 2019 Jun 20
- Carcinoid classification in the lung is still based on morphological criteria. Although there are many studies investigating the role of Ki-67 proliferation index in the classification of lung neuroe…
Carcinoid classification in the lung is still based on morphological criteria. Although there are many studies investigating the role of Ki-67 proliferation index in the classification of lung neuroendocrine tumours, it is still not used in routine diagnostics. Interestingly, cyclins, which have a crucial role in controlling the cell cycle, have not been thoroughly studied in lung neuroendocrine tumours. The aim of our study was to investigate the correlation of cyclin A2 and B1 expression with prognosis, Ki-67 proliferation index, and carcinoid morphology. A cohort of 134 resected typical and atypical carcinoids was stained with antibodies against Ki-67, cyclin A2 and B1. The positive nuclear reaction was assessed in hot spot areas and expressed as the percentage of tumour cells. Univariate analyses found the highest relative hazard between low and high cyclin A2 expression both with respect to overall survival [hazard ratio (HR)=16; 95% confidence interval (CI) 4.8-51; p=0.0000054], and relapse (HR=8; 95% CI 3.1-21; p=0.00002). In multivariate analysis for overall survival cyclin A2 (HR=10; 95% CI 2.5->100; p=0.0082) and B1 (HR=6.5; 95% CI 1.5-35; p=0.02) remained significant when adjusted for other risk factors, whereas Ki-67 was no longer significant (HR=0.64; 95% CI 0.003-5.5; p=0.65). This suggests that Ki-67 is closer to conventional risk factors for survival than cyclin A2 and B1. Furthermore, the analysis revealed 4 mitoses per 2 mm2 as a more powerful prognostic cut-off than currently accepted 2 mitoses. We have clearly demonstrated that application of cyclin A2 and cyclin B1 might bring additional value regarding the overall and progression-free survival of patients with carcinoids of the lung.
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- Pale (Clear) Cell Acanthoma of the Palate. [Journal Article]
- HNHead Neck Pathol 2019 Jun 22
- Clear cell acanthoma (CCA), also known as pale cell acanthoma, represents a rare benign epidermal tumor with strong predilection for the lower extremities of middle-aged individuals and no frank gend…
Clear cell acanthoma (CCA), also known as pale cell acanthoma, represents a rare benign epidermal tumor with strong predilection for the lower extremities of middle-aged individuals and no frank gender preference. The etiology of CCA is poorly understood, although a localized psoriasiform reaction is favored. Herein, we report on the clinicopathologic and immunohistochemical features, and HPV status of an apparent example of oral CCA. A 58-year-old female presented with a well-circumscribed, asymptomatic, exophytic, sessile and erythematous nodule of the right hard palate, measuring 0.7 cm in greatest dimension. Microscopically, the lesion featured parakeratosis and acanthosis with neutrophilic microabscesses and broad elongated rete pegs. In areas, spinous epithelial cells exhibited pale or clear cytoplasm without nuclear pleomorphism, mitoses or cytologic atypia. The supporting connective tissue revealed mild chronic inflammation with few scattered neutrophils and numerous capillary vessels. PAS histochemical stain with and without diastase disclosed the presence of cytoplasmic glycogen in the pale cells. The majority of glycogen-rich epithelial cells stained strongly for EMA and were negative for D2-40. Ki-67 immunostaining was confined only to the basal cell layer of the epithelium. A diagnosis of CCA was rendered. The lesion was negative for human papillomavirus (HPV) infection, as assessed by HPV-DNA PCR using the MY09/11 primers for the L1 conserved region, thus HPV infection does not appear to contribute to the pathogenesis of oral CCA. In conclusion, we report an intraoral example of CCA in order to raise awareness about this entity.