CT Quantification of Interstitial Lung Abnormalities and Changes of Agerelated Pathomorphology.

BACKGROUND: Interstitial lung abnormalities (ILA) are associated with further disease progression, increased mortality risk, and decline in lung function in the elderly, which deserves enough attention. OBJECTIVE: The objective of this study was to quantify the extent of interstitial lung abnormalities (ILA) in a non-smoking asymptomatic urban cohort in China using low-dose CT (LDCT) and to analyze the age-related pathological changes. METHODS: We retrospectively analyzed clinical data and chest LDCT images from a cohort of 733 subjects who were categorized into 3 groups: 18-39, 40-59, and ≥60 years old according to age. Furthermore, we selected 40 cases of wax-embedded lung tissue blocks archived after pulmonary bullectomy and the same age groups were categorized. Four representative CT signs of ILA, including interlobular septal thickening (ILST), intralobular interstitial thickening (ILIT), ground-glass opacity (GGO), and reticular shadow (RS), were semi-quantified based on the percentage of the affected area. The scores and distribution of four CT signs of ILA were compared between different sex and age groups. The age-related pathological changes were analyzed. RESULTS: The ILA findings were found predominantly in the lower lobes and the subpleural region. The semi-quantitative scores of four CT signs in all subjects under 40 were 0. However, in subjects over 40 years old, the scores gradually increased with age, although most of them remained low. The size of the alveoli increased, the number of alveoli decreased, the alveolar septum became thinner, and the number of ATII cells increased with age. A statistically significant difference was observed among the different age groups (χ2=50.624, P=0.033; χ2=80.000, P=0.043; χ2=33.833, P=0.000; χ2=13.525, P=0.031). The macrophage population and the percentage of collagen fibers in the alveolar septum increased, while the percentage of elastic fibers decreased with age. There was no significant difference among the different age groups (χ2=19.817, P=0.506; χ2=52.419, P=0. 682; χ2=54.868, P=0.518). CONCLUSION: When the four CT signs mentioned above are in the upper central area, and the score has a medium or high score, it is crucial to determine the underlying pathological causes. ILA may be the result of chronic lung injury.

S-9-PAHSA's neuroprotective effect mediated by CAIII suppresses apoptosis and oxidative stress in a mouse model of type 2 diabetes.

BACKGROUND: With the rapidly increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), neuronal complications associated with these diseases have resulted in significant burdens on healthcare systems. Meanwhile, effective therapies have remained insufficient. A novel fatty acid called S-9-PAHSA has been reported to provide metabolic benefits in T2DM by regulating glucose metabolism. However, whether S-9-PAHSA has a neuroprotective effect in mouse models of T2DM remains unclear. METHODS: This in vivo study in mice fed a high-fat diet (HFD) for 5 months used fasting blood glucose, glucose tolerance, and insulin tolerance tests to examine the effect of S-9-PAHSA on glucose metabolism. The Morris water maze test was also used to assess the impact of S-9-PAHSA on cognition in the mice, while the neuroprotective effect of S-9-PAHSA was evaluated by measuring the expression of proteins related to apoptosis and oxidative stress. In addition, an in vitro study in PC12 cells assessed apoptosis, oxidative stress, and mitochondrial membrane potential with or without CAIII knockdown to determine the role of CAIII in the neuroprotective effect of S-9-PAHSA. RESULTS: S-9-PAHSA reduced fasting blood glucose levels significantly, increased insulin sensitivity in the HFD mice and also suppressed apoptosis and oxidative stress in the cortex of the mice and PC12 cells in a diabetic setting. By suppressing oxidative stress and apoptosis, S-9-PAHSA protected both neuronal cells and microvascular endothelial cells in in vivo and in vitro diabetic environments. Interestingly, this protective effect of S-9-PAHSA was reduced significantly when CAIII was knocked down in the PC12 cells, suggesting that CAIII has a major role in the neuroprotective effect of S-9-PAHSA. However, overexpression of CAIII did not significantly enhance the protective effect of S-9-PAHSA. CONCLUSION: S-9-PAHSA mediated by CAIII has the potential to exert a neuroprotective effect by suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, S-9-PAHSA has the capability to reduce fasting blood glucose and LDL levels and enhance insulin sensitivity in mice fed with HFD.

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

Microstructure and Crystallization Kinetics of Silica-Based Ceramic Cores with Enhanced High-Temperature Property.

Silica-based ceramic cores play key roles in the casting of aeroengine blades, but they are highly limited by the poor high-temperature mechanical property. Here, fused mullite (FM) and sintered mullite (SM) powders were modified in silica-based ceramic cores, and the microstructure evolution and crystallization kinetics of ceramic cores depending on mullite types were studied. The ceramic cores with FM showed a dense microstructure and superior mechanical properties compared to those with SM. The ceramic cores with 10 wt.% of FM showed a crystallization activation energy of 1119.5 kJ/mol and a crystallization exponent of 1.74, and the values of 938.4 kJ/mol and 1.86 as SM were employed; the decreased crystallization activation energy and the elevated crystallization exponent by SM suggested that the excess impurities of alkali oxides and alkaline-earth oxides significantly promoted the crystallization of cristobalite. Even though the ceramic cores with mullite powders decreased slightly in the room-temperature mechanical property, their high-temperature flexure strength and creep deformation resistance were enhanced. The ceramic cores with 10 wt.% of FM showed excellent comprehensive performance, with linear shrinkage of 0.69%, room-temperature strength of 18.9 MPa, and high-temperature strength of 15.5 MPa, which satisfied the demands for hollow-blade casting.

[Quality evaluation methods and quality transfer law of Mori Cortex, fried Mori Cortex and its standard decoction].

This study aims to establish a method for the component content determination and fingerprint evaluation of Mori Cortex, fried Mori Cortex and its standard decoction, and to reveal the quality transfer law among the three based on transfer rate, extraction rate, and fingerprint similarity.Fifteen representative batches of Mori Cortex decoction pieces were collected to prepare fried Mori Cortex and its standard decoction.UPLC-PDA was employed to establish the content determination method and fingerprint.The established UPLC method and fingerprint could be applied to the detection of Mori Cortex, fried Mori Cortex and its standard decoction.The UPLC fingerprints of the 15 batches of Mori Cortex and fried Mori Cortex had good similarity(>0.9) and the same common peaks.However, only one characteristic peak(mulberroside A) could be observed in the fingerprint of fried Mori Cortex standard decoction, which indicated that the corresponding components of other common peaks in the fingerprint of Mori Cortex had low content in the water extract.The extraction rates of mulberroside A from Mori Cortex, fried Mori Cortex and its standard decoction were 1.49%-2.00%, 1.62%-2.27% and 0.75%-1.29%, respectively.Mulberroside A showed the transfer rate of 103.7%-116.3% from Mori Cortex to fried Mori Cortex and 45.7%-56.9% from fried Mori Cortex to its standard decoction.The extraction rates of the 15 batches of fried Mori Cortex standard decoctions were 14.7%-19.5%.All the above indicators were within±30% of the mean value.This study established a method for the determination of mulberroside A content and fingerprint of Mori Cortex, fried Mori Cortex and its standard decoction, and clarified the quality transfer law among the three.It established the method for quality evaluation of Mori Cortex and fried Mori Cortex and can provide reference for the whole-process quality control in the preparation of the agents containing fried Mori Cortex.

Chemical constituents of Viscum coloratum (Kom.) Nakai and their cytotoxic activities.

A new diarylheptanoid, (1 R,2S,3S,5S)-2,3-dihydroxy-3',3''-dimethoxy-4'-de-O-methylcentrolobine (1) and a new bisabolane-type sesquiterpenoid, (1 R,7S)-1,12,13-trihydroxybisabola-3,10-diene (2), together with nineteen known compounds (3-21) were isolated from the EtOH extract of the stems and branches of Viscum coloratum (Kom.) Nakai. Their structures were elucidated by extensive analysis of 1 D and 2 D NMR spectra and from the HRESIMS. All the compounds were evaluated for their cytotoxic activity against eight human tumor cell lines.

Efficacy and safety of left atrial appendage occlusion in atrial fibrillation patients with chronic kidney disease: a systematic review and meta-analysis.

Atrial fibrillation (AF) is the most common arrhythmia among the elderly, and more frequently occur in those with chronic kidney disease (CKD). Left atrial appendage occlusion (LAAO) is used as a mechanical alternative approach for prevention of AF-related thromboembolisms. This meta-analysis was conducted to provide suggestions for the clinical application of LAAO in AF patients with CKD. The incidence of perioperative adverse events and other clinical effects after operation was by a single rate meta-analysis. Results showed that incidence of adverse events in the perioperative period after LAAO was generally low, with only pericardial effusion / tamponade (1.90%) and mortality rate (1.10%). During the follow-up period, the incidence of stroke/transient ischemic attack (TIA) and bleeding were 2.17% and 4.53%, respectively. A low incidence rate of adverse events was found in the perioperative period following LAAO. These results indicate that LAAO more effectively prevents the occurrence of stroke/TIA and minimizes bleeding events than oral anticoagulants.

Pathophysiologic Role of Molecules Determining Arteriovenous Differentiation in Adult Life.

The structural differences between arteries and veins are genetically predetermined. Vascular identity markers, the molecular markers specific to veins and arteries, determine the differential development of vessels during embryogenesis and their expression persists in adult vessels. It is revealed that they can be reactivated under various pathophysiologic conditions even after vessel differentiation. Thus, once considered as quiescent in adults, vascular identity markers may actually play significant roles in vascular remodeling. Manipulation of vascular identity and the underlying molecular mechanisms might be a novel strategy to improve vascular remodeling for clinical application.

[Quality evaluation methods for standard decoction of Nelumbinis Folium].

The quality evaluation method for standard decoction of Chinese herbal slices is the basis for the quality evaluation of granules and preparations of classical formula(decoction)of traditional Chinese medicine. This study aimed to establish a method for the determination of quercetin-3-O-glucuronic acid in Nelumbinis Folium(NF)and its standard decoction, so as to provide reference for the quality control of NF and its standard decoction. Fifteen batches of representative NF were collected to prepare standard decoction, and the parameters of dry extract rate, transfer rate of index component, and pH value were calculated. HPLC was used to establish the content determination method for quercetin-3-O-glucuronic acid in NF and its standard decoction. The concentration range of quercetin-3-O-glucuronic acid in the standard decoction of NF was 1.09-3.06 g·L~(-1), while the concentration range of nuciferine was 0.01-0.17 g·L~(-1). The average extraction rate of NF standard decoction was(14.4±2.6)%, the average transfer rate of quercetin-3-O-glucuronic acid was(70.7±18.6)%, and the average transfer rate of nuciferine was(9.6±5.4)%. Compared with Nuciferine, quercetin-3-O-glucuronic acid had a high content and stable transfer rate in standard decoction, and was recommended to be the quality control marker for NF and its standard decoction. This paper establishes a quality evaluation method for NF standard decoction, and can provide reference for the quality control of all preparations derived from NF and its decoction.

[Study on compatibility of active ingredients of Simiao Yongan Decoction in rats with in situ single-pass intestinal perfusion model].

To study the compatibility rule of Simao Yongan Decoction,the rat single pass intestinal perfusion model in situ was used in this study. On the basis of early research,the five kinds of anti-inflammatory active ingredients,i.e. chlorogenic acid,liquiritin,hyperoside,angoroside C and isochlorogenic acid C in Simao Yongan Decoction were selected as research objects. The contents of the above five actives compounds with various compatibility combinations and in different intestinal segment perfusates were determined by using the method of ultra-performance liquid chromatography-mass spectrometry( UPLC-MSn). The kinetic parameters of intestinal absorption of the five anti-inflammatory active ingredients were calculated,which could be used to evaluate the intestinal absorption of each component in different combinations. The results showed that the absorption parameters of liquiritin in ileum were highest in Glycyrrhizae Radix et Rhizoma single herb,while the absorption parameters of other four components in ileum and duodenum were highest in the compatible combinations. Among them,the absorption parameters of chlorogenic acid in ileum and duodenum were highest in the whole prescription compatibility; ischlorogenic acid C showed higher absorption levels in the whole prescription and the herb compatibility of Lonicerae Japonicae Flos-Scrophulariae Radix-Glycyrrhizae Radix et Rhizoma. However,the absorption levels of hyperoside and angoroside C in different compatibilities were quite different in ileum and duodenum. In this study,the intestinal absorption of five anti-inflammatory active ingredients in Simiao Yongan Decoction with different compatibility combinations was investigated,revealing that the absorption of active ingredients varied with the different compatibility combinations and different intestinal segments. At the same time,the above research also indicated that the absorption of active ingredients could be obviously promoted by the compatibility of compound prescriptions,laying a foundation for the research on the compatibility rule of Simiao Yongan Detection from the biological point of view.

Knockdown of microRNA-17-5p Enhances the Neuroprotective Effect of Act A/Smads Signal Loop After Ischemic Injury.

Cerebral ischemic injury is a leading cause of human mortality and disability, seriously threatening human health in the world. Activin A (Act A), as a well-known neuroprotective factor, could alleviate ischemic brain injury mainly through Act A/Smads signaling. In our previous study, a noncanonical Act A/Smads signal loop with self-amplifying property was found, which strengthened the neuroprotective effect of Act A. However, this neuroprotective effect was limited due to the self-limiting behavior mediated by Smad anchor for receptor activation (SARA) protein. It was reported that microRNA-17-5p (miR-17-5p) could suppress the expression of SARA in esophageal squamous cell carcinoma. Thus we proposed that knockdown of miR-17-5p could strengthen the neuroprotective effect of Act A/Smads signal loop through SARA. To testify this hypothesis, oxygen-glucose deficiency (OGD) was introduced to highly differentiated rattus pheochromocytoma (PC12) cells. After the transfection of miR-17-5p mimic or inhibitor, the activity of Act A signal loop was quantified by the expression of phosphorylated Smad3. The results showed that suppression of miR-17-5p up-regulated the expression of SARA protein, which prolonged and strengthened the activity of Act A signaling through increased phosphorylation of downstream Smad3 and accumulation of Act A ligand. Further luciferase assay confirmed that SARA was a direct target gene of miR-17-5p. These practical discoveries will bring new insight on the endogenous neuroprotective effects of Act A signal loop by interfering a novel target: miR-17-5p.

Production of L-alanyl-L-glutamine by immobilized Pichia pastoris GS115 expressing α-amino acid ester acyltransferase.

BACKGROUND: L-Alanyl-L-glutamine (Ala-Gln) represents the great application potential in clinic due to the unique physicochemical properties. A new approach was developed to synthesize Ala-Gln by recombinant Escherichia coli OPA, which could overcome the disadvantages of traditional chemical synthesis. Although satisfactory results had been obtained with recombinant E. coli OPA, endotoxin and the use of multiple antibiotics along with toxic inducer brought the potential biosafety hazard for the clinical application of Ala-Gln. RESULTS: In this study, the safer host Pichia pastoris was applied as an alternative to E. coli. A recombinant P. pastoris (named GPA) with the original gene of α-amino acid ester acyltransferase (SsAet) from Sphingobacterium siyangensis SY1, was constructed to produce Ala-Gln. To improve the expression efficiency of SsAet in P. pastoris, codon optimization was conducted to obtain the strain GPAp. Here, we report that Ala-Gln production by GPAp was approximately 2.5-fold more than that of GPA. The optimal induction conditions (cultivated for 3 days at 26 °C with a daily 1.5% of methanol supplement), the optimum reaction conditions (28 °C and pH 8.5), and the suitable substrate conditions (AlaOMe/Gln = 1.5/1) were also achieved for GPAp. Although most of the metal ions had no effects, the catalytic activity of GPAp showed a slight decrease in the presence of Fe3+ and an obvious increase when cysteine or PMSF were added. Under the optimum conditions, the Ala-Gln generation by GPAp realized the maximum molar yield of 63.5% and the catalytic activity of GPAp by agar embedding maintained extremely stable after 10 cycles. CONCLUSIONS: Characterized by economy, efficiency and practicability, production of Ala-Gln by recycling immobilized GPAp (whole-cell biocatalyst) is represents a green and promising way in industrial.

Investigation on the Crystallization Behaviors of Polyoxymethylene with a Small Amount of Ionic Liquid.

Polyoxymethylene (POM) blends with excellent stiffness⁻toughness balance are successfully developed using Tributyl(octyl)phosphonium bis(trifloromethanesulfonyl) imide (TBOP-TFSI), one type of room-temperature ionic liquid, as the nucleating agent. Crystallization behaviors of POM blends have been studied by differential scanning calorimetry (DSC) and polarized light microscopy (PLM). The incorporation of TBOP-TFSI induces the crystal nucleation and fine crystal grain of POM, and also a much shorter hemi-crystalline time with only 0.5 wt% addition. The nucleation effect of ionic liquid leads to considerable improvement in the impact strength of POM blends while not sacrificing its tensile strength. Moreover, antistatic properties with a long-time stable performance are achieved by TBOP-TFSI addition as the electrical resistance reaches 1011 Ω/sq.

Expression changes of the notch signaling pathway of PC12 cells after oxygen glucose deprivation.

Ischemic stroke is caused by obstructed blood supply to the brain. It is a common as well as a serious health problem worldwide, which is often linked to disability and mortality. Here we studied, under the conditions of oxygen glucose deprivation (OGD), the expression of Notch signaling pathway proteins in PC12 cells. PC12 cells were stimulated and converted into neuron-like cells by nerve growth factor. Exposure to OGD was used as an in vitro model of cerebral hypoxia-ischemia. Our findings demonstrate that, after 3 h of OGD exposure, the expression of Notch1, Hes1 and Hes5 significantly increased, on both mRNA and protein levels. This effect gradually reduced with continuous OGD treatment, but the expression levels of these three genes remained higher, compared to untreated controls, even after 24 h of OGD exposure. Our results suggest that OGD exposure up-regulates the expression of Notch1, Hes1 and Hes5, which are important participants in Notch signaling pathway. Since their regulatory roles appear to change dynamically with the extension of OGD, the activation of the Notch pathway may play an important role in cerebral ischemic injury.

Rapid Characterization and Identification of Non-Diterpenoid Constituents in Tinospora sinensis by HPLC-LTQ-Orbitrap MSn.

Tinospora sinensis, a kind of Chinese folk medicine, has functions of harmonizing qi and blood, dredging the channels and collaterals, calming and soothing the nerves. In the present study, a method based on high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) was developed for the systematical characterization of the non-diterpenoid constituents which possessed remarkable biological activities in T. sinensis, like anti-tumor, anti-inflammatory, hypoglycemic activity and immunomodulatory activity. Based on the accurate mass measurement (<5 ppm), retention times and MS fragmentation ions, 60 non-diterpenoid constituents were unambiguously or tentatively characterized from T. sinensis extract, including 27 alkaloids, 23 phenylpropanoids, seven sesquiterpenoids and three other constituents. Among them, 13 compounds were tentatively identified as new compounds. Finally, three of the non-diterpenoid constituents were purified and identified, which further confirmed the validity of the results. This study demonstrated that the HPLC-LTQ-Orbitrap MSn platform was a useful and efficient analytical tool to screen and identify constituents in natural medicine.

Polyphenolic compounds from Malus hupehensis and their free radical scavenging effects.

One new 4-chromanone glycoside, 5-O-ß-d-glucopyranoside-4-chromanone (1), together with 21 known polyphenols, was isolated from the leaves of Malus hupehensis. Their structures were elucidated on the basis of extensive spectroscopic methods including NMR (1D and 2D), mass (ESIMS and HRESIMS), IR, and by comparison with the data reported in the literature. Some of the isolated compounds were screened for antioxidant activity. Compounds 18 and 14 exhibited significant antioxidant activities with SC50 values 2.73 and 2.91 µg/mL, respectively, while 17, 19, 11, 7, 20, 22, 12 and 13 exhibited moderate activities with SC50 values ranging from 5.24-11.86 µg/mL. The HPLC fingerprint profiles of the leaves and fruits extracts were also analysed, which showed that the constituents were almost the same in both the extracts except for the content of phlorizin which was present in higher amount in the leaves.

Triterpenoid saponins from the pulp of Sapindus mukorossi and their antifungal activities.

Under the guidance of anti-fungal bioassay, four previously undescribed oleanane-type and one lupane-type triterpenoid saponins, along with twelve known analogues, were isolated from the extract of Sapindus mukorossi pulps. Their structures were determined on the basis of spectroscopic analysis and chemical methods. In vitro biotests, oleanolic acid 3-O-ß-D-xylopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranoside showed inhibitory activity against Trichophyton rubrum with MIC80 value of 8 µg/mL, while oleanolic acid 3-O-α-L-arabinopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-α-L-arabinopyranoside exhibited inhibitory activity against both Trichophyton rubrum and Candida albicans with MIC80 values of 8 µg/mL.

RNA-binding Protein UNR Promotes Glioma Cell Migration and Regulates the Expression of Ribosomal Protein L9 / 中国医学科学杂志(英文版)

Objective To investigate the role of RNA binding protein─upstream-of-N-Ras (UNR) in the development of glioma and its molecular mechanism.Methods First, bioinformatics analysis of CGGA database was performed to detect UNR expression level and prognosis of patients with glioma. Western blot and real-time PCR were used to detect UNR expression level in glioma cell lines and tissues. Next, UNR siRNAs were transfected in glioma cells, and MTS assay and scratch wound-healing assay were used to detect changes in cell proliferation and migration. Then, the candidate UNR target mRNAs were identified by analyzing the sequencing data of UNR iCLIP-seq, RNA sequencing and ribosome profiling databases of human melanoma. RNA immunoprecipitation and biotin pull-down assays were used to identify the UNR target mRNAs in glioma cells. Finally, western blot was used to detect the effect of UNR knockdown on ribosomal protein L9 (RPL9) and RPL9 protein expression level in glioma cell lines. RPL9 siRNA was transfected in A172 and T98G and the expression of vimentin in the cells was detected with western blot.Results Bioinformatics analysis showed that UNR mRNA expression level was significantly higher in high-grade glioma [Grade 2 (n=126), Grade 3 (n=51), Grade 4 (n=128), P<0.001]. UNR high expression levels were associated with poor prognosis (P=0.0177). UNR had high expression level in glioma cell lines and patient samples compared with normal cell lines and normal brain samples (P<0.01). Knockdown of UNR inhibited glioma cells migration (P<0.05), but did not inhibit glioma cells growth in three glioma cell lines. UNR binded the 3' untranslated region (UTR) of PTEN and RPL9 mRNAs. RPL9 protein was significantly highly expressed in most glioma cell lines (n=9) and knockdown of UNR resulted in a downregulation of RPL9 protein expression. Epithelial-mesenchymal transition (EMT)-related marker─vimentin was positively regulated by RPL9.Conclusions UNR could bind to the 3'UTR of PTEN and RPL9 in glioma cell lines, therefore promoting glioma cell migration and regulating the expression of RPL9. Here, we establish a link between UNR and RPL9 protein, which will provide new ideas for the further study of glioma.

Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death.

Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER) stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP) and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3), and downregulated the expression of thapsigargin-induced ER stress-associated proteins [inositol requiring enzyme-1 (IRE1), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38]. The inhibition of thapsigargin-induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1-TRAF2-ASK1-JNK/p38 cascade.

Activin A/Smads signaling pathway negatively regulates Oxygen Glucose Deprivation-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells.

Activin A (Act A), a member of the transforming growth factor-beta (TGF-ß), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells. In addition, we found that c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways are involved in the OGD-induced autophagy. The activation of JNK and p38 MAPK pathways in OGD-treated PC12 cells was suppressed by exogenous Act A and enhanced by ActRIIA-Ab. Together, our results suggest that Act A/Smads signaling pathway negatively regulates OGD-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells.