In addition, the optimal culture conditions were determined by an orthogonal experiment. Under these conditions, the yield of macrolactin J was increased to 2.41 mg/L, which was 2.2 times the original yield. This work lays a foundation for follow-up mechanistic and application research on macrolactin J.Most small molecule anticancer drugs have high lipophilicity and low water solubility, which is often regarded as a key obstacle to their development and clinical applications. A variety of nano-size drug carriers, like liposomes, has been developed for solubilizing these drugs. Naturally secreted by cells, exosomes have good biocompatibility and are considered as “natural liposomes.” Exosomes released by mesenchymal stem cells (MSCs) not only have the properties like the ones generated by other cells but may also possess many therapeutic bioactive factors uniquely secreted by stem cells. In the present study, exosomes secreted by murine adipose stem cells (mASCs) were isolated, identified, and characterized. Its potential as drug delivery carrier and its biological effects on hepatoma cells and normal liver cell lines were explored in vitro. The data indicated that mASC exosomes separated by our improved sequential filtration method have particle size distribution in 30-150 nm, positively expresses TSG101, CD63, CD9, GADPH, and negatively expresses calnexin. The exosomes of mASCs obtained by this method could be taken up by cells and inhibit the cell activity of hepatoma cells HepG2, while enhance the normal cell activity of THLE-2. The results suggest that ASC exosomes are ideal potential drug delivery carriers and have the prospect of applications in carcinoma treatments.The breakdown of the blood-brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood-brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential.

No imaging biomarkers are available for the prediction of cardiac events following concurrent chemoradiation therapy (CCRT) for non-small-cell lung cancer (NSCLC). We evaluated whether F-18 fluorodeoxyglucose positron emission tomography (FDG PET) early after CCRT, in addition to cardiac dosimetry, could predict late cardiac events in NSCLC.

We retrospectively enrolled 133 consecutive patients with locally advanced, unresectable stage III NSCLC, who underwent FDG PET early after CCRT and survived at least 6months. The primary endpoint was cardiac event ≥ grade 2 according to the Common Terminology Criteria for Adverse Events (version 5.0). Myocardial FDG uptake was measured and its association with the risk of cardiac events was evaluated.

FDG PET was performed after a median interval of 11days of completing CCRT. Overall, 42 (32%) patients experienced cardiac events during a median follow-up of 45months. The mean heart dose, maximum left ventricular (LV) standardized uptake value (SUV), changes in maximum and mean LV SUV, right ventricular uptake, tumor stage, white blood cell count, and diabetes were associated with cardiac events in univariable analysis. In multivariable analysis, maximum LV SUV (cutoff > 12.84; hazard ratio [95% confidence interval] = 2.140 [1.140-4.016]; p = 0.018) was an independent predictor of cardiac events along with the mean heart dose (> 11.1Gy; 3.646 [1.792-7.417]; p < 0.001) and tumor stage (IIIB; 1.986 [1.056-3.734]; p = 0.033). It remained predictive of cardiac events in those with higher mean heart dose but not in those with lower mean heart dose.

Early FDG PET after CCRT for NSCLC could aid in predicting late cardiac events, especially in patients with higher mean heart dose.

Early FDG PET after CCRT for NSCLC could aid in predicting late cardiac events, especially in patients with higher mean heart dose.Primary granular cell tumors (GCTs) of the thyroid are exceptionally rare. We report the clinicopathologic and molecular features of three cases and review the literature. Two patients (20-year-old, Case 1, and 26-year-old, Case 2, black American females) presented with painless masses with a preoperative fine-needle aspiration biopsy (FNAB) diagnosis of “Hürthle cell neoplasm,” while one additional patient, 51-year-old white American female (Case 3), presented as an incidental finding within a background of chronic lymphocytic thyroiditis. On resection, morphologic, histochemical and immunohistochemical features were typical of GCT in all cases. Cases 1 and 2 had adequate material for molecular testing and demonstrated a clonal ATP6AP1 p.G381Vfs*15 frameshift mutation (Case 1) and a clonal ATP6AP2 p.L182Pfs*22 frameshift mutation along with a PIK3CA H1047R hotspot mutation (Case 2). Obeticholic All patients showed no evidence of GCT following resection (Cases 1, 3 96-month follow-up; Case 2 48-month follow-up). A literature review demonstrates similar clinicopathologic features and indolent course with only rare histologically or clinically aggressive outcomes. On FNAB, lesional cells are frequently miscategorized as Hürthle cells or oncocytes. In summary, GCT of the thyroid is rare but shows similar clinical, morphologic, immunophenotypic and genetic characteristics of GCT of other sites. This unusual site poses unique differential diagnostic pitfalls by mimicking other oncocytic head and neck lesions, particularly thyroid Hürthle cell neoplasms. We confirm that thyroid GCT also harbor V-ATPase component inactivating mutations that characterize these tumors, and that additional PI3K pathway alterations may not necessarily predict aggressive behavior.We earlier reported that arsenic induced hippocampal neuronal loss, causing cognitive dysfunctions in male rats. This neuronal damage mechanism involved an altered bone morphogenetic protein (BMP2)/Smad and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Susceptibility to toxicants is often sex-dependent, and hence we studied the comparative effects of arsenic in adult male and female rats. We observed that a lower dose of arsenic reduced learning-memory ability, examined through passive avoidance and Y-maze tests, in male but not female rats. Again, male rats exhibited greater learning-memory loss at a higher dose of arsenic. Supporting this, arsenic-treated male rats demonstrated larger reduction in the hippocampal NeuN and %-surviving neurons, together with increased apoptosis and altered BMP2/Smad and BDNF/TrkB pathways compared to their female counterparts. Since the primary female hormone, estrogen (E2), regulates normal brain functions, we next probed whether endogenous E2 levels in females offered resistance against arsenic-induced neurotoxicity. We used ovariectomized (OVX) rat as the model for E2 deficiency. We primarily identified that OVX itself induced hippocampal neuronal damage and cognitive decline, involving an increased BMP2/Smad and reduced BDNF/TrkB. Further, these effects appeared greater in arsenic + OVX compared to arsenic + sham (ovary intact) or OVX rats alone. The OVX-induced adverse effects were significantly reduced by E2 treatment. Overall, our study suggests that adult males could be more susceptible than females to arsenic-induced neurotoxicity. It also indicates that endogenous E2 regulates hippocampal BMP and BDNF signaling and restrains arsenic-induced neuronal dysfunctions in females, which may be inhibited in E2-deficient conditions, such as menopause or ovarian failure.Parkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.