Targeting cholesterol trafficking to mitigate axonal degeneration in hereditary spastic paraplegia

Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.

FOXO1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission

OBJECTIVE Diabetes-induced endothelial cell(EC) dysfunction and neovasculariza.tion impairment constitute vascular complications with limited treatment regimens.Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes.The pres.ent study was designed to determine the involvement of FOXO1 in impaired EC function and post-isch.emic neovascularization in diabetes and investigate underlying mechanisms.RESULTS We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb,and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice.In vitro,treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-in.duced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells(HU.VECs).FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the over production of mitochondrial reactive oxygen species(mtROS) induced by high glucose in ECs.Expression of dynamin-relatedprotein-1(Drp1) and phosphorylation at Ser616,a protein required for mitochondrial fission,were enhanced by hyperglycemia,which could be neutralized by FOXO1 inhibition.Moreover,the transcription of Rho-associated coiled-coil containing protein kinase 1(ROCK1),which phosphorylates Drp1 at Ser616,was shown by luciferase assay to be directly regulated by FOXO1.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and func.tion in ECs,and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.

Coexistence of ovarian serous papillary cystadenofibroma and type A insulin resistance syndrome in a 14-year-old girl: A case report

BACKGROUND Type A insulin resistance syndrome is a rare disorder caused by mutations in the gene encoding the insulin receptor.Its coexistence with ovarian serous papillary cystadenofibroma is even rarer.CASE SUMMARY A 14-year-old girl developed type A insulin resistance syndrome and showed high fasting insulin,glucose,and hemoglobin A1c(HbA1c)levels.The girl suffered from ovarian serous papillary cystadenofibroma.The laboratory results were as follows:fasting insulin was 2624.90 pmol/L and HbA1c was 8.5%.A heterozygous missense mutation on exon 20 of the insulin receptor gene(c.3601C>T,Arg1201Trp)was observed.The histopathological diagnosis was a cystic lesion that extended to the upper right uterus,indicating a right ovarian serous papillary cystadefibroma accompanied by focal interstitial hyperplasia.The patient was treated with metformin for over 6 mo.Additionally,laparoscopic resection(bilateral)of the ovarian lesion and laparoscopic intestinal adhesiolysis were performed under general anesthesia.Diet therapy combined with exercise was then initiated.The patient had an uneventful recovery.The patient also showed improved blood glucose control,with reduced levels of fasting insulin(857.84 pmol/L)and HbA1c(7.0%).CONCLUSION Insulin resistance may play a significant role in the induction of tumors.It is important to investigate further the association between insulin resistance and tumors and the underlying mechanism.

Investigation of Induced Unbalance Magnitude on Dynamic Characteristics of High-speed Turbocharger with Floating Ring Bearings

Due to operational wear and uneven carbon absorption in compressor and turbine wheels, the unbalance(me) vibration is induced and could lead to sub?synchronous vibration accidents for high?speed turbocharger(TC). There are very few research works that focus on the magnitude e ects on such induced unbalance vibration. In this paper, a finite element model(FEM) is developed to characterize a realistic automotive TC rotor with floating ring bearings(FRBs). The nonlinear dynamic responses of the TC rotor system with di erent levels of induced unbalance magni?tude in compressor and turbine wheels are calculated. From the results of waterfall and response spectral intensity plots, the bifurcation and instability phenomena depend on unbalance magnitude during the startup of TC. The sub?synchronous component 0.12× caused rotor unstable is the dominant frequency for small induced unbalance. The nonlinear e ects of induced unbalance in the turbine wheel is obvious stronger than the compressor wheel. As the unbalance magnitude increases from 0.05 gbration 1·mm to 0.2 g·mm, the vibration component changes from mainly 0.12× to synchronous vi×. When unbalance increases continuously, the rotor vibration response amplitude is rapidly growing and the 1× caused by the large unbalance excitation becomes the dominant frequency. A suitable un?balance magnitude of turbine wheel and compressor wheel for the high?speed TC rotor with FRBs is proposed: the value of induced un?balance magnitude should be kept around 0.2 g·mm.

Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias

Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.

Inhibitory effect of ZX-1201 on pancreatic cancer and the relevant molecular mechanism

Pancreatic ductal adenocarcinoma(PDAC) is one of the five most malignant cancer.ZX-1201 is one of the active constituents in Alismatis Rhizoma,a well-known traditional Chinese medi.cine with a wide variety of pharmacological properties including diuretic,anti-hyperlipidemic,anti-atheroscle.rotic,anti-cancer,anti-inflammatory and anti-oxidative activities.We investigated the inhibitory effect of ZX-1201 on pancreatic cancer and the relevant molecular mechanism in vitro and in vivo.ZX-1201 inhibited the growth and metastasis of PANC-1 cells in BALB/c nude mice significantly.ZX-1201 inhibited the function of AQP1 via directly interaction and involved in the reversion process of ZX-1201 on TGF-β_1.CTGF was an important protein in the reversion process of ZX-1201 on TGF-β_1.ZX-1201 inhibited the migration of PANC-1 and CPFAC-1 cells induced by TGF-β_1 in vitro.ZX-1201 reversed the down-regu.lated of epithelial markers and up-regulated of mesenchymal markers,as well as the up-regulated of Snail and p-Smad2/3 induced by TGF-β_1.And ZX-1201 reversed Epithelial-Mesenchymal Transition by down-regulating AQP1 and inhibiting translocation of β-catenin,the promotor of CTGF.According to these,ZX-1201 inhibited the migration of pancreatic cancer cells.We concluded that ZX-1201 inhibited the growth and metastasis of PANC-1 cells in vivo significantly.And AQP1,β-catenin and CTGF were the pivotal proteins in the process of ZX-1201 inhibiting PANC-1 cells migration induced by TGF-β_1.

Discovery of natural BH3 mimetics and research on related mechanism

In the past two decades,with the increase of smoking population,more and more people are suffering from small cell lung cancer(SCLC).Besides,it is difficult to find an effective way to cure SCLC,since patience can easily develop drug resistance.On the other hand,with the development of science and technology,people began to study the anti-cancer strategy to increase apoptosis,such as inhibiting the overexpression of survival factors.In these survival factors,BCL-2 family has attracted a lot of attention.BH3-only protein is a member of BCL-2 family and it can directly inhibit the expression of BCL-2 protein,thereby prompting apoptosis.Since the BH3-only protein itself is difficult to become a clinical drug,to find alternatives BH3-only protein-BH3 mimetics is particularly important.Plus,more and more researchers have paid attention on the natural BH3 mimetic since it has less side-effect than artificial BH3 mimetics.To find possible BH3 mimetics,we made a primary screening with this pharma.cophore on a small molecular compounds library via Discovery Studio software.And then MTS assay were introduced to verify the activity of compounds.After that,we use Western Blot and Co-IP meth.ods to test the effect of BH3 mimetics.And finally use CDOCKER to predict the further mechanism on autophagy and apoptosis.In our studies,we found 3 possible BH3 mimetics compounds from 170,000 natural small molecular compounds via pharmacophore-based virtual screening.Furthermore,we dem.onstrated AD23,one of the 3 possible natural BH3 mimetics,induced autophagy and apoptosis simulta.neously in dose-time dependence in SCLC cell line.Finally,we use Molecular Docking to predict the further mechanism on autophagy and apoptosis.We believe our works would provide evidences and clues for the structural optimizing and further study of new drugs in the future.

Non-cell autonomous role of astrocytes in axonal degeneration of cortical projection neurons in hereditary spastic paraplegias

Impai red axonal deve lopment and degeneration underlie many debilitating diseases,including hereditary spastic paraplegia(HSP).HSPs are a heterogeneous group of neurogenetic disorders characterized by axonopathy of cortical motor neurons(Fink,2006;Blackstone et al.,2010).The axonal degeneration of these cortical projection neurons(PNs)in HSP patients disrupts the signals from brain to spinal motor neurons,leading to muscle weakness and spasticity.Since the discovery of the first HSP gene(SPAST)in 1999,over 80 distinct genetic loci associated with HSP have been identified.How the mutations of these divergent genes specifically result in axonal degeneration of cortical PNs remains largely unclear,which contributes to the lack of effective treatment to ameliorate,stop,or reverse axonal defects in HSPs.

Clinical features of pediatric patients with COVID-19: a report of two family cluster cases

Background Coronovirus disease 2019 (COVID-19) has spread rapidly across the globe.People of all ages are susceptible to COVID-19.However,literature reports on pediatric patients are limited.Methods To improve the recognition of COVID-19 infection in children,we retrospectively reviewed two confirmed pediatric cases from two family clusters.Both clinical features and laboratory examination results of the children and their family members were described.Results The two confirmed children only presented with mild respiratory or gastrointestinal symptoms.Both of them had normal chest CT images.After general and symptomatic treatments,both children recovered quickly.Both families had travel histories to Hubei Province.Conclusions Pediatric patients with COVID-19 are mostly owing to family cluster or with a close contact history.Infected children have relatively milder clinical symptoms than infected adults.We should attach importance to early recognition,early diagnosis,and early treatment of infected children.

Application of DNA barcoding to the identification of Hymenoptera parasitoids from the soybean aphid （Aphis glycines） in China

Aphis glycines Matsumura is an important pest of soybean in Asia and North America. Hymenoptera parasitoids play a key role in the control of the soybean aphid. Thecorrect identification of parasitoids is a critical step that precedes the assessment of their potential biological control agents. Accurate identification of the majority of the speciesattacking the soybean aphid often requires elaborate specimen preparation and expert taxonomic knowledge. In this study, we facilitated the identification of soybean aphidparasitoids by applying a DNA barcoding approach following a preliminary morphological identification. We generated DNA sequence data from the mitochondrial COI gene andthe D2 region of 28S rDNA to assess the genetic variation within and between parasitoid species emerging from the soybean aphid in China. Fifteen Hymenoptera parasitoid speciesbelonging to 10 genera of five families were identified with little intra-specific variation （0.09% ± 0.06% for 28S and 0.36% ± 0. 18% for COI） and large inter-specific divergence（30.46% ± 3.42% for 28S and 20.4% ± 1.20% for COI）.

The 96-week clinical outcomes after cessation of nucleos(t)ide analog treatment in chronic hepatitis B patients

Background:Chronic hepatitis B(CHB)patients have a high virological relapse rate after cessation of nucleos(t)ide analog(NA)treatment,but the clinical outcome remains unclear.This study aimed to investigate the 96-week clinical outcomes and the risk factors for relapse in CHB after cessation of NAs.Methods:This study was a prospective trial;74 eligible patients were enrolled.The patients underwent NA cessation and follow-up according to the 2012 Asian Pacific Association for the Study of the Liver Guideline.Symptoms,biochemical(aspartate aminotransferase[AST],alanine aminotransferase[ALT],total bilirubin,urea nitrogen,creatinine),virological data(hepatitis B surface antigen[HBsAg],hepatitis B e antigen[HBeAg],hepatitis B e antibody[HBeAb],hepatitis B virus[HBV]DNA levels),and color Doppler ultrasound examination results were recorded and analysed.Results:After NA cessation,19 cases were HBsAg-negative without relapse during the 96-week follow-up.Of the 55 cases of HBsAg-positive after cessation,four types of clinical outcomes were observed.Twelve patients had no relapse during the 96-week follow-up(type A,21.8%),7 patients underwent virological relapses but spontaneously had a non-virological relapse(type B,12.7%),10 patients maintained virological relapse(type C,18.2%),and 26 patients turned to clinical relapse,received NA retreatment,and achieved ALT normalization and negative conversion of HBV DNA within 12 months(type D,47.3%).The 2-year overall cumulative rates of virological and clinical relapses were 58.1%and 24.3%,respectively.Independent factors associated with virological relapse were duration of negative HBV DNA,EOT(end of treatment)HBsAg,and original status of HBeAg.The EOT HBsAg was also an independent factor for clinical relapse.Conclusions:There are four types of clinical outcomes in patients with CHB after cessation of NA treatment.Further research is needed to explore the mechanism of different clinical outcomes.The EOT HBsAg level is an independent factor associated with both virological and clinical relapse.

Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells

BACKGROUND： Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia （HSP）. Since the discovery of the first HSP gene, SPASTthat encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell （iPSC） technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects. METHODS： In this article, we will first review the pathology and pathways affected in the common forms of liSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions. RESULTS： HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects. CONCLUSIONS： These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.

Proteomics identifies EGF-like domain multiple 7 as a potential therapeutic target for epidermal growth factor receptor-positive glioma

Background:Glioma,the most frequent primary tumor of the central nervous system,has poor prognosis.The epidermal growth factor receptor(EGFR)pathway and angiogenesis play important roles in glioma growth,invasion,and recurrence.The present study aimed to use proteomic methods to probe into the role of the EGF-EGFR-angiogenesis axis in the tumorigenesis of glioma and access the therapeutic efficacy of selumetinib on glioma.Methods:Proteomic profiling was used to characterize 200 paired EGFRpositive and EGFR-negative glioma tissues of all pathological types.The quantitative mass spectrometry data were used for systematic analysis of the proteomic profiles of 10 EGFR-positive and 10 EGFR-negative glioma cases.Consensusclustering analysis was used to screen target proteins.Immunofluorescence analysis,cell growth assay,and intracranial xenograft experiments were used to verify and test the therapeutic effect of selumetinib on glioma.Results:Advanced proteomic screening demonstrated that the expression of EGF-like domain multiple 7(EGFL7)was higher in EGFR-positive tumor tissues than in EGFR-negative tumor tissues.In addition,EGFL7 could act as an activatorin vitro and in vivo to promote glioma cell proliferation.EGFL7 was associated strongly with EGFR and prognosis.EGFL7 knockdown effectively suppressed glioma cell proliferation.Selumetinib treatment showed tumor reduction effect in EGFR-positive glioblastoma xenograft mouse model.Conclusions:EGFL7 is a potential diagnostic biomarker and therapeutic target of glioma.Selumetinib could target the EGFR pathway and possibly improve the prognosis of EGFR-positive glioma.

Future Strategies on Glioma Research:From Big Data to the Clinic

Glioma, as the most common and aggressive malignant central nervous system （CNS） tumor with generally poor prognosis, has been attracting much attention in the last decade [1]. Temozolomide was firstly available in the United States in 1999 as a chemotherapy drug for treating brain cancers and remains as the first-line treatment for glioma. The World Health Organization （WHO） classified glioma into four main grades according to the degree of malignancy in 2007, which were updated in 2016 with the introduction of significant molecular alternations. Also in 2016, the Chinese Glioma Cooperative Group （CGCG） published the first guideline for adult diffuse gliomas [2], representing the only national consensus for the diagnosis and treatment of adult gliomas up till nOW.