Reflections on the complex mechanisms of endometriosis from the perspective of ferroptosis.

Ferroptosis is a novel type of iron-dependent programmed cell death characterised by intracellular iron overload, increased lipid peroxidation and abnormal accumulation of reactive oxygen species.It has been implicated in the progression of several diseases including cancer, ischaemia-reperfusion injury, neurodegenerative diseases and liver disease. The etiology of endometriosis (EMS) is still unclear and is associated with multiple factors, often accompanied by various forms of cell death and a complex microenvironment. In recent decades, the role of non-traditional forms of cell death, represented by ferroptosis, in endometriosis has come to the attention of researchers. This article reviews the transitional role of iron homeostasis in the development of ferroptosis, the characteristics and regulatory mechanisms of ferroptosis, and focuses on summarising the links between iron death and various pathogenic mechanisms of EMS, including oxidative stress, dysregulation of lipid metabolism, inflammation, autophagy and epithelial-mesenchymal transition. The possible applications of ferroptosis in the treatment of EMS, future research directions and current issues are discussed with the aim of providing new ideas for further understanding of EMS.

Interleukin-22 promotes proliferation and reverses LPS-induced apoptosis and steroidogenesis attenuation in human ovarian granulosa cells: implications for polycystic ovary syndrome pathogenesis.

OBJECTIVE: Interleukin 22 (IL-22) plays a role in inflammatory diseases. However, whether IL-22 affects the function of ovarian granulosa cells (GCs) and its relationship with Polycystic Ovary Syndrome (PCOS)remains unclear. METHODS: We investigated the level of IL-22 in human follicular fluid using ELISA. The expression and localization of the IL-22 receptor 1 (IL-22R1) in GCs were investigated by RT-PCR and immunofluorescence staining, respectively. The proliferation of KGN cells (human GCs line) was assessed by CCK-8 assay and EdU assay after treatment with recombinant human IL-22 (rhIL-22) and lipopolysaccharide (LPS). Apoptosis was assessed using flow cytometry. Apoptotic proteins and steroidogenic genes were detected by western blotting. RESULTS: ELISA's results showed that compared with the control group, PCOS patients showed lower expression of IL-22 in follicular fluid. Immunofluorescence showed that IL-22R1 is expressed and localized in human granulosa cell membranes. IL-22 promoted cell proliferation and reversed LPS-induced inhibition of cell proliferation. IL-22 alone did not affect apoptotic or steroidogenic protein expression, however, it reversed LPS-induced apoptosis via downregulation of Bcl-2, upregulation of Bax and cleaved caspase-3, and restoration of LPS-downregulated StAR, CYP11A1, and CYP19A1 expression. Western blotting confirmed that IL-22 activated the JAK2/STAT3 signaling. CONCLUSION: IL-22 promotes cell proliferation, inhibits apoptosis, and regulates KGN cell steroidogenesis confronted with LPS, and decreased IL-22 may be involved in the development of PCOS.

Cerebral-Organoid-Derived Exosomes Alleviate Oxidative Stress and Promote LMX1A-Dependent Dopaminergic Differentiation.

The remarkable advancements related to cerebral organoids have provided unprecedented opportunities to model human brain development and diseases. However, despite their potential significance in neurodegenerative diseases such as Parkinson's disease (PD), the role of exosomes from cerebral organoids (OExo) has been largely unknown. In this study, we compared the effects of OExo to those of mesenchymal stem cell (MSC)-derived exosomes (CExo) and found that OExo shared similar neuroprotective effects to CExo. Our findings showed that OExo mitigated H2O2-induced oxidative stress and apoptosis in rat midbrain astrocytes by reducing excess ROS production, antioxidant depletion, lipid peroxidation, mitochondrial dysfunction, and the expression of pro-apoptotic genes. Notably, OExo demonstrated superiority over CExo in promoting the differentiation of human-induced pluripotent stem cells (iPSCs) into dopaminergic (DA) neurons. This was attributed to the higher abundance of neurotrophic factors, including neurotrophin-4 (NT-4) and glial-cell-derived neurotrophic factor (GDNF), in OExo, which facilitated the iPSCs' differentiation into DA neurons in an LIM homeobox transcription factor 1 alpha (LMX1A)-dependent manner. Our study provides novel insight into the biological properties of cerebral organoids and highlights the potential of OExo in the treatment of neurodegenerative diseases such as PD.

Iron metabolism: An emerging therapeutic target underlying the anti-Alzheimer's disease effect of ginseng.

Finding neuroprotective drugs with fewer side effects and more efficacy has become a major problem as the global prevalence of Alzheimer's disease (AD) rises. Natural drugs have risen to prominence as potential medication candidates. Ginseng has a long history of use in China, and it has a wide range of pharmacological actions that can help with neurological issues. Iron loaded in the brain has been linked to AD pathogenesis. We reviewed the regulation of iron metabolism and its studies in AD and explored how ginseng might regulate iron metabolism and prevent or treat AD. Researchers utilized network pharmacology analysis to identify key factive components of ginseng that protect against AD by regulating ferroptosis. Ginseng and its active ingredients may benefit AD by regulating iron metabolism and targeting ferroptosis genes to inhibit the ferroptosis process. The results present new ideas for ginseng pharmacological studies and initiatives for further research into AD-related drugs. To provide comprehensive information on the neuroprotective use of ginseng to modulate iron metabolism, reveal its potential to treat AD, and provide insights for future research opportunities.

TOP2A deficiency leads to human recurrent spontaneous abortion and growth retardation of mouse pre-implantation embryos.

BACKGROUND: Recurrent spontaneous abortion (RSA), is a dangerous pregnancy-related condition and is a subject of debate in the gynaecology and obstetrics communities. The objective of this study was to determine the function of DNA Topoisomerase II Alpha (TOP2A) in RSA and elucidate the underlying molecular mechanisms. METHODS: In vitro models of TOP2A-knockdown and -overexpression were generated by transfecting specific sh-RNA lentivirus and overexpression plasmid, respectively. An in vitro TOP2A inhibition model was established by culturing mouse embryos at the two-cell stage in a medium containing PluriSIn2, a TOP2A inhibitor. Immunohistochemical staining was used to analyse expression of TOP2A in villi tissues of patients with RSA. Western blotting and qRT-PCR were used to analyse the expression of TOP2A and proteins involved in trophoblast functions, the FOXO signalling pathway, and the development of pre-implantation embryos. 5-Ethynyl-2'-deoxyuridine staining, TUNEL assay and flow cytometry were used to further evaluate the effect of TOP2A on cell proliferation and apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. Moreover, the effect of TOP2A inhibitor on embryos was determined by immunofluorescence and mitochondrial-related dyes. RESULTS: Evaluation of clinical samples revealed that the villi tissues of patients that have experienced RSA had lower TOP2A expression compared with that from women who have experienced normal pregnancy (P < 0.01). In vitro, TOP2A knockdown decreased the proliferation, migration, and invasion of trophoblast cell lines, and increased apoptosis and activation of the FOXO signalling pathway (P < 0.05). Conversely, TOP2A overexpression reversed these effects. Moreover, in vivo experiments confirmed that inhibition of TOP2A impairs trophectoderm differentiation, embryonic mitochondrial function as well as the developmental rate; however, no differences were noted in the expression of zygotic genome activation-related genes. CONCLUSIONS: Collectively, our data suggest that lower TOP2A expression is related to RSA as it inhibits trophoblast cell proliferation, migration, and invasion by activation of the FOXO signalling pathway. Additionally, TOP2A inhibition resulted in impaired development of pre-implantation embryos in mice, which could be attributed to excessive oxidative stress.

TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway.

BACKGROUND: Successful implantation is a complex process that is influenced by embryo quality, endometrial receptivity, immune factors, and the specific type of in vitro fertilization protocol used. DNA topoisomerase IIα (TOP2A) is a well-known protein involved in cell proliferation; however, its expression and effect on the endometrium in recurrent implantation failure (RIF) have not been fully elucidated. METHODS: The human endometrial tissues of healthy controls and patients with RIF were collected. A proteomic analysis was performed to evaluate the differentially expressed proteins between the RIF group and the fertile control group. The expression patterns of TOP2A in the human preimplantation endometrium of the patients with RIF were determined by immunohistochemical staining, Western blotting and qRT-PCR. TOP2A knockdown (sh-TOP2A) T-HESCs were generated using lentiviruses. The expression of TOP2A in T-HESCs was manipulated to investigate its role in decidualization. The TOP2A-related changes in decidualization were screened by mRNA sequencing in decidualized TOP2A knockdown and control T-HESCs and then confirmed by Western blotting and immunofluorescence staining. TOP2A-deficient mice were generated by injection of TOP2A-interfering adenovirus on GD2.5 and GD3.5. RESULTS: We performed a proteomic analysis of endometrial tissues to investigate the potential pathogenesis of RIF by comparing the patients with RIF and the matched controls and found that TOP2A might be a key protein in RIF. TOP2A is ubiquitously expressed in both stromal and glandular epithelial cells of the endometrium. The data indicate that TOP2A expression is significantly lower in the mid-secretory endometrium of women with RIF. TOP2A expression was downregulated under stimulation by 8-bromo-cAMP and MPA. Ablation of TOP2A resulted in upregulated expression of decidual biomarkers and morphological changes in the cells. Mechanistic analysis revealed that TOP2A regulates the NF-κB signaling pathway in decidualized T-HESCs. The TOP2A-deficient mice exhibited lower fetal weights. CONCLUSIONS: Our findings revealed that abnormal expression of TOP2A affects decidualization and changes the "window of implantation", leading to RIF. TOP2A participates in the processes of decidualization and embryo implantation, functioning at least in part through the NF-κB pathway. Regulating the expression of TOP2A in the endometrium may become a new strategy for the prevention and treatment of RIF.

A bifunctional fluorescent probe based on PET & ICT for simultaneously recognizing Cys and H2S in living cells.

Most reported probes that respond to Cysteine (Cys) and Hydrogen sulfide (H2S) can only identify one analyte, or they were interfered with homocysteine (Hcy) and glutathione (GSH) when recognizing Cys and H2S. In addition, nitrobenzoxadiazole (NBD) ether, as one of thiols recognition sites, inevitably encounters the situation that Cys, GSH and H2S cannot be distinguished on the same channel at the cellular level. In this work, by introducing NBD ether and NBD amine, we constructed a bifunctional fluorescent probe NJB for dual-site response to Cys and H2S via PET & ICT processes. NJB has wonderful selectivity for identifying Cys and HS-, with limits of detection as low as 58.4 nM and 81.1 nM, respectively. Interestingly, NJB has been successfully applied to detect Cys and HS- in MCF-7 cells. Therefore, the probe that serves as a great tool for inquiring the physiological and pathological functions of Cys and H2S in living cells is promising.

ANKRD37 inhibits trophoblast migration and invasion by regulating the NF-κB pathway in preeclampsia.

BACKGROUND: Inadequate trophoblast invasion is associated with preeclampsia (PE). Ankyrin repeat domain protein 37 (ANKRD37) has been reported to be abnormally expressed in PE placentas. However, the role of ANKRD37 in trophoblasts has not been investigated. We aimed to determine the functions of ANKRD37 in PE and to explore the molecular mechanisms. METHODS: Here, fluorescence in situ hybridization, immunohistochemistry, Western blotting and quantitative real-time polymerase chain reaction were used to detect protein and mRNA expression levels. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, wound healing assay, transwell assay and RNA sequencing were performed to investigate the role of ANKRD37 and the underlying mechanism in HTR8/SVneo and JEG-3 cells, and extravillous explant cultures were used to evaluate the migration and invasion abilities of extravillous cytotrophoblasts. RESULTS: We found that ANKRD37 expression was upregulated in PE placentas compared to normal pregnancy placentas. ANKRD37 knockdown enhanced trophoblast migration and invasion, promoted extravillous explant outgrowth, and regulated the expression of key invasion proteins, whereas ANKRD37 overexpression exerted the opposite effects. RNA sequencing indicated that nuclear factor-kappa B (NF-κB) was the potential downstream pathway of ANKRD37, which was confirmed by the change in p-p65 and p-IκBα expression in JEG-3 and HTR8/SVneo cells. CONCLUSIONS: Our findings suggest that high expression of ANKRD37 inhibits trophoblast cell migration and invasion possibly via the NF-κB pathway, and may be related to the development of PE.

A dye encapsulated zinc-based metal-organic framework as a dual-emission sensor for highly sensitive detection of antibiotics.

Self-assembly of two Zn-MOFs, [Zn2L(DMF)3]·H2O·5DMF (1) and [Zn2L(H2O)2]·4H2O·3DMF (2), was achieved with an amide-functionalized tetracarboxylate ligand under similar conditions. Incorporated amide groups make the tetratopic linkers exhibit different configurations, tetrahedron and square, and subsequently combine tetrahedral [Zn2(CO2)4] clusters or square paddle-well [Zn2(CO2)4] clusters to afford a lon net for 1 and a nbo net for 2. Remarkably, 2 demonstrated high porosity and amide group decorated cages, and thereby proved to be a good capturing agent for a fluorescent dye molecule (DMASM). Consequently, a dual-emitting DMASM@2 sensor was successfully fabricated based on effective energy transfer from the host framework to DMASM with the variable luminescent color being visible to the naked eye. DMASM@2 could be used for the detection of metronidazole (MDZ) and dimetridazole (DTZ) with high sensitivity and remarkable recyclability.

Maritimibacter alexandrii sp. nov., a New Member of Rhodobacteraceae Isolated from Marine Phycosphere.

Marine phycosphere hosts cross-kingdom algae-bacteria interactions playing a variety of crucial roles in aquatic ecosystems especially for the prevention and control of harmful algal blooms (HABs). During the investigation of structural composition of phycosphere microbiota (PM) of diverse marine HAB dinoflagellates, a Gram-negative, strictly aerobic, non-motile and rod-shaped bacterium designated LZ-17T was isolated from the phycosphere of highly toxic Alexandrium catenella LZT09. The 16S rRNA gene sequence analysis and the multilocus sequence analysis (MLSA) based on five protein-coding housekeeping genes (atpD, gyrB, mutL, topA and rpoD) indicated that strain LZ-17T was affiliated to the genus Maritimibacter within the family Rhodobacteraceae, and closely related to Maritimibacter alkaliphilus HTCC2654T (99.1%), 'Maritimibacter harenae' DP07T (97.9%) and M. lacisalsi X12M-4T (95.7%). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain LZ-17T and the type strain of M. alkaliphilus were 96.9% and 74.7%. However, strain LZ-17T could be clearly distinguished from its closest by the phenotypical and phenotypical characteristics. Strain LZ-17T contained Q-10 as its major isoprenoid quinone, and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c), C16:0 and C16:0 2-OH as the predominant fatty acids (>10%). The major polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylcholine. The DNA G + C content was 64.3 mol%. Based on the polyphasic taxonomic characterization, strain LZ-17T represents a novel species of the genus Maritimibacter, for which the name Maritimibacter alexandrii sp. nov. is proposed, with the type strain LZ-17T (=CCTCC 2019005T = KCTC 72193T).

Marinobacter shengliensis subsp. alexandrii Subsp. Nov., Isolated from Cultivable Phycosphere Microbiota of Highly Toxic Dinoflagellate Alexandrium catenella LZT09 and Description of Marinobacter shengliensis Subsp. shengliensis Subsp. Nov.

Phycosphere hosts the boundary of unique holobionts harboring dynamic algae-bacteria interactions. During our investigating the microbial consortia composition of phycosphere microbiota (PM) derived from diverse harmful algal blooms (HAB) dinoflagellates, a novel rod-shaped, motile and faint yellow-pigmented bacterium, designated as strain LZ-6 T, was isolated from HAB Alexandrium catenella LZT09 which produces high levels paralytic shellfish poisoning toxins. Phylogenetic analysis based on 16S rRNA gene and two housekeeping genes, rpoA and pheS sequences showed that the novel isolate shared the highest gene similarity with Marinobacter shengliensis CGMCC 1.12758 T (99.6%) with the similarity values of 99.6%, 99.9% and 98.5%, respectively. Further phylogenomic calculations of average nucleotide identity (ANI), average amino acid identity (AAI) and digital DNA-DNA hybridization (dDDH) values between strains LZ-6 T and the type strain of M. shengliensis were 95.9%, 96.4% and 68.5%, respectively. However, combined phenotypic and chemotaxonomic characterizations revealed that the new isolate was obviously different from the type strain of M. shengliensis. The obtained taxonomic evidences supported that strain LZ-6 T represents a novel subspecies of M. shengliensis, for which the name is proposed, Marinobacter shengliensis subsp. alexandrii subsp. nov. with the type strain LZ-6 T (= CCTCC AB 2018388TT = KCTC 72197 T). This proposal automatically creates Marinobacter shengliensis subsp. shengliensis for which the type strain is SL013A34A2T (= LMG 27740 T = CGMCC 1.12758 T).

Limnobacter alexandrii sp. nov., a thiosulfate-oxidizing, heterotrophic and EPS-bearing Burkholderiaceae isolated from cultivable phycosphere microbiota of toxic Alexandrium catenella LZT09.

A novel Gram-negative, aerobic, motile and short rod-shaped bacterium with exopolysaccharides production, designated as LZ-4T, was isolated from cultivable phycosphere microbiota of harmful algal blooms-causing marine dinoflagellate Alexandrium catenella LZT09 which produces paralytic shellfish poisoning toxins. Strain LZ-4T was able to use thiosulfate (optimum concentration 10 mM) as energy source for bacterial growth. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain LZ-4T belonged to the genus Limnobacter, showing high 16S rRNA gene sequences similarities with L. thiooxidans DSM 13612T (99.4%), L. humi NBRC 11650T (98.2%) and L. litoralis NBRC 105857T (97.2%), respectively. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between LZ-4T and L. thiooxidans DSM 13612T were 78.9 and 21.9%, respectively. Both values were far lower than the thresholds (95-96% for ANI and 70% for dDDH) generally accepted for new species delineation. The respiratory quinone of strain LZ-4T was Q-8. The dominant cellular fatty acids were determined as summed feature 3 (C16:1 ω6c/ω7c), summed feature 8 (C18:1 ω6c/ω7c) and C16:0. Polar lipids profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids and three unidentified polar lipids. The genomic DNA G+C content of strain LZ-4T was 52.5 mol%. Based on polyphasic characterization, strain LZ-4T represents a novel species of the genus Limnobacter, for which the name Limnobacter alexandrii sp. nov. is proposed. The type strain is LZ-4T (=CCTCC AB 2019004T =KCTC 72281T).

Nitratireductor alexandrii sp. nov., from phycosphere microbiota of toxic marine dinoflagellate Alexandrium tamarense.

A taxonomic study was carried out on a novel algae-associated bacterial strain Z3-1T, which was isolated from phycosphere microbiota of toxic marine dinoflagellate Alexandrium tamarense 880. Cells of strain Z3-1T were Gram-stain-negative, rod-shaped and strictly aerobic and were motile by means of flagella. Strain Z3-1T grew at 25-42 °C, pH 5.0-10.0 and 1.0-5.0 % (w/v) NaCl. Strain Z3-1T reduced nitrate to nitrite, but did not reduce nitrite to nitrogen gas. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain Z3-1T belongs to the genus Nitratireductor showing the highest sequence similarity (97.0 %) to Nitratireductor basaltis JCM 14935T. The average nucleotide identity and digital DNA-DNA hybridization relatedness between strain Z3-1T and type strains of genus Nitratireductor with available genome sequences were in the ranges of 72.4-74.4 % and 22.7-23.3 %, respectively. The major fatty acids were summed in feature 8 (C18:1 ω7c and/or C18:1 ω6c), C19:0 ω8c cyclo, C18:1 ω7c 11-metyl and iso-C17:0. The major polar lipids were determined as diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, two unidentified phospholipids and four unidentified polar lipids. The genomic DNA G+C content calculated from genome sequence was 65.6 mol%. Based on genotypic, chemotaxonomic and phenotypic data obtained, strain Z3-1T represents a novel species of the genus Nitratireductor, for which the name Nitratireductor alexandrii sp. nov. is proposed with the type strain Z3-1T (=KCTC 62458T=CCTCC AB 2017227T).

Enlarged responsivity-ZnO honeycomb nanomaterials UV photodetectors with light trapping effect.

The ability of ZnO photodetectors to absorb UV light plays a key role in enhancing responsivity and performance in electronic, optical, and photonic devices. Herein, the light trapping effect of ZnO is used to design and fabricate a novel honeycomb-like ZnO nanomaterial-based UV photodetector with an excellent photoelectric performance. Compared with the traditional ZnO film UV photodetector, the photoresponsivity of the film with honeycomb nanomaterials can reach up to 4.79 A W-1, which is an improvement of about 300 times. In addition, the honeycomb ZnO nanomaterials UV photodetectors exhibit an improved light absorption, a very photo-to-dark current ratio (2.46 × 103), and an excellent detectivity (4.61 × 1012 Jones). The ZnO honeycomb nanostructure synthesized in this work exhibits a strong trapping effect, providing new insights into the research of nanomaterials used for UV photodetectors.

Detection of Cell-Free Mitochondrial DNA in Cerebrospinal Fluid of Creutzfeldt-Jakob Patients.

Background: The current diagnosis method for Creutzfeldt-Jakob disease (CJD) is post-mortem examination, so early detection of CJD has been historically problematic. Auxiliary detection of CJD based on changes in levels of components of the cerebrospinal fluid (CSF) has become a focus of research. In other neurodegenerative diseases such as Alzheimer's disease (AD), cell-free mitochondrial DNA (mtDNA) in the CSF of patients may serve as a biomarker that could facilitate early diagnosis and studies of the mechanisms underlying the disease. Methods: In this study, the cell-free mitochondrial DNA in the CSF of patients with sCJD and control patients was compared by digital droplet PCR. Results: The cell-free mitochondrial DNA copy number in the CSF of sCJD patients was significantly increased in comparison with that of the control group, and this difference was pathologically related to CJD. Conclusion: Therefore, we speculate that changes in cerebrospinal fluid mitochondrial DNA copy number play an important role in the study of CJD mechanism and diagnosis.

Improved responsivity performance of ZnO film ultraviolet photodetectors by vertical arrays ZnO nanowires with light trapping effect.

The light trapping effect of zinc oxide (ZnO) ultraviolet photodetectors (UV PDs) has been established as a promising way to optimize the performance of optoelectronic devices. In this paper, we report a light trapping fabricated metal-semiconductor-metal structure, consisting of a ZnO nanowire array as a top layer light absorber supported by a ZnO film. The ZnO film is bridged between two interdigitated metal electrodes for collecting photo-generated carriers. In this connection, high-dense ZnO nanowires can be used as a light trapping unit and to transmit the photogenerated carriers towards the ZnO film. The photogenerated carriers diffuse along the longitudinal direction of the ZnO nanowire and then to the ZnO film and are collected by the applied bias electrode. Compared to present ZnO thin film UV PDs, our device has an effective light trapping effect and the enhancement of photo-generated carriers at the top interface by a ZnO nanowire array structure are highly beneficial to UV light detection as they can provide a long optical path and more surface area. In addition, when the device was connected with nanowires, a 10 times augment of responsivity appeared accompanied by a giant photo-to-dark current ratio (1.6 × 103). This novel work not only enhanced fundamental improvement of nanowires to ZnO film UV PDs, but also provided a distinct contrast between light trapping UV PDs and ZnO film UV PDs.

Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway.

Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells' (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor⁻erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.

Significant Enhancement of MgZnO Metal-Semiconductor-Metal Photodetectors via Coupling with Pt Nanoparticle Surface Plasmons.

We proposed and demonstrated MgZnO metal-semiconductor-metal (MSM) ultraviolet photodetectors (UV) assisted with surface plasmons (SPs) prepared by the radio frequency magnetron sputtering deposition method. After the decoration of their surface with Pt nanoparticles (NPs), the responsivity of all the electrode spacing (3, 5, and 8 µm) photodetectors were enhanced dramatically; to our surprise, comparing with them the responsivity of larger spacing sample, more SPs were gathered which are smaller than others in turn. A physical mechanism focused on SPs and depletion width is given to explain the above results.

[Positive Distribution Rate of Coombs Test in Patients with Clinical Anemia and Blood Transfusion and Its Effect on Clinical Blood Transfusion].

OBJECTIVE: To study the positive distribution rate of Coombs test in patients with clinical anemia and blood transfusion, and its effect on clinical blood transfusion. METHODS: Seventy patients with hemoglobin level in the normal range were enrolled into control group, while 130 patients with anemia or blood transfusion who' s hemoglobin level was lower comfirmed by micro-column gel antihuman globin detection card and 70 surgical patients with anemia or blood transfusion who' s hemoglobin level was lower comfirmed by micro-column gel anti-human globin card were enrolled into anemia or blood transfusion (A or BT) group. And coomb' s test performed for all the patients, in which the positive patients in Department of Internal Medicine need to be re-typed. RESULTS: Among 70 surgical patients with anemia or blood transfusion, 14 cases were directly detected to be anti-human globine positive with detection rate 20%; among 130 internal medicine patients with anemia or blood transfusion, 54 cases were directly detected to be anti-human globine positive with detection rate 41.4%. Among 270 cases, the highest positive rate (66.7%) was observed in patients with 50-59 g/L of hemoglobin. According to type test, the samples of 54 patients with anemia in Department of Internal Medicine, who were directly selected to be anti-human globin positive, could be divided into anti-C3d(7 cases, accounting for 13.0%), anti-IgG(12 cases accounting for, 22.2%) and anti-C3d+anti-IgG(35 cases, accounting for 64.8%), while according to diseases, the anti-human globin positive ratio was high in tumor cancer, hephropathy and gastroenteropathy patients, and patients in intensive care unit, moreover the blood transfusion frequency of these patients was higher than that of patients with anti-human globin negative(P<0.05). CONCLUSION: The important causes affecting the anemia in patients may relate with direct anti- human globulin positive test, therefore the interference of direct anti-human globin positive should be excluded in the course of blood transfusion, so as to ensure the effectiveness of blood transfusion.

DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.

Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin-like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106-126 in vitro as well as in prion strain-infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion-induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106-126 . On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106-126 -induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD-95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106-126 -induced neuron loss and degeneration. Our findings suggest that DLP1-dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPSc -associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.