Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

VEGF overexpression in transplanted NSCs promote recovery of neurological function in rats with cerebral ischemia by modulating the Wnt signal transduction pathway.

Neural stem cell transplantation is a good method to treat stroke, but the mechanism is still unclear. Therefore, this study aims to explore the regulatory mechanism of VEGF overexpression in transplanted NSCs to promote the recovery of neural function in ischemic rats by regulating Wnt signal transduction pathways. We amplified VEGF gene fragments by PCR and transfected them into NSCs with Ad5 adenovirus. Rat brain IRI model was established by MCAO method, and VEGF transfected NSCs (VEGF-NSCs) were transplanted 24 h after successful IRI model. One week after the transplant, cognitive function was assessed using a neurological deficit score; Brain injury was assessed by histopathology; Photochemical and ELISA methods were used to detect oxidative stress markers and inflammatory factors, respectively. Western blotting has been detected in molecules of the Wnt signaling pathway. The results showed that the transduced NSCs express VEGF at least for 14 days. VEGF-NSCs transplantation (VNT) improved spatial learning and memory in rats, and inhibited oxidative stress injury, inflammatory response, and histopathological injury. VNT also resulted in significant changes in the phosphorylation levels of ß-catenin and GSK-3ß proteins, ultimately triggering activation of the Wnt signal transduction pathway. These results suggest that the neuroprotective effects of VNT may be related to the regulation of the Wnt signal transduction pathway.

Effect of Oxygen-Glucose Deprivation of Microglia-Derived Exosomes on Hippocampal Neurons: A Study on miR-124 and Inflammatory Cytokines.

Stroke is a cerebrovascular disease that threatens human health. Developing safe and effective drugs and finding therapeutic targets has become an urgent scientific problem. The aim of this study was to investigate the effect of oxygen-glucose deprivation of the microglia-derived exosome on hippocampal neurons and its relationship to miR-124 in the exosome. We incubated hippocampal neurons with exosomes secreted by oxygen-glucose deprivation/ reoxygenation (OGD/R) microglia. The levels of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) in the culture supernatant were detected by ELISA. CCK-8 was used to measure neuronal survival rates. The mRNA levels of TNF-α and IL-6 were detected by RT-qPCR to evaluate the effect of exosomes on neurons. RT-qPCR was then used to detect miR-124 in microglia and their secreted exosomes. Finally, potential targets of miR-124 were analyzed through database retrieval, gene detection with dual luciferase reporters, and western blotting experiments. The results showed that the contents of GLU, TNF-α and IL-6 mRNA increased in the supernatant of cultured hippocampal neurons, the content of GABA decreased, and the survival rate of neurons decreased. Oxygen-glucose deprivation increases miR-124 levels in microglia and their released exosomes. miR-124 acts as a target gene on cytokine signaling suppressor molecule 1(SOCS1), while miR-124 inhibitors reduce the expression of TNF-α and IL-6 mRNA in neurons. These results suggest that oxygen- and glucose-deprived microglia regulate inflammatory cytokines leading to reduced neuronal survival, which may be achieved by miR-124 using SOCS1 as a potential target.

Cellular senescence in metastatic prostate cancer: A therapeutic opportunity or challenge (Review).

The treatment of patients with metastatic prostate cancer (PCa) is considered to be a long­standing challenge. Conventional treatments for metastatic PCa, such as radical prostatectomy, radiotherapy and androgen receptor­targeted therapy, induce senescence of PCa cells to a certain extent. While senescent cells can impede tumor growth through the restriction of cell proliferation and increasing immune clearance, the senescent microenvironment may concurrently stimulate the secretion of a senescence­associated secretory phenotype and diminish immune cell function, which promotes PCa recurrence and metastasis. Resistance to established therapies is the primary obstacle in treating metastatic PCa as it can lead to progression towards an incurable state of disease. Therefore, understanding the molecular mechanisms that underly the progression of PCa is crucial for the development of novel therapeutic approaches. The present study reviews the phenomenon of treatment­induced senescence in PCa, the dual role of senescence in PCa treatments and the mechanisms through which senescence promotes PCa metastasis. Furthermore, the present review discusses potential therapeutic strategies to target the aforementioned processes with the aim of providing insights into the evolving therapeutic landscape for the treatment of metastatic PCa.

Four-Component Radical 1,2-Selenosulfonylation of Allenes.

Selenosulfones, as pivotal pharmaceutical molecule frameworks, have become a research hotspot in modern organic synthesis due to their vital need for efficient preparation. Herein, we have developed an iron-catalyzed four-component controllable radical tandem reaction of allenes involving cycloketone oxime esters, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and diphenyl diselenides for the synthesis of complex selenosulfones. This is the first case of achieving the 1,2-selenosulfonylation of allenes via a radical process, wherein precise control of radical rates and polarity matching enhance high regioselective conversion. The reaction conditions are ecofriendly and mild with step-efficiency by forming two new C-S bonds and one C-Se bond in one pot. Moreover, the 1,2-selenosulfonylation of allenes can be achieved by replacing cycloketone oxime esters with aryldiazonium tetrafluoroborates in this system.

YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study

OBJECTIVE: This study aimed to determine the natural prevalence of variants of tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels. METHODS: A total of 1,042 antiviral treatment naïve CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real-time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA. RESULTS: YMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild-type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level. CONCLUSION: Mutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level.

Analysis of the genetic relationships from different genetic systems between the amylose content and the appearance quality of indica rice across environments

The genetic relationships between amylose content (AC) and appearance quality traits of indica rice (Oryza sativa L.) were investigated using conditional analysis and unconditional analysis in present experiment. The results from the unconditional analysis indicated that AC of rice positively correlated with brown rice (BR, i.e., dehulled but unmilled rice) length (BRL), width (BRW) and thickness (BRT), but was negatively correlated with the ratio of length to width (RLW). The conditional analysis showed that weight of brown rice (WBR) negatively affected the genetic relationships between AC and the appearance quality traits of rice except between AC and BRW, while the genetic relationships between AC and most appearance quality traits were negatively affected by protein content (PC). However, these influences were not apparent due to the impact of WBR or PC on the most covariance components of the different genetic systems between AC and the appearance quality traits. The conditional analysis showed that it was possible to improve AC while significantly reduce BRL and BRT under maintaining WBR. Furthermore, AC could be improved when BRL was reduced under maintaining PC, but BRW and BRT could be significantly increased.