Hongliang Xu

Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments

Background Ginsenoside Rb1 (Rb1), a dominant component from the extract of Panax ginseng root, exhibits neuroprotective functions in many neurological diseases. This study was intended to investigate whether Rb1 can attenuate cisplatin-induced memory impairments and explore the potential mechanisms. Methods Cisplatin was injected intraperitoneally with a dose of 5 mg/kg/wk, and Rb1 was administered in drinking water at the dose of 2 mg/kg/d to rats for 5 consecutive wk. The novel objects recognition task and Morris water maze were used to detect the memory of rats. Nissl staining was used to examine the neuron numbers in the hippocampus. The activities of superoxide dismutase, glutathione peroxidase, cholineacetyltransferase, acetylcholinesterase, and the levels of malondialdehyde, reactive oxygen species, acetylcholine, tumor necrosis factor-α, interleukin-1β, and interleukin-10 were measured by ELISA to assay the oxidative stress, cholinergic function, and neuroinflammation in the hippocampus. Results Rb1 administration effectively ameliorates the memory impairments caused by cisplatin in both novel objects recognition task and Morris water maze task. Rb1 also attenuates the neuronal loss induced by cisplatin in the different regions (CA1, CA3, and dentate gyrus) of the hippocampus. Meanwhile, Rb1 is able to rescue the cholinergic neuron function, inhibit the oxidative stress and neuroinflammation in cisplatin-induced rat brain. Conclusion Rb1 rescues the cisplatin-induced memory impairment via restoring the neuronal loss by reducing oxidative stress and neuroinflammation and recovering the cholinergic neuron functions.

Association between small intestinal bacterial overgrowth and deep vein thrombosis in patients with spinal cord injuries.

Essentials Gastrointestinal dysfunction and vein thrombosis are complications after spinal cord injuries (SCI). We assess the deep vein thrombosis (DVT) and small intestinal bacterial overgrowth (SIBO) in SCI. 76 of the 377 SCI patients were DVT positive (20.2%) and 145 were defined as SIBO positive (38.5%). This study defines an association between SIBO and DVT in patient with SCI.

Silencing of Long Noncoding RNA SOX21-AS1 Relieves Neuronal Oxidative Stress Injury in Mice with Alzheimer’s Disease by Upregulating FZD3/5 via the Wnt Signaling Pathway

Alzheimer’s disease (AD) represents a progressive neurodegenerative disorder characterized by distinctive neuropathological changes. Recently, long noncoding RNAs (lncRNAs) have become a key area of interest due to their potential in AD therapy. Hence, the aim of the current study was to investigate the effect of lncRNA SOX21-AS1 on neuronal oxidative stress injury in mice with AD via the Wnt signaling pathway by targeting FZD3/5. Microarray analysis was performed to screen AD-related differentially expressed genes (DEGs). Following verification of the target relationship between SOX21-AS1 and FZD3/5, the contents of OH−, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were determined, with the expressions of SOX21-AS1, FZD3/5, β-catenin, cyclin D1, and 4-HNE in hippocampal neuron cells subsequently detected. Cell cycle distribution and apoptosis were evaluated. Bioinformatics analysis revealed that SOX21-AS1 was upregulated in AD, while highlighting the co-expression of SOX21-AS1 and FZD3/5 genes and their involvement in the Wnt signaling pathway. AD mice exhibited diminished memory and learning ability, increased rates of MDA, OH−, SOX21-AS1, 4-HNE, and elevated levels of hippocampal neuron cell apoptosis, accompanied by decreased levels of SOD, CAT, GSH-Px, FZD3/5, β-catenin, and cyclin D1. Silencing of SOX21-AS1 resulted in decreased OH−, MDA contents, SOX21-AS1, and 4-HNE, and increased SOD, CAT, GSH-Px, FZD3/5, β-catenin, and cyclin D1, as well as reduced apoptosis of hippocampal neuron cells. Taken together, the key findings of the present study demonstrated that silencing of lncRNA SOX21-AS1 could act to alleviate neuronal oxidative stress and suppress neuronal apoptosis in AD mice through the upregulation of FZD3/5 and subsequent activation of the Wnt signaling pathway.

Curcumin Exerts Effects on the Pathophysiology of Alzheimer’s Disease by Regulating PI(3,5)P2 and Transient Receptor Potential Mucolipin-1 Expression

Background To validate our speculation that curcumin may ameliorate Alzheimer’s disease (AD) pathogenesis by regulating PI(3,5)P2 and transient receptor potential mucolipin-1 (TRPML1) expression levels. Methods We developed an animal model presenting AD by APP/PS1 transgenes. The mouse clonal hippocampal neuronal cell line HT-22 was treated with amyloid-β1-42 (Aβ1-42). Curcumin was administrated both in vivo and in vitro. MTS assay was used to detect cell viability, and the lysosomal [Ca2+] ion concentration was detected. The number of autophagosomes was detected by the transmission electron microscopic examination. Illumina RNA-seq was used to analyze the different expression patterns between Aβ1-42-treated cells without and with curcumin treatment. The protein level was analyzed by the Western blotting analysis. PI(3,5)P2 or TRPML1 was knocked down in HT-22 cells or in APP/PS1 transgenic mice. Morris water maze and recognition task were performed to trace the cognitive ability. Results Curcumin increased cell viability, decreased the number of autophagosomes, and increased lysosomal Ca2+ levels in Aβ1-42-treated HT-22 cells. Sequencing analysis identified TRPLML1 as the most significantly upregulated gene after curcumin treatment. Western blotting results also showed that TRPML1 was upregulated and mTOR/S6K signaling pathway was activated and markers of the autophagy–lysosomal system were downregulated after curcumin use in Aβ1-42-treated HT-22 cells. Knockdown of PI (3,5)P2 or TRPML1 increased the protein levels of markers of the autophagy–lysosomal system after curcumin use in Aβ1-42-treated HT-22 cells, inhibited mTOR/S6K signaling pathway, increased the protein levels of markers of the autophagy–lysosomal system after curcumin use in APP/PS1 mice. Besides, knockdown of PI(3,5)P2 or TRPML1 reversed the protective role of curcumin on memory and recognition impairments in mice with APP/PS1 transgenes. Conclusion To some extent, it suggested that the effects of curcumin on AD pathogenesis were, at least partially, associated with PI(3,5)P2 and TRPML1 expression levels.

Novel compound heterozygous mutations causing Kufs disease type B

ABSTRACT Background: Kufs disease type B (also termed CLN13), an adult-onset form of neuronal ceroid lipofuscinosis (NCL), is genetically heterogeneous and challenging to diagnose. Recently, mutations in cathepsin-F have been identified as the causative gene for autosomal recessive Kufs disease type B. Results: Here, we report a sporadic case of Kufs disease type B with novel compound heterozygous mutations, a novel missense mutation c.977G>T (p.C326F) and a novel nonsense mutation c.416C>A (p.S139X), in the cathepsin-F gene. The magnetic resonance imaging findings were consistent with those demonstrated in adult neuronal ceroid lipofuscinosis: diffuse cortical atrophy, mild hyperintensity and reduction of the deep white matter on T2-weighted images. A skin biopsy was negative for abnormalities. Conclusions: Altogether, our findings broaden the mutation database in relation to the neuronal ceroid lipofuscinosis, and the clinical diagnosis of Kufs disease type B was confirmed.

A novel ETFDH mutation in an adult patient with late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency

ABSTRACT Aim of the study: To report a novel mutation in the electron transfer flavoprotein dehydrogenase (ETFDH) gene in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Materials and methods: The genomic DNAs from a patient whose main clinical presentations are muscles weakness and hypoglycemia was analysed. Results: The patient was identified to carry compound heterozygous mutations in ETFDH gene. Two missense mutations c.814 G > A and c.389 A > T were found. Conclusion: This is the first report of c.814G > A mutation in ETFDH in adult patient with MADD.

The Potential Protective Effect of Curcumin on Amyloid-β-42 Induced Cytotoxicity in HT-22 Cells

Background We aimed to investigate the effect and mechanism of curcumin (CUR) in Alzheimers disease (AD). Methods Mouse hippocampal neuronal cell line HT-22 was treated with Aβ1–42 and/or CUR, and then cell viability was evaluated by cell counting kit 8, Beclin-l level was detected using western blotting, and the formation of autophagosomes was observed by transmission electron microscopy (TEM). Furthermore, transcriptome sequencing and analysis were performed in cells with Aβ1–42 alone or Aβ1–42 + CUR. Results Aβ1–42 treatment significantly inhibited cell viability compared with untreated cells (P < 0.01). After treatment for 48 h, CUR remarkably promoted cell viability compared with cell treated with Aβ1–42 alone (P < 0.01). Compared with cells treated with Aβ1–42 alone, the expression of Beclin-1 was slightly reduced in cells with combined treatment of Aβ1–42 with CUR (P < 0.05). Consistently, TEM results showed that CUR inhibited the formation of autophagosomes in cells treated with Aβ1–42. Furthermore, the protein-protein interaction network showed five key genes, including MYC, Cdh1, Acaca, Egr1, and CCnd1, likely involved in CUR effects. Conclusions CUR might have a potential neuroprotective effect by promoting cell viability in AD, which might be associated with cell autophagy. Furthermore, MYC, Cdh1, and Acaca might be involved in the progression of AD.

Biochemical aspirin resistance is associated with increased stroke severity and infarct volumes in ischemic stroke patients

To explore the correlation of aspirin resistance (AR) with clinical stroke severity and infarct volume using diffusion-weighted imaging (DWI) in 224 Chinese ischemic stroke patients who were taking aspirin before stroke onset. In those patients, the median age was 64 years (IQR, 56-75 years), and males accounting for 54.9%(123)of the total subjects. Fifty of 224 enrolled patients (22.3%; 95% confidence interval (CI), 16.9% to 27.7%) showed AR. In the median regression model, significant increase was estimated in NIHSS score of 0.04 point for every 1-point increase in aspirin reaction units (ARU) (95% CI, 0.02 to 0.06; P<0.001). Diffusion-weighted MRI (DWI)-measured infarct volume were significantly higher in patients with AR as compared with those with AS [13.21 (interquartile ranges [IQR], 8.51-23.88) vs.4.26 (IQR, 1.74-11.62); P<0.001). Furthermore, a statistically significant increase was also measured in NIHSS score of 0.05 point for every 1-point increase in ARU in the median regression model (95% CI, 0.03 to 0.08; P<0.001). The median DWI infarct volume was significantly larger in the highest ARU quartile when compared to that in the low 3 quartiles (P<0.001). In conclusion, stroke patients with AR indicated higher risk of severe strokes and large infarcts compared to patients in the aspirin-sensitive group.

TRPML1 Participates in the Progression of Alzheimer’s Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway

Background: TRPML1 is reported to be involved in the pathogenesis of Alzheimer’s disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear. Methods: We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Aβ1-42 or Aβ1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca2+ was also measured. Results: In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARγ/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARγ and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Aβ1-42-suppressed cell viability and the Aβ1-42-decreased lysosomal [Ca2+] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Aβ1-42-inhibited mTOR/S6K signalling pathway and the Aβ1-42-induced ALR-related protein expression levels. Conclusion: TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARγ/AMPK/mTOR signallingpathway.