Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Alzheimer’s disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

Investigation of the Relationship between MBP Gene Polymorphisms and Delayed Encephalopathy after Acute Carbon Monoxide Poisoning

Background Increasing evidence reveals that delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) results from the combined effects of environmental and genetic factors. The main pathological feature of DEACMP was generalized demyelination of cerebral white matter. Myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) and serum samples from DEACMP patients were elevated.Objectives This study investigated the association of MBP single nucleotide polymorphisms(SNPs) (rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336) with DEACMP. Methods We genotyped 416 DEACMP patients and 785 age, educational level, and sex-matched ACMP patients for rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336 SNPs using the Agena MassArray. Results There were no significant differences in the allele frequency distribution, four genetic models, and genotype distributions between the DEACMP and ACMP groups for rs470555, rs470724, rs4890785, and rs595997. However, significant differences were observed for rs76452994 and rs921336.Conclusions This study revealed that the MBP polymorphisms, rs470555, rs470724, rs4890785, and rs595997, were not associated with DEACMP. Based on the codominant, dominant, and overdominant genetic inheritability patterns, the MBP rs76452994 and rs921366 polymorphisms were associated with DEACMP. Furthermore, the G allele of rs76452994 and T allele of rs921336 could lead to higher DEACMP risk.

Herbal Mixture of Carthamus tinctorius L. Seed and Taraxacum coreanum Attenuates Amyloid Beta-Induced Cognitive Dysfunction In Vivo

Deposition of amyloid-beta (Aβ) in the aging brain has been often observed and is thought to be a pathological feature of Alzheimer’s disease. The use of natural products for disease prevention and treatment is gaining attention worldwide. Carthamus tinctorius L. seed and Taraxacum coreanum have been used as traditional medicines in Asian countries, where they have been reported to exert anti-inflammatory and anti-oxidative effects. It has been demonstrated that the combination of C. tinctorius L. seed and T. coreanum has an effect on cognitive enhancement, indicating a ratio of 5:5 synergistically enhancing learning and memory abilities in comparison with a single treatment. Here, we aimed to investigate the protective effect of C. tinctorius L. seed and T. coreanum mixture (CT) at different concentrations on cognition in Aβ25-35-infused mice. CT-administered mice showed significant cognitive improvement in the T-maze, novel object recognition, and Morris water maze tests. Moreover, amyloidogenesis-related proteins, such as β-secretase and γ-secretase, were detected and their protein levels decreased after treatment with CT. Our study shows that CT attenuates cognitive dysfunction by improving learning and memory capability and regulating Aβ-related proteins in Aβ25-35-injected mice. These findings suggest that CT might be a candidate for functional food on cognitive improvement.

circHIPK3 Exacerbates Folic Acid-Induced Renal Tubulointerstitial Fibrosis by Sponging miR-30a

Renal tubulointerstitial fibrosis is a common pathological feature of progressive chronic kidney disease (CKD), and current treatment has limited efficacy. The circular RNA circHIPK3 is reported to participate in the pathogenesis of various human diseases. However, the role of circHIPK3 in renal fibrosis has not been examined. In this study, we aimed to determine whether and how circHIPK3 might participate in the pathogenesis of renal fibrosis. Mice received a peritoneal injection of folic acid (250 mg/kg). Of note, 30 days later, renal fibrosis was present on periodic acid–Schiff (PAS) and Masson staining, and mRNA and protein of profibrotic genes encoding fibronectin (FN) and collagen 1 (COL1) were increased. Renal circHIPK3 was upregulated, while miR-30a was downregulated, assessed by quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). The expression of transforming growth factor beta-1 (TGF-β1) was increased by qPCR analysis, immunoblotting, and immunofluorescence. Renal circHIPK3 negatively correlated with miR-30a, and kidney miR-30a negatively correlated with TGF-β1. Target Scan and miRanda algorithms predicted three perfect binding sites between circHIPK3 and miR-30a. We found that circHIPK3, miR-30a, and TGF-β1 colocalized in the cytoplasm of human tubular epithelial cells (HK-2 cells) on FISH and immunofluorescence staining. We transfected circHIPK3 and a scrambled RNA into HK-2 cells; miR-30a was downregulated, and the profibrotic genes such as TGF-β1, FN, and COL1 were upregulated and assessed by qPCR, immunoblotting, and immunofluorescence staining. Third, the upregulation of circHIPK3, downregulation of miR-30a, and overproduction of profibrotic FN and COL1 were also observed in HK-2 cells exposed to TGF-β1. Finally, renal biopsies from patients with chronic tubulointerstitial nephritis manifested similar expression patterns of circHIPK3, miR-30a, and profibrotic proteins, such as TGF-β1, FN, and COL1 as observed in the experimental model. A feed-forward cycle was observed among circHIPK3, miR-30a, and TGF-β1. Our results suggest that circHIPK3 may contribute to progressive renal fibrosis by sponging miR-30a. circHIPK3 may be a novel therapeutic target for slowing CKD progression.

Reduction of Pulmonary Inflammation by pH Modifiers

Pulmonary inflammation is a common pathological feature of a variety of diseases, ofwhich successful therapy with currently available anti-inflammatory drugs is limited byresistance and adverse side effects. Using the ovalbumin-induced mouse allergic asthma model,the present study shows that treatments with pH modifiers, particularly simple acids such asacetate or hydrochloric acid, effectively depleted inflammatory cells in the lungs and blood aswell as hyperplastic lung tissue cells while preserving the structure of the blood vessels and lungparenchyma. The acid treatments also suppressed mucus hypersecretion. These resultsdemonstrated pH modifiers as a new class of broad-spectrum anti-inflammatory agents with antiproliferationand mucus suppression activities.

Disrupting ATXN1 Nuclear Localization in a Knock-in SCA1 Mouse Model Improves a Spectrum of SCA1-Like Phenotypes and their Brain Region Associated Transcriptomic Profiles

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with the amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes whose expression was corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.

Secretases Related to Amyloid Precursor Protein Processing

Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.

Potential Role of CTNNA3 and FRMPD4 in Vascular Thrombosis of Colon Adenocarcinoma

Background: Vascular tumor thrombus is an important pathological feature of malignant tumors, closely related to lymph node metastasis, and considered to be tumor micrometastasis. Two down-regulated genes, Catenin Alpha 3 (CTNNA3) and FERM And PDZ Domain Containing 4 (FRMPD4) were selected via analyzing the differential expression of vascular tumor thrombus in colon adenocarcinoma and paracancerous tissues. Furthermore, we observed the potential role of them in vascular thrombosis of colon adenocarcinoma.Method: Candidate genes for vascular thrombosis of colon adenocarcinoma were screened by GSE127069, and then pan-cancer verification and immune infiltration analysis were performed. The relationship between gene and vascular thrombosis was analyzed from the level of gene mutation by cBioPortal. Finally, the clinical samples collected were used for expression verification.Results: CTNNA3 and FRMPD4 were low-expressed in vascular tumor thrombus of colon adenocarcinoma, which were positively correlated with microsatellite instability (MSI). They were also closely related to immune microenvironment and immune cell subtype infiltration. According to the analysis of gene mutation, their gene deletion was related to the vascular invasion indicator. Finally, the protein and mRNA expression of CTNNA3 and FRMPD4 were down-regulated in the samples of vascular thrombosis of colon adenocarcinoma, compared with the normal glands which from paracancerous tissues.Conclusion: Our study demonstrates that CTNNA3 and FRMPD4 may be potential biomarkers of vascular thrombosis in colon adenocarcinoma. These results may provide a new strategy to identify the micrometastasis in colon adenocarcinoma.

WNT1-inducible-signaling pathway protein 1 regulates kidney inflammation through the NF-κB pathway

Inflammation is a pathological feature of kidney injury and its progression correlates with the development of kidney fibrosis which can lead to kidney function impairment. This project investigated the regulatory function of WNT1-inducible-signaling pathway protein 1 (WISP1) in kidney inflammation. Administration of recombinant WISP1 protein to healthy mice induced kidney inflammation (macrophage accrual and production of TNFα, CCL2 and IL-6), which could be prevented by inhibition of NF-κB. Furthermore, inhibition of WISP1, by gene knockdown or neutralising antibody, could inhibit cultured macrophages producing inflammatory cytokines following stimulation with lipopolysaccharides (LPS) and kidney fibroblasts proliferating in response to TNFα, which both involved NF-κB signalling. Kidney expression of WISP1 was found to be increased in mouse models of progressive kidney inflammation- unilateral ureter obstruction (UUO) and streptozotocin-induced diabetic nephropathy. Treatment of UUO mice with WISP1 antibody reduced the kidney inflammation in these mice. Therefore, pharmacological blockade of WISP1 exhibits potential as a novel therapy for inhibiting inflammation in kidney disease.

Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects

Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.