Loss of SARM1 ameliorates secondary thalamic neurodegeneration after cerebral infarction.

Ischemic stroke causes secondary neurodegeneration in the thalamus ipsilateral to the infarction site and impedes neurological recovery. Axonal degeneration of thalamocortical fibers and autophagy overactivation are involved in thalamic neurodegeneration after ischemic stroke. However, the molecular mechanisms underlying thalamic neurodegeneration remain unclear. Sterile /Armadillo/Toll-Interleukin receptor homology domain protein (SARM1) can induce Wallerian degeneration. Herein, we aimed to investigate the role of SARM1 in thalamic neurodegeneration and autophagy activation after photothrombotic infarction. Neurological deficits measured using modified neurological severity scores and adhesive-removal test were ameliorated in Sarm1-/- mice after photothrombotic infarction. Compared with wild-type mice, Sarm1-/- mice exhibited unaltered infarct volume; however, there were markedly reduced neuronal death and gliosis in the ipsilateral thalamus. In parallel, autophagy activation was attenuated in the thalamus of Sarm1-/- mice after cerebral infarction. Thalamic Sarm1 re-expression in Sarm1-/- mice increased thalamic neurodegeneration and promoted autophagy activation. Auotophagic inhibitor 3-methyladenine partially alleviated thalamic damage induced by SARM1. Moreover, autophagic initiation through rapamycin treatment aggravated post-stroke neuronal death and gliosis in Sarm1-/- mice. Taken together, SARM1 contributes to secondary thalamic neurodegeneration after cerebral infarction, at least partly through autophagy inhibition. SARM1 deficiency is a potential therapeutic strategy for secondary thalamic neurodegeneration and functional deficits after stroke.

Chinese Medicine Formula Siwu-Yin Inhibits Esophageal Precancerous Lesions by Improving Intestinal Flora and Macrophage Polarization.

Siwu-Yin (SWY), a traditional Chinese medicinal formula, can replenish blood and nourish Yin. It was recorded in ancient Chinese medicine books in treating esophageal dysphagia, which has similar symptoms and prognosis with esophageal precancerous lesions and esophageal cancer. However, its effect has not been established in vivo. This study explores the antiesophageal cancer effect of SWY on rats with esophageal precancerous lesions. By performing 16S rRNA gene sequencing and metabolomics, it was suggested that SWY may improve the composition of intestinal flora of rats by regulating the synthesis and secretion of bile acids. In addition, flow cytometry results showed that SWY treatment modified tumor microenvironment by improving macrophage polarization and therefore inhibiting the occurrence of esophageal precancerous lesions.

Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) Inhibits Autophagic Activation and Prevents Secondary Neuronal Damage in the Thalamus after Focal Cerebral Infarction in Hypertensive Rats.

Focal cerebral infarction leads to autophagic activation, which contributes to secondary neuronal damage in the ipsilateral thalamus. Although Nogo-A deactivation enhances neuronal plasticity, its role in autophagic activation in the thalamus after ischemic stroke remains unclear. This study aimed to investigate the potential roles of Nogo-A/Nogo-66 receptor 1 (NgR1) in autophagic activation in the ipsilateral thalamus after cerebral infarction. Focal neocortical infarction was established using the middle cerebral artery occlusion (MCAO) method. Secondary damage in the ipsilateral thalamus was assessed by Nissl staining and immunostaining. The expression of Nogo-A, NgR1, Rho-A and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as well as autophagic flux were evaluated by immunofluorescence and immunoblotting. The roles of Nogo-A-NgR1 signaling in autophagic activation were determined by intraventricular delivery of an NgR1 antagonist peptide, NEP1-40, at 24 h after MCAO. The results showed that Nogo-A and NgR1 overexpression temporally coincided with marked increases in the levels of Beclin1, LC3-II and sequestosome 1 (SQSTM1)/p62 in the ipsilateral thalamus at seven and fourteen days after MCAO. In contrast, NEP1-40 treatment significantly reduced the expression of Rho-A and ROCK1 which was accompanied by marked reductions of LC3-II conversion as well as the levels of Beclin1 and SQSTM1/p62. Furthermore, NEP1-40 treatment significantly reduced neuronal loss and gliosis in the ipsilateral thalamus, and accelerated somatosensory recovery at the observed time-points after MCAO. These results suggest that blockade of Nogo-A-NgR1 signaling inhibits autophagic activation, attenuates secondary neuronal damage in the ipsilateral thalamus, and promotes functional recovery after focal cerebral cortical infarction.

Neuronal loss without amyloid-ß deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys.

Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid-ß (Aß) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aß deposits in the ipsilateral thalamus and hippocampus 12 months post-stroke in non-human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham-operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post-operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aß load in the non-affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aß antibodies recognizing both the N-terminal and C-terminal epitopes of Aß peptides were used to avoid antibody cross-reactivity. Aß levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme-linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post-stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aß plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aß40 , Aß42 or the Aß40 /Aß42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non-affected thalamus and hippocampus without Aß deposits in the late period after MCAO in non-human primates.

Tongxinluo attenuates neuronal loss and enhances neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological outcome after focal cortical infarction in hypertensive rats.

PURPOSE: Tongxinluo, a well-known traditional Chinese medicine complex, has been widely used for the treatment of cerebrovascular diseases in China. The present study was to explore whether treatment with tongxinluo could improve neurological function and alleviate secondary damage in the ipsilateral thalamus after focal cortical infarction in hypertensive rats. METHODS: Tongxinluo was given through oral gavage starting 24 h after distal middle cerebral artery occlusion (MCAO). Neurological function was assessed and then rats were sacrificed 7 and 14 days after MCAO. Brains were harvested for examining infarction volume, Nissl staining and immunofluorescence analysis. RESULTS: Compared with vehicle treatment, tongxinluo remarkably improved neurological function without reducing infarction volume, attenuated neuronal loss and astrocyte activation in the ipsilateral thalamus 7 and 14 days after MCAO (all p < 0.05). Also, tongxinluo markedly increased the number of BrdU+/nestin+ and BrdU+/NeuN+ cells 14 days after MCAO. Moreover, vascular density, the number of BrdU+ vascular endothelial cells, and vascular perimeter in the ipsilateral thalamus were markedly increased in the tongxinluo group relative to that of the vehicle group (all p < 0.05). CONCLUSION: Administration of tongxinluo 24 h after cortical infarction may promote neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological function after cortical infarction in rats.

Effect of simultaneous supplementation of vitamin A and iron on diarrheal and respiratory tract infection in preschool children in Chengdu City, China.

OBJECTIVE: The goal of this study was to investigate whether vitamin A combined with iron supplementation for preschool children resulted in improved changes in children's infectious morbidity. METHOD: In this randomized placebo-controlled and blinded field intervention trial, totally 445 preschoolers, ages 3 to 6 y old, were randomly selected. All children were randomly divided into four groups: vitamin A supplement-only group (group I), iron supplement-only group (group II), vitamin A and iron supplement group (group III), and no vitamin A and ferrous sulfate as placebo-control (group IV) for 6 mo. The morbidity of diarrhea and respiratory infections, were collected during supplementation. RESULTS: There was evidence of the lowest incidence rate of respiratory-related illnesses and fewest symptoms of runny nose, cough, and fever for children in group III compared with children in groups I, II and IV (P < 0.05). Moreover, despite the undistinguished incidence rate of vomiting, nausea, and stomach pain, the rate of diarrhea-related illness was significantly lower for children in group III than for those in the other three groups. CONCLUSION: The beneficial affects on infectious morbidity over 6 mo, highlight the potential of vitamin A plus an iron supplement for preschool-aged children.