Would Combination Be Better: Swimming Exercise and Intermittent Fasting Improve High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Obese Rats via the miR-122-5p/SREBP-1c/CPT1A Pathway.

Background: Swimming and intermittent fasting can both improve obesity-induced NAFLD, but which of the two is more effective and whether the combination of the two has a superimposed effect is inconclusive. Methods: The model of NAFLD in obese rats was established by a high-fat diet and performed swimming, intermittent fasting, and a combination of both interventions for 8 weeks. Serum lipids and enzyme activity were measured by an automatic biochemical analyzer. Liver morphostructural analysis was observed by transmission electron microscopy, and morphology was observed by HE staining. RT‒PCR was used to detect the mRNA level. Results: Morphology and microstructure of the liver of model rats were impaired, with the upregulation of miR-122-5p, SREBP-1c, FASN and ACC1. Eight weeks of swimming exercise, intermittent fasting and the combination of both attenuate these effects, manifested by the downregulation of miR-122-5p and upregulation of CPT1A mRNA levels. There was no significant stacking effect of the combination of the swimming and intermittent fasting interventions. Conclusion: NAFLD leads to pathology in model rats. Eight weeks of swimming exercise, intermittent fasting and the combination of both can inhibit miR-122-5p and improve hepatic lipid metabolism, while no significant additive effects of combining the interventions were found.

Construction of a diagnostic model for osteoarthritis based on transcriptomic immune-related genes.

Background: Osteoarthritis (OA) is a leading cause of disability globally, affecting over 500 million individuals worldwide. However, accurate and early diagnosis of OA is challenging to achieve. Immune-related genes play an essential role in OA development. Therefore, the objective of this study was to develop a diagnostic model for OA based on immune-related genes identified in synovial membrane. Methods: The gene expression profile of OA were downloaded based on four datasets. The significantly differentially expressed genes (DEGs) between OA and control groups were selected. The differential immune cells were analyzed, followed by immune-related DEGs screening. WGCNA was used to screen module genes and these genes were further selected through optimization algorithm. Then, nomogram model was constructed. Chemical drug small molecule related to OA was predicted. Finally, expression levels of several key genes were validated by qRT-PCR through construction of OA rat models. Results: The total 656 DEGs were obtained. Eight immune cells were significantly differential between two groups, and 317 immune-related DEGs were obtained. WGCNA identified three modules. The genes in modules were significantly involved in 15 pathways, involving in 65 genes. Then 12 DEGs were screened as the final optimal combination of DEGs, such as CEBPB, CXCL1, JUND, GABARAPL2 and PDGFC. The Nomogram model was also constructed. Furthermore, the chemical small molecules, such as acetaminophen, aspirin, and caffeine were predicted. The expression levels of CEBPB, CXCL1, GABARAPL2 and PDGFC were validated in OA rat models. Conclusion: A diagnostic model based on twelve immune related genes was constructed. These model genes, such as CEBPB, CXCL1, GABARAPL2, and PDGFC, may serve as diagnostic biomarkers and immunotherapeutic targets.

Mental health and fatigue status of the medical workforce during the COVID-19 outbreak in the Yangzhou city, China.

Background: When the coronavirus disease 2019 (COVID-19) erupted in Yangzhou, China, at the end of July 2021, medical workers in Yangzhou immediately joined the frontline for the fight against the pandemic. This study aimed to identify the mental health and fatigue experienced by the medical workers in Yangzhou during the COVID-19 outbreak. Methods: We included 233 medical workers who participated in the front-line work for more than 1 month through the questionnaire, including doctors, nurses, medical technicians and medical students. The generalized anxiety disorder-7 (GAD-7), patient health questionnaire-9 (PHQ-9), and Fatigue self-assessment scale (FSAS) were administered to the participants and their responses were evaluated. Results: A total of 233 eligible questionnaires were received. Among them, 130 people (57.08%) were probably anxious and 141 (60.52%) people were clinically depressed. Poor sleep was considered an independent risk factor for anxiety (OR = 7.164, 95% CI: 3.365 15.251, p = 0.000) and depression (OR = 6.899, 95% CI: 3.392 14.030, p = 0.000). A high PHQ-9 score was considered an independent risk factor for general fatigue (OR = 1.697, 95% CI: 1.481 1.944, p = 0.000). Mental fatigue (OR = 1.092, 95% CI: 1.027 1.161, p = 0.005) and fatigue response to sleep/rest (OR = 1.043, 95% CI: 1.011 1.076 p = 0.008) were considered independent risk factors for general fatigue. Conclusion: Poor quality of sleep led to probable anxiety, depression, and general fatigue. Mental fatigue and fatigue response to sleep/rest were independent risk factors for depression, which merits attention for battling COVID-19.

An enriched environment reduces hippocampal inflammatory response and improves cognitive function in a mouse model of stroke.

An enriched environment is used as a behavioral intervention therapy that applies sensory, motor, and social stimulation, and has been used in basic and clinical research of various neurological diseases. In this study, we established mouse models of photothrombotic stroke and, 24 hours later, raised them in a standard, enriched, or isolated environment for 4 weeks. Compared with the mice raised in a standard environment, the cognitive function of mice raised in an enriched environment was better and the pathological damage in the hippocampal CA1 region was remarkably alleviated. Furthermore, protein expression levels of tumor necrosis factor receptor-associated factor 6, nuclear factor κB p65, interleukin-6, and tumor necrosis factor α, and the mRNA expression level of tumor necrosis factor receptor-associated factor 6 were greatly lower, while the expression level of miR-146a-5p was higher. Compared with the mice raised in a standard environment, changes in these indices in mice raised in an isolated environment were opposite to mice raised in an enriched environment. These findings suggest that different living environments affect the hippocampal inflammatory response and cognitive function in a mouse model of stroke. An enriched environment can improve cognitive function following stroke through up-regulation of miR-146a-5p expression and a reduction in the inflammatory response.

Thermosensitive Hydrogel Loaded with Primary Chondrocyte-Derived Exosomes Promotes Cartilage Repair by Regulating Macrophage Polarization in Osteoarthritis.

BACKGROUND: Intra-articular injection is a classic strategy for the treatment of early osteoarthritis (OA). However, the local delivery of traditional therapeutic agents has limited benefits for alleviating OA. Exosomes, an important type of extracellular nanovesicle, show great potential for suppressing cartilage destruction in OA to replace drugs and stem cell-based administration. METHODS: In this study, we developed a thermosensitive, injectable hydrogel by in situ crosslinking of Pluronic F-127 and hyaluronic acid, which can be used as a slow-release carrier to durably retain primary chondrocyte-derived exosomes at damaged cartilage sites to effectively magnify their reparative effect. RESULTS: It was found that the hydrogel can sustainedly release exosomes, positively regulate chondrocytes on the proliferation, migration and differentiation, as well as efficiently induce polarization of M1 to M2 macrophages. Intra-articular injection of this exosomes-incorporated hydrogel significantly prevented cartilage destruction by promoting cartilage matrix formation. This strategy also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+ regenerative M2 macrophages over CD86+ M1 macrophages in synovial and chondral tissue, with a concomitant reduction in pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and increase in anti-inflammatory cytokine (IL-10) in synovial fluid. CONCLUSION: Our results demonstrated that local sustained-release primary chondrocyte-derived exosomes may relieve OA by promoting the phenotypic transformation of macrophages from M1 to M2, which suggesting a great potential for the application in OA.

Bone Autophagy: A Potential Way of Exercise-Mediated Meg3/P62/Runx2 Pathway to Regulate Bone Formation in T2DM Mice.

BACKGROUND: Meg3 has been shown to attenuate T2DM bone autophagy by activating p62 to inhibit bone formation. However, whether exercise can reverse this process to promote T2DM bone formation and its mechanism remains unknown. METHODS: A T2DM mouse model was established by a high-fat diet and STZ injection, and the mice were trained with 8-week HIIT and downhill running exercise. Micro-CT was used to scan the bone microstructure. Bone morphology was observed by HE staining, and the osteoblast (OB) activity in bones was observed by AKP staining. Calcium ion and phosphorus concentration in serum was detected by ELISA; RT-PCR was used to detect the mRNA level, and Western blot was used to detect the protein level of related indexes in Meg3/p62/Runx2 pathway. RESULTS: The inhibition of bone autophagy, in the bones of T2DM mice, resulted in the degradation of the bone tissue morphology and structure, with the increase of the expressions of Meg3, PI3K, Akt, mTOR, p62 and NF-κB. However, 8-week HIIT and downhill running could reverse this process, especially downhill running, manifested with the up-regulation of miR-16 mRNA level, along with Beclin-1, LC3 II and Runx2 mRNA and protein level. CONCLUSION: T2DM leads to pathology in model mice. Eight-week HIIT and downhill running exercise can inhibit Meg3, activate autophagy of osteoblasts and promote bone formation in T2DM mice.

[Clinical observation of dynamic scalp acupuncture combined with task-oriented mirror therapy for upper limbs function impairment in patients with hemiplegia after ischemic stroke].

OBJECTIVE: To explore the effect of dynamic scalp acupuncture combined with task-oriented mirror therapy (TOMT) for upper limb motor function and activity ability of daily living in patients with hemiplegia after ischemic stroke. METHODS: Seventy-eight patients with hemiplegia after ischemic stroke were randomly divided into a dynamic scalp acupuncture group, a TOMT group, and a scalp acupuncture group, 26 cases in each group (1 case dropped off in the TOMT group and the scalp acupuncture group respectively). All three groups received routine rehabilitation training and medication treatment. The TOMT group was treated with TOMT for 40 min a day, 5 days a week for 8 weeks. The scalp acupuncture group was treated with TOMT after the scalp acupuncture, and the dynamic scalp acupuncture group was treated with TOMT during the scalp acupuncture treatment. The scalp acupuncture treatment was applied at ipsilateral up 1/5 and mid 2/5 of Dingnie Qianxiexian and Dingnie Houxiexian, and the needles were retained for 40 min. The scalp acupuncture treatment was given once a day, 5 days a week for 8 weeks. Before treatment and after 4 weeks and 8 weeks of treatment, the functions of upper limb and hand were evaluated by simplified Fugl-Meyer assessment (FMA) scale upper limb part and functional test for the hemiplegic upper extremity-Hong Kong version (FTHUE-HK) grade, the muscle tension of the upper extremity flexor elbow muscle group was assessed by modified Ashworth scale (MAS) and the activity ability of daily living was assessed by modified Barthel index (MBI). RESULTS: After 4 weeks and 8 weeks of treatment, the FMA scores, FTHUE-HK grades and MBI scores in the three groups were better than those before treatment (P<0.01, P<0.05), and MAS scores after 4 weeks of treatment in the three groups were better than those before treatment (P<0.05). After 4 weeks and 8 weeks of treatment, the FMA scores, FTHUE-HK grades and MBI scores in the dynamic scalp acupuncture group were better than those in the TOMT group and the scalp acupuncture group (P<0.05), and these items in the scalp acupuncture group were better than those in the TOMT group (P<0.05). CONCLUSION: The dynamic scalp acupuncture combined with TOMT treatment can effectively improve the upper limb function and the activities ability of daily living in patients with hemiplegia after ischemic stroke, which is better than TOMT after scalp acupuncture and simple TOMT treatment.

Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice.

The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month-old C57BL/6 male mice ("young" mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment ("age-associated memory impairment" mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cognitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dysfunction in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017.

Synthetic progress toward the marine natural product zamamiphidin A.

An asymmetric synthetic approach to the octahydrofuro[3,4-b]pyridine framework of marine natural product zamamiphidin A has been described. The key steps include an asymmetric Michael addition of (R)-N-tert-butanesulfinyl imidate with enamidomalonate to install the C10 stereocenter, an intramolecular alkoxide exchange/Michael addition/hydrogenation sequence to construct the bicyclic ring system.

Asymmetric Total Synthesis of (+)-Strychnine.

A synthetic strategy for the catalytic asymmetric total synthesis of (+)-strychnine is disclosed. Key features of this synthesis include an organocatalytic enantioselective Michael addition to establish the chirality of the starting building block, a photoinduced radical cascade reaction to access the Corynanthe alkaloid intermediate, and a bioinspired cascade rearrangement to generate the core of the Strychnos alkaloids.

Enriched environment improves working memory impairment of mice with traumatic brain injury by enhancing histone acetylation in the prefrontal cortex.

Working memory impairment is a common cognitive dysfunction after traumatic brain injury (TBI), which severely affects the quality of life of patients. Acetylcholine is a neurotransmitter which is closely related to cognitive functions. In addition, epigenetic modifications are also related to cognitive functions. A neurorehabilitation strategy, enriched environment (EE) intervention, has been widely used to improve cognitive impairment. However, studies of the mechanism of EE on cholinergic system and epigenetic modifications in mouse with TBI have not been reported yet. In this paper, a mouse model with traumatic frontal lobe injury was established, and the mechanism on EE for the mice with TBI was explored. It was found that EE could improve Y-maze performance of mice with TBI, the function of cholinergic system, and the imbalance of acetylation homeostasis in the prefrontal cortex of contralateral side of TBI. In addition, EE also could increase the level of CREB binding protein and histones H3 acetylation at ChAT gene promoter region in the prefrontal cortex of contralateral side of TBI. These indicate that EE has an important effect on the improvement of working memory impairment and the underlying mechanism may involve in histones H3 acetylation at ChAT gene promoter regions in the prefrontal cortex.

Gait disorder as a predictor of spatial learning and memory impairment in aged mice.

OBJECTIVE: To investigate whether gait dysfunction is a predictor of severe spatial learning and memory impairment in aged mice. METHODS: A total of 100 12-month-old male mice that had no obvious abnormal motor ability and whose Morris water maze performances were not significantly different from those of two-month-old male mice were selected for the study. The selected aged mice were then divided into abnormal or normal gait groups according to the results from the quantitative gait assessment. Gaits of aged mice were defined as abnormal when the values of quantitative gait parameters were two standard deviations (SD) lower or higher than those of 2-month-old male mice. Gait parameters included stride length, variability of stride length, base of support, cadence, and average speed. After nine months, mice exhibiting severe spatial learning and memory impairment were separated from mice with mild or no cognitive dysfunction. The rate of severe spatial learning and memory impairment in the abnormal and normal gait groups was tested by a chi-square test and the correlation between gait dysfunction and decline in cognitive function was tested using a diagnostic test. RESULTS: The 12-month-old aged mice were divided into a normal gait group (n = 75) and an abnormal gait group (n = 25). Nine months later, three mice in the normal gait group and two mice in the abnormal gait group had died. The remaining mice were subjected to the Morris water maze again, and 17 out of 23 mice in the abnormal gait group had developed severe spatial learning and memory impairment, including six with stride length deficits, 15 with coefficient of variation (CV) in stride length, two with base of support (BOS) deficits, five with cadence dysfunction, and six with average speed deficits. In contrast, only 15 out of 72 mice in the normal gait group developed severe spatial learning and memory impairment. The rate of severe spatial learning and memory impairment was significantly higher in the abnormal gait group as compared to that in the normal gait group (x = 21.986, P < 0.001). All five parameters used to assess gait predicted severe spatial learning and memory impairment in aged mice (P < 0.01). However, the difference of the area under the ROC (receiver operating characteristic) curve for each quantitative gait parameter was not statistically significant. CONCLUSION: Gait disorders are a predictor of severe spatial learning and memory impairment in aged mice, and stride length, variability of stride length, base of support, cadence, and average speed are all sensitive parameters for assessing gait.

[Clinical research of electroacupuncture combined with transperineal injection of BTX-A for neurogenic bladder after spinal cord injury].

OBJECTIVE: To evaluate the clinical efficacy of electroacupuncture (EA) combined with transperineal injection of botulinum toxin-A (BTX-A) on neurogenic bladder caused by spinal cord injury. METHODS: One day af ter surgery, 35 cases of spinal cord injury accompanied with neurogenic bladder were randomly divided into a BTX-A plus EA group (20 cases, group A) and a BTX-A group (15 cases, group B). The two groups were both treated with regular rehabilitation training of bladder function and injection of 200 IU (4 ml) BTX-A through perineum external urethral sphincter; the group A was additionally treated with EA at Zhongji (CV 3), Guanyuan (CV 4), Shenshu (3BL 23), Huiyang (BL 35) and Baliao (Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33), Xialiao (BL 34)), once a day, 40 min per treatment. The treatment was given 6 times per week for 4 weeks. The urination status in two groups before and after treatment was observed, and urodynamics examination and urethral pressure test were also made. RESULTS: After 4-week treatment, mean times of urinary incontinence, mean urethral catheter output, pressure of bladder and volume of urinary incontinence were all improved in two groups (all P<0.05), which were more significant in the group A (all P<0.05). The residual urine, maximum bladder capacity, maximum urethral closure pressure and maximum urine flow rate were all improved in two groups after treatment (all P<0.01); the improvement of residual urine, maximum bladder capacity, maximum urethral closure pressure in the group A was more significant than that in the group B (all P<0.05). CONCLUSION: Electroacupuncture com bined with transperineal injection of BTX-A could effectively improve the urination dysfunction in patients with neurogenic bladder after spinal cord injury.