Effectiveness and mechanism of action of rTMS combined with quadriceps strength training in individuals with knee osteoarthritis: study protocol for a randomized controlled trial.

BACKGROUND: Quadriceps training is necessary in function and activity of daily living for patients with knee osteoarthritis (KOA). However, it did not reduce the rate of surgical treatment for end-stage KOA in the long term. This may be related to brain structure changes and maladaptive plasticity in KOA patients. Transcranial Magnetic Stimulation (TMS) could enhance the functional connectivity of brain regions and improves maladaptive plasticity. However, the synergistic effect of the combination of the two for treat KOA is still unclear. Therefore, the purpose of this study is to investigate whether the High-Frequency rTMS combined with quadriceps strength training can improve the pain and function in KOA more effectively than quadriceps training alone and explore the mechanism of action. METHODS: This study is an assessor-blind, sham-controlled, randomized controlled trial involving 12 weeks of intervention and 6 months follow-up. 148 participants with KOA will receive usual care management and be randomized into four subgroups equally, including quadriceps strength training, high-frequency rTMS training, sham rTMS and quadriceps strength training, high-frequency rTMS and quadriceps strength training. The rehabilitation interventions will be carried out 5 days per week for a total of 12 weeks. All outcomes will be measured at baseline, 4 weeks, 8 weeks, and 12 weeks during the intervention and 1 month, 3 months and 6 months during the follow-up period. The effectiveness outcomes will be included visual analog scale, isokinetic knee muscle strength, Knee Injury and Osteoarthritis Outcome score and 36-Item Short-Form Health Survey score; The act mechanism outcomes will be included motor evoked potential, grey matter density, white matter, subcortical nuclei volumes, cortical thickness and functional connectivity by MRI. Two-way of variance with repeated measures will be used to test the group and time effect for outcome measures. DISCUSSION: The study will be the first protocol to examine whether there are synergistic effects following high-frequency rTMS combined with quadriceps strength training for treat KOA and clarify the mechanism of action. High-frequency rTMS can be added into the training program for KOA patients if it is proven effective. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300067617. Registered on Jan.13,2023.

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction / 神经科学通报·英文版

Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca

Study on Periplaneta americana Polypeptide PAE2 in Reversing Multidrug Resistance for Liver Cancer / 中国实验方剂学杂志

Objective:To investigate the effect and mechanism of PAE₂， a polypeptide of <italic>Periplaneta americana， </italic>in reversing multidrug resistance （MDR） for liver cancer <italic>in vivo</italic>. Method:Balb/c-nude mice were inoculated with HepG2 and HepG2/ADM cells under the armpits to establish animal models of liver cancer sensitive strains and animal models of MDR respectively. After successful modeling， the nude mice were randomly divided into normal group， HepG2 model group， HepG2/ADM model group， sorafenib group （positive drug control group， <italic>ig</italic> 30 mg·kg^-1）， HepG2/ADM+PAE₂ （<italic>iv</italic>） low， medium and high dose groups （50， 100， 200 mg·kg^-1）， HepG2/ADM+PAE₂ （<italic>ig</italic>） low， medium， and high dose groups （50， 100， 200 mg·kg^-1）， skim cream group （<italic>ig</italic> 200 mg·kg^-1）， and CⅡ-3 group （<italic>ig</italic> 200 mg·kg^-1）， all of which received corresponding drug treatment. The body weight and tumor volume of nude mice were measured and recorded every 2 days. The next day after the last administration， tumor tissues of nude mice were taken to record the tumor weight. The effect of <italic>P. americana </italic>polypeptide PAE₂ on permeability-glycoprotein（P-gp）， lung resistance protein（LRP） ， breast cancer resistance protein（BCRP）， protein kinase C（PKC）， glutathione S-transferase-π（GST-π）， topo-isomerase typeⅡ（ToPoⅡ）， multidurg resistance gene 1（MDR1）and Multidrug resistance-associated proteins（MRP1） of the protein level and gene level expression in tumor tissues were determined by immunohistochemistry （IHC） and real-time quantitative polymerase chain reaction （Real-time PCR）. In addition， both oral and intravenous administration groups were set up at the same time for preliminary study on the basic pharmacokinetic characteristics of <italic>P. americana </italic>polypeptide PAE₂. Result:After the successful modeling， the body weight of the nude mice was significantly lower than that in the normal mice（<italic>P</italic><0.05）. After treatment with corresponding drugs， the body weight increased to a certain extent， but it was still not as good as the normal nude mice. In <italic>iv</italic> administration， the medium-dose <italic>P. americana </italic>polypeptide PAE₂ showed the best anti-tumor effect as compared with the model group （<italic>P</italic><0.05）， while in oral administration， the anti-effect increased with the increase of the dose， so the high-dose group showed the best effect （<italic>P</italic><0.05）. Preliminary crude extract CII-3 had no obvious anti-tumor effect， and skim cream showed a certain anti-tumor effect （<italic>P</italic><0.05）. <italic>P. americana </italic>polypeptide PAE₂ had certain effects on MDR related proteins and enzymes<italic> in vivo</italic>， mainly by inhibiting the expression of LRP and BCRP in tumor tissues and affecting the expression of these related proteins and genes to different degrees to inhibit intracellular drugs outflow， thereby promoting tumor apoptosis， and the effect was superior to that of the <italic>P. americana</italic> crude extract CⅡ-3 and skim cream. Conclusion:<italic>P. americana</italic> polypeptide PAE₂ may reduce the drug efflux， promote intracellular drug accumulation and apoptosis by affecting the expression of related proteins and enzymes that mediate multidrug resistance， thereby exerting a reverse effect on HepG2/ADM cells Balb/c MDR in nude mice.

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction / 神经科学通报·英文版

Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca

Astrocytic GABA Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF / 神经科学通报·英文版

Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA receptors (GABARs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABARs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABARs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABAR-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABARs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABARs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.

Macromolecular crowding agents for the extracellular matrix: mechanisms and unfavorable factors to be comfirmed / 中国组织工程研究

BACKGROUND:Macromolecule crowding agents exert a certain effect on collagen,glycosaminoglycans and growth factors in the extracellular matrix.OBJECTIVE:To summarize the effects of macromolecule crowding agents on the extracellular matrix and their applications in various cells or tissues.METHODS:"Macromolecular crowding,MMC,Tissue Engineering,Collagen" were used as key words to retrieve articles addressing the application of macromolecular crowding agents in the extracellular matrix and in the tissue engineering in PubMed,NCBI,CNKI from 2001 to 2017.RESULTS AND CONCLUSION:Macromolecule crowding agents can increase the deposition of extracellular matrix components,such as collagen,glycosaminoglycans and growth factors,to promote osteoblast adhesion,migration,growth and differentiation,as well as to promote the development of regenerative medicine in bone tissue engineering.However,some roles and mechanisms of macromolecule crowding agents have yet to be found or confirmed,and whether they can produce toxic effects in the human body has yet to be confirmed.Therefo further experimental research on these problems is warranted.