BACKGROUND:Prolyl hydroxylase domain 2(PHD2)inhibitors can regulate bone metabolism and relieve osteoporosis in ovariectomized rats.cpd17 is a small molecule oral PHD2 inhibitor newly developed by China Pharmaceutical University.It is effective in the treatment of renal anemia with few side effects,but its effect on bone formation and bone resorption is still unclear. OBJECTIVE:To investigate the effects of cpd17 on mouse osteogenic precursor cells. METHODS:Osteogenic precursor cells were treated with cpd17.Alkaline phosphatase activity and extracellular matrix mineralization were measured,and the expression levels of osteogenesis-and osteoclastogenesis-related markers,as well as PHD2 and hypoxia-inducible factor 1α,were detected.After inhibition of the hypoxia-inducible factor 1α pathway using LW6(a hypoxia-inducible factor 1α pathway inhibitor),alkaline phosphatase activity and extracellular matrix mineralization were detected again,as well as the expression levels of osteogenesis-and osteoclastogenesis-related markers,PHD2 and hypoxia-inducible factor 1α. RESULTS AND CONCLUSION:cpd17 significantly enhanced alkaline phosphatase activity and extracellular matrix mineralization,up-regulated the expression of osteogenesis-related markers,down-regulated the expression of osteoclastogenesis-related markers,up-regulated the expression of hypoxia-inducible factor 1α,down-regulate the expression of PHD2.However,cpd17's effects were significantly attenuated by LW6.To conclude,the PHD2 inhibitor cpd17 promotes osteogenic differentiation and inhibits osteoclastic differentiation through activation of the hypoxia-inducible factor 1α signaling pathway.

ObjectiveTo investigate the intervention effects of Suanzaoren Tang on depression model rats induced by isolation combined with chronic unpredictable mild stress （CUMS）， and to examine its influence on the c-Jun N-terminal kinase （JNK）/proto-oncogene protein （c-Myc）/tumor suppressor protein 53 （p53） signaling pathway， thereby revealing its potential functional mechanism. MethodsA total of 72 male SD rats were randomly divided into six groups using a strict random number table： blank group， model group， fluoxetine group （3.6 mg·kg^-1）， and high-， medium-， and low-dose Suanzaoren Tang groups （10， 5， 2.5 g·kg^-1），with 12 rats in each group. A depression model was established using isolation combined with CUMS. Fluoxetine and different doses of Suanzaoren Tang were administered continuously for 28 days. Behavioral indicators such as sucrose water consumption and open field test scores were recorded. Western blot and immunohistochemistry （IHC） were employed to analyze the expression of key proteins in the JNK/c-Myc/p53 signaling pathway， and the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay was used to evaluate the number of apoptotic cells in the hippocampus. ResultsCompared with the blank group， the model group exhibited a significantly reduced sucrose preference index （P<0.01）， a lower total score of horizontal and vertical movements in the open field test （P<0.01）， significantly increased expression of JNK， c-Myc， and p53 proteins in the hippocampus （P<0.01）， and a higher number of TUNEL-positive cells in the hippocampus （P<0.01）. Compared with the model group， the sucrose preference index and the total score of horizontal and vertical movements in the open field test significantly increased in the high- and medium-dose Suanzaoren Tang groups and the fluoxetine group （P<0.05， P<0.01）. The expression of JNK， c-Myc， and p53 proteins significantly decreased in all Suanzaoren Tang groups （high， medium， and low doses） and the fluoxetine group （P<0.05， P<0.01）. The number of TUNEL-positive cells in the hippocampus also significantly decreased in these groups （P<0.01）. ConclusionSuanzaoren Tang can regulate the expression of JNK/c-Myc/p53 proteins in the hippocampus of depression model rats， and its antidepressant mechanism may be related to its protective effect on hippocampal neurons.

Objective To investigate the effects of acute sleep deprivation on the behavior and synaptic protein expression of rats.Methods Seventy healthy male Wistar rats were randomly divided into seven groups,a Control group and sleep deprivation groups(24,48,72,96,120 and 144 hours).The sleep deprivation rat model was established by the modified multiplatform water environment sleep deprivation method.Spatial learning and memory were assessed by the Morris water maze.Anxiety was assessed by the open field test.The morphology and quantity of hippocampal neurons were observed by Nissl staining.Western blot and Real-time PCR were used to determine the expression of synaptophysin(SYN),post-synaptic density protein-95(PSD-95),and brain-derived neurotrophic factor(BDNF)in rats.Results Compared with the Control group,the numbers of standing and modification were significantly increased by prolongation of the sleep deprivation time(P＜0.05).The escape latency and path length were significantly increased in 120 and 144 h groups(P＜0.05),whereas the number of platform crossings and the percentage of the target quadrant time were significantly decreased(P＜0.01)and negatively correlated to the sleep deprivation time.The expression levels of BDNF,SYN,and PSD-95 were significantly decreased with the prolongation of sleep deprivation time(P＜0.01).Conclusions With the increase in sleep deprivation time,cognitive dysfunction and anxiety gradually deteriorated,which may be related to decreases in the expression of synaptic biomarkers.

Objective:To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS.Methods:The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects.Results:At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] ( P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m 2] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) ( P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions:Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.

Objective To investigate the effects of abdominal massage combined with electroacupuncture point-through-point method on the expressions of circadian clock genes of Clock,BMAL1,PER1 and neurotransmitters contents of ACh and Glu in insomnia rats and its possible mechanism.Methods Totally 50 SD male rats were randomly divided into normal group,model group,abdominal massage group,electroacupuncture point-through-point group and combination group,with 10 rats in each group.Except for the normal group,an insomnia rat model was established by intraperitoneal injection of p-chlorophenylalanine.Abdominal massage group received abdominal massage;electroacupuncture point-through-point group was treated with flat acupuncture,"Baihui"through"Shenting","Sanyinjiao"through"Yinlingquan"(bilateral),"Shenmen"through"Neiguan"(bilateral),the electroacupuncture instrument dilatational wave,frequency of 1 Hz/20 Hz was connected;the combination group was treated with electroacupuncture through acupoints after abdominal massage;1 time/d for each treatment group,a total of 7 days.The normal group and model group were not intervened.HE staining was used to observe the pathological changes of neurons in hypothalamic tissue,the expression of Clock,BMAL1 and PER1 mRNA were detected by RT-qPCR,the expressions of Clock,BMAL1 and PER1 in hypothalamic tissue were detected by immunohistochemical staining,the expression of Clock,BMAL1 and PER1 protein in hypothalamic tissue were detected by Western blot,the contents of ACh and Glu in serum were detected by ELISA.Results Compared with the normal group,the model group rats had a longer sleep latency,shorter sleep duration,severe damage to the cellular structure of the hypothalamic tissue,and a vacuolar like change,with a decrease in the number of neuronal cells,the expressions of Clock and BMAL1 mRNA and protein in hypothalamic tissue increased,while the expressions of PER1 mRNA and protein decreased;the contents of serum ACh and Glu increased,with statistical significance(P<0.05).Compared with the model group,the abdominal massage group,electroacupuncture point-through-point group,and combination group could all shorten the sleep latency,prolong sleep duration,and improve the morphology of hypothalamic neurons,reduce the expressions of Clock and BMAL1 mRNA and protein in hypothalamic tissue,up-regulate the expressions of PER1 mRNA and protein,and reduce the contents of serum ACh and Glu,with statistical significance(P<0.05),the combination group showed the most obvious effects(P<0.05).Conclusion Abdominal massage combined with electroacupuncture point-through-point method can improve insomnia.Its mechanism may be related to the regulation of circadian clock genes Clock,BMAL1,PER1 mRNA and protein expression,as well as neurotransmitter content.

Objective To explore the funding situation and hot research directions of NSFC(National Natural Science Foundation of China)projects in the discipline of acupoints and meridians from 1991 to 2022;To provide reference for this discipline to apply for the NSFC.Methods National Natural Science Foundation of China was login in to query website.The acupoints and meridians discipline project from 1991 to 2022 were retrieved.The project leader,project name,supporting unit,province,funding category,funding amount,keywords and other information were extracted.The data were input to Excel 2023 to establish a database,and descriptive analysis of project funding situation was performed.Target keywords were extracted,and the word table was classified and uploaded to the micro-word cloud online to draw the word cloud map to analyze the research hotspots.Results From 1991 to 2022,the number of projects funded by the NSFC for acupoints and meridians was 173.The funding category was mainly general projects,and the supporting units were mainly TCM colleges and universities and scientific research institutions.The main research directions were meridian essence,acupoint-viscera/body related effects and mechanism of action,and the signal molecules and related pathways were the entry points.Conclusion From 1991 to 2022,the NSFC-funded acupoints and meridians disciplines are mainly based on general projects,mainly concentrated in scientific research institutions and TCM colleges and universities,with uneven regional distribution.The essence of meridians and collaterals,acupoints-viscera/body-related effects and mechanisms(mechanisms)are the key research directions.

In recent years， NOD-like receptor protein 3 （NLRP3） inflammasome in tumors has become a research hotspot， especially in melanoma， colorectal cancer， lung cancer， and breast cancer， and more and more evidence has shown that inflammation plays a role in the development， progression， angiogenesis， and invasion of cancer. Hepatocellular carcinoma （HCC） is the most common type of primary liver cancer， and there are still controversies over the role of NLRP3 inflammasome in the development and progression of HCC. Therefore， this article reviews the potential impact of NLRP3 inflammasome in the progression of HCC and its mechanism of action in anticancer therapy， and it is believed that NLRP3 inflammasome can be used as an effective therapeutic target for HCC patients.

Objective To research the procedure for creating an animal model of mitral regurgitation by implanting a device through the apical artificial chordae tendineae, and to assess the stability and dependability of the device. Methods Twelve large white swines were employed in the experiments. Through a tiny hole in the apex of the heart, the artificial chordae tendineae of the mitral valve was inserted under the guidance of transcardiac ultrasonography. Before, immediately after, and one and three months after surgery, cardiac ultrasonography signs were noted. Results All models were successfully established. During the operation and the follow-up, no swines died. Immediately after surgery, the mitral valve experienced moderate regurgitation. Compared with preoperation, there was a variable increase in the amount of regurgitation and the values of heart diameters at a 3-month follow-up (P<0.05). Conclusion In off-pump, the technique of pulling the mitral valve leaflets with chordae tendineae implanted transapically under ultrasound guidance can stably and consistently create an animal model of mitral regurgitation.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

OBJECTIVE To analyze the clinical characteristics of nephrotic syndrome induced by sunitinib， and to provide reference for clinical rational drug use. METHODS Retrieved from CNKI， VIP， Wanfang data， PubMed， Web of Science and Medline， case report about sunitinib-induced nephrotic syndrome were collected from the inception to Oct. 30th， 2022. Those case reports were analyzed statistically in terms of gender， age， primary disease， drug use， clinical manifestations， treatment and outcome. RESULTS A total of 15 pieces of literature were collected and 17 patients were involved， including 10 males and 7 females. The average age of patients was （59.35±15.72） years. Among 17 patients， there were 10 patients with renal cell carcinoma and 7 patients with gastrointestinal stromal tumor， all of whom received evidence-based medication； the dosage of sunitinib in 15 cases was recorded， and all of them were within the recommended range of the instructions； 9 patients received combined therapy； the time from sunitinib application to the occurrence of nephrotic syndrome was 21 days-52 months， of which 11 cases were ≤2 years. The clinical manifestations in 13 patients were described， including edema， oliguria， foamy urine， weight gain， fatigue， dyspnea on exertion， etc. Eight patients had other adverse reactions induced by sunitinib before suffering from nephrotic syndrome， including new hypertension or worsening of original hypertension， and hand-foot syndrome. Renal biopsy mainly manifested as thrombotic microangiopathy， focal segmental glomerular sclerosis and immune complex glomerulonephritis. Sunitinib withdrawal or dosage reduction was adopted in all patients， and they were given symptomatic treatment such as glucocorticoids and antihypertensive agents. Symptoms of 16 patients were improved， and renal function of one patient deteriorated and hemodialysis was started. Sunitinib was re-challenged in 6 patients， elevated creatinine and substantial proteinuria recurred in 5 patients. CONCLUSIONS In clinical use of sunitinib， it is advisable to periodically monitor renal function. In case of deterioration of renal function， albuminuria， edema， etc.， relevant examinations should be implemented in time， and symptomatic intervention should be taken as soon as possible. Besides， we should be alert to the recurrence of nephrotic syndrome after sunitinib rechallenge.