Mechanism of Hedysari Radix Polysaccharide on Diabetic Nephropathy in db/db Mice Based on JAK2/STAT3 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of Hedysari Radix polysaccharide （HRP） on the Janus kinase 2 （JAK2）/signal transducer and activator of transcription protein 3 （STAT3） signaling pathway in diabetic nephropathy db/db mice. MethodFifty db/db mice were randomly divided into model group， irbesartan group （irbesartan suspension， 22.75 mg·kg-1）， and high-， medium-， and low-dose HRP groups （HRP suspension， 200， 100， 50 mg·kg-1） according to the body weight， with 10 mice in each group. Another 10 C57BL/6 mice were assigned to the normal group. The mice were treated with corresponding drugs by gavage， while those in the normal group and the model group received distilled water at 5 mL·kg-1. The mice in the six groups were administered once a day by gavage for 12 consecutive weeks. The uric acid （UA）， triglycerides （TG）， and total cholesterol （TC） were detected. Periodic acid-Schiff （PAS） staining and Masson staining were used to observe the pathological changes in kidney tissues. Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） were used to detect the protein and mRNA expression levels of JAK2， STAT3， suppressor of cytokine signaling 3 （SOCS3）， and tumor necrosis factor-α （TNF-α） in the kidney. ResultAfter 12 weeks of treatment， compared with the normal group， the model group showed significant pathological ultrastructural changes in kidney tissues and increased UA， TG， and TC levels （P<0.01）. Compared with the model group， the high- and medium-dose HRP groups and the irbesartan group showed improvement in pathological ultrastructure of kidney tissues and reduced UA， TG， and TC levels （P<0.05， P<0.01）. Compared with the normal group， the model group showed a decrease in SOCS3 protein and mRNA expression levels and an increase in JAK2， STAT3， and TNF-α protein and mRNA expression levels （P<0.01）. Compared with the model group， the high- and medium-dose HRP groups and the irbesartan group showed an increase in SOCS3 protein and mRNA expression levels and a decrease in JAK2， STAT3， and TNF-α protein and mRNA expression levels （P<0.05， P<0.01）. ConclusionHRP can alleviate renal damage in diabetic nephropathy to a certain extent， and its mechanism may be related to the inhibition of the activation of the JAK2/STAT3 signaling pathway.

Mechanism of Fructus Lycii against dry eye: an analysis based on network pharmacology and experimental verification / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the mechanism of fructus lycii in treating dry eye based on network pharmacology and experimental verification.METHODS: Taking “fructus lycii” as key words, the active ingredients and target of fructus lycii were searched by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Gene targets related to dry eye(DE)were searched by GeneCards and OMIM databases. The target genes of fructus lycii and DE were imported into Venn software to obtain the intersection target map of them. After that, the data were imported into the String database to obtain the PPI protein-protein interaction network diagram. Using Cytoscape3.7.2 software, the PPI protein-protein interaction network diagram was constructed for active ingredients, target sites and related diseases of fructus lycii. The Bioconductor platform and R language were used for gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis. And the key targets in the pathogenesis of DE were verified by experiments.RESULTS: Through TCMSP, 45 types of effective chemical components of fructus lycii, 174 target genes corresponding to active components and 131 common target genes with DE were screenedout. In accordance with the network topology of “drug-composition-disease-target”, 27 main effective components of fructus lycii were found in the treatment of DE. The PPI network was analyzed according to the high degree value, which is the key targets of fructus lycii for DE treatment, mainly including AKT1, VEGFA, CASP3, IL1B, JUN, PTGS2, CXCL8, etc. According to GO enrichment analysis, 166 biological functions and processes of fructus lycii for DE treatment were obtained. KEGG enrichment analysis showed that 31 signaling pathways were involved. Additionally, experimental verification displayed that the protein expressions of AKT1, interleukin-6(IL-6), tumor necrosis factor(TNF-α)and IL-17 in conjunctiva tissue of the DE model group were significantly increased.CONCLUSIONS: Through network pharmacology, this study confirmed that the treatment of DE by fructus lycii is a complex process involving multi-components, multi-targets and multi-pathways, and that the treatment of DE by fructus lycii is mainly regulated by anti-inflammatory and apoptosis-related molecules.

Effect of histone H4 on polarization of alveolar macrophages in mice with acute respiratory distress syndrome / 中国职业医学

Objective To investigate the role of histone H4 in the polarization of alveolar macrophages (AM) in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) in mice. Methods i) The specific pathogen free male C57BL/6 mice were randomly divided into control group and 2, 4, 6 and 8 mg/kg LPS groups, with six mice in each group. The mice in the LPS groups were intratracheally administered LPS according to their respective doses, while the mice in the control group received an equivalent volume of 0.9% saline. After 12 hours, the arterial blood gas was analyzed, and the pulmonary edema and histopathological changes in lung tissues of mice in each group were observed. The level of histone H4 in bronchoalveolar lavage fluid (BALF) of mice was detected using enzyme-linked immunosorbent assay , and mice AMs of the five group were isolated using adherent method. ii) AMs from normal mice were isolated using adherent method and randomly divided into control group, histone H4 injury group, BALF injury group and anti-histone H4 antibody (anti-H4) intervention group. In the histone H4 injury group, AMs were treated with histone H4 at a final concentration of 20 mg/L. In the BALF injury group and anti-H4 intervention group, AMs were treated with 200 μL BALF supernatant from mice intratracheally administered 6 mg/kg body weight LPS, with the latter group treated with 25 mg/L anti-H4 antibody. The control group AMs were treated with phosphate-buffered saline. iii) After 12 hours of stimulation, the cells were collected, and the relative expression of tumor necrosis factor-α (Tnfa), interleukin-1β (Il1b), differentiation antigen 206 (Cd206) and arginase 1 (Arg1) in AMs was detected using real-time quantitative polymerase chain reaction. Results i) Compared with the control group, mice in all four LPS groups exhibited rapid breathing, inflammatory reaction and lung edema in lung tissues, which were aggravated in a dose-dependent manner. The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen in mice decreased with the increase of LPS dose (P<0.05). The wet/dry weight ratio of lung, the level of histone H4 in BALF and the relative expression of Tnfa and Il1b mRNA in AMs increased with the increase of LPS dose (all P<0.05). The mice in the 6 and 8 mg/kg LPS groups developed ARDS. The level of histone H4 in BALF and the relative expression of Tnfa and Il1b mRNA in AMs of mice in 6 and 8 mg/kg LPS groups were higher than those in the other three groups (all P<0.05). ii) The relative expression of Tnfa and Il1b mRNA increased (both P<0.05), and the relative expression of Cd206 and Arg1 mRNA decreased (both P<0.05) in AMs of histone H4 injury group and BALF injury group compared with the control group. Compared with BALF injury group, the relative mRNA expression of Tnfa and Il1b in AMs of anti-H4 intervention group decreased (both P<0.05), while the relative expression of Arg1 mRNA increased (P<0.05). Conclusion LPS can induce a dose-dependent increase in histone H4 levels in BALF in mice. Histone H4 drives the development of ARDS by activating AMs to M1 polarization. Antagonizing histone H4 to interfere with AM polarization to M1 could be a target for the treatment of ARDS.

Literature analysis of drug-induced autoimmune hepatitis induced by tumor necrosis factor-α inhibitor / 中国药房

OBJECTIVE To analyze the characteristics of drug-induced autoimmune hepatitis （DIAIH） induced by tumor necrosis factor-α inhibitor （TNFi）， and to provide reference for clinical drug treatment. METHODS Retrieved from PubMed， Embase， China Academic Journal full-text Database， VIP and Wanfang database， the case reports of TNFi-induced DIAIH were collected to conduct descriptive analysis. RESULTS A total of 33 case reports involving 44 patients were collected， including 31 females and 13 males， with an average age of （41.14±2.20） years old， mostly aged 30 to 60 years （77.27%）. The primary diseases were Crohn disease （CD）， ulcerative colitis （UC） and rheumatoid arthritis （RA） （68.18%）. Of the 44 patients， 35 were treated with infliximab （IFX）， 7 with adalimumab， and 2 with etanercept. The dosage of 37 patients was within the scope of the instructions， and 31 received other drugs additionally； DIAIH mainly occurred ≤24 weeks after medication （68.18%）； 21 patients （47.73%） had no clinical manifestations； alanine aminotransferase and aspartate aminotransferase were abnormally elevated in all patients； anti-nuclear antibodies were positive in 38 patients. Except for 3 patients who required liver transplantation， all the other patients improved after drug withdrawal and/or symptomatic treatment such as glucocorticoid therapy. CONCLUSIONS TNFi- induced DIAIH is more common in female patients and can occur with conventional doses， with significant differences in occurrence time. However， the intervention measures are basically the same for DIAIH induced by different types of TNFi. Clinical use of TNFi， especially the use of IFX， requires close attention to the clinical manifestations， liver function and autoantibody level， and a detailed evaluation should be conducted to detect DIAIH as soon as possible. If liver function continues to not improve， it is necessary to stop taking medicine as soon as possible and receive symptomatic treatment to avoid developing acute or severe DIAIH or liver failure.

Effect of Zhuangyao Tongluo Formula（壮腰通络方） Containing Serum on TNF-α-mediated Vicious Circle of Pyroptosis of Nucleus Pulposus Cells / 中医杂志

ObjectiveTo explore the mechanism of Zhuangyao Tongluo Formula（壮腰通络方，ZTF） in delaying intervertebral disc degeneration. MethodsM1 macrophages were induced from THP-1 cells using LPS， IFN-γ and PMA. The induced M1 macrophages were then co-cultured with nucleus pulposus cells in a transwell system. Fetal bovine serum was used as the control serum， and the effects of different concentrations （5%， 10%， 15%， 20%） of serum from rats treated with ZTF on the activity of M1 macrophages and nucleus pulposus cells were analyzed using MTT assay. Experiment 1 was established， including the nucleus pulposus cell control group， M1 macrophage control group， nucleus pulposus cell + ZTF group， nucleus pulposus cell + TNF control group， nucleus pulposus cell + TNF + ZTF group， co-culture group， and co-culture + ZTF group. The levels of IL-1β， and IL-18 in the culture supernatant were detected using ELISA. The mRNA expression of IL-1β and IL-18 in nucleus pulposus cells was detected using qPCR. Additionally， the expression of GSDMD protein in nucleus pulposus cells was detected using cell immunofluorescence. In experiment 2， co-culture groups were constructed using TNF-α overexpression （OE） or empty vector （EV） plasmids， including co-culture group， TNF-EV + co-culture group， TNF-EV co-culture group + ZTF， co-culture + ZTF group， TNF-OE co-culture group + ZTF， and TNF-OE + co-culture group. The mRNA and protein expression of TNF-α in M1 cells in each group were detected using qPCR and WB. ResultsThe ZTF with 10% serum was selected for subsequent experiments. The results of experiment 1 showed that compared to the control group of nucleus pulposus cells， there was no statistically significant difference in the levels of IL-1β， IL-18， mRNA， and GSDMD expression in the nucleus pulposus cells + ZTF group （P＞0.05）. However， the TNF-α + co-culture group showed a significant increase in IL-1β， IL-18 levels， mRNA， and GSDMD expression （P＜0.01）. When compared to the co-culture group， the ZTF+ co-culture group showed a significant decrease in IL-1β， IL-18 levels， mRNA， and GSDMD expression （P＜0.01）. The results of experiment 2 showed that there was no statistically significant difference in TNF-α mRNA and protein expression between the empty vector plasmids + co-culture group and the co-culture group （P＞0.05）. Compared to the empty vector + co-culture group， the expression of TNF-α mRNA and protein was significantly reduced in the empty vector co-culture + ZTF group （P＜0.01）. Compared to the co-culture group and the empty vector + co-culture group， the expression of TNF-α mRNA and protein was significantly reduced in the co-culture + ZTF group （P＜0.01）. Compared to the co-culture + ZTF group， the expression of TNF-α mRNA and protein significantly increased in the overexpression vector co-culture + ZTF group （P＜0.01）. Compared to the overexpression vector co-culture + ZTF group， the expression of TNF-α mRNA and protein significantly increased in the overexpression vector co-culture group （P＜0.01）. ConclusionZTF serum can inhibit the TNF-α-induced apoptosis of nucleus pulposus cells and delay lumbar disc degeneration by reducing the expression of TNF-α in M1 macrophages.

The protective effect of inhibiting CD47 expression on radiation-induced lung injury / 中华放射肿瘤学杂志

Objective:To study the protective anti-radiation effect of inhibiting CD47 expression in the lung tissues of mice and to explore the associated mechanism.Methods:Female C57BL/6 mice ( n = 60) were randomly divided into four groups: normal, blank, negative and positive. The blank group received only whole-lung irradiation; The negative group received whole-lung irradiation and tracheal infusion of adeno-associated virus containing nonsense sequence shRNA; The positive group received whole lung irradiation and tracheal drip containing adeno-associated virus containing shRNA expression of CD47. Fresh blood samples were collected at 24 h, 4 weeks, and 12 weeks post-irradiation, respectively. The expression level of CD47 mRNA was determined by RT-PCR. Determination of hydroxyproline content by alkaline hydrolysis. The LC3 expression level was measured by immunohistochemical staining. Serum transforming growth factor-β 1 (TGF-β 1) and tumor necrosis factor-α (TNF-α) levels were assessed by ELISA. Results:RT-PCR showed that the relative expression level of CD47 mRNA in the lung tissues in the positive group was significantly lower compared to those in the negative group, the normal group, the blank group (24-hour, P were <0.001,<0.001,<0.001, respectively. 4-weeks, P were <0.001,0.003,0.001, respectively. 12-weeks, P were 0.009, 0.002, 0.005, respectively). There were no significant differences in CD47 mRNA expression in the three groups except the positive group (all P>0.05), and there was no significant difference in CD47 mRNA expression with time in each group (all P>0.05).The serum TGF-β1 content was higher in the 24 h, 4-week, and 12-week blank groups ( P were <0.001, 0.003 and 0.003, respectively) and negative groups( P were 0.001, 0.021 and 0.034, respectively) after irradiation than that in the mice in the normal group. At the same time, the serum TNF-α of positive group after irradiation (24 hours, 4 weeks, 12 weeks, P were 0.022, <0.001, <0.001, respectively) were significantly higher than those of the normal group. The content of hydroxyproline in the blank group was significantly higher than that in the normal group (4 weeks, 12 weeks, P were 0.002, <0.001, respectively). Immunohistochemical indications: 24 h after irradiation was higher than the expression of LC3 in mouse lung tissue at 4 weeks and 12 weeks (all P < 0.001). The difference between the negative group and the blank group was not obvious ( P>0.05). Conclusions:Inhibition of CD47 expression can reduce the degree of radiation-induced pneumonia and pulmonary fibrosis probably via enhanced autophagy. CD47 may represent a novel target for the protection of radiation-induced lung injury.

The value of baseline Doppler ultrasonography in the prediction of treatment response with recombinant human tumor necrosis factor-α receptor Ⅱ immunoglobulin G Fc fusion protein in patients with ankylosing spondylitis / 中华风湿病学杂志

Objective:To predict the inflammatory activity of patients with ankylosing spondylitis (AS) after 12 weeks treatment with recombinant human tumor necrosis factor-α receptor Ⅱ immunoglobulinG Fc fusion protein (rhTNFR:Fc) by Doppler ultrasonography at baseline.Methods:A total of 60 patients with AS were selected, and their general clinical characteristics before and after treatment were compared. Meanwhile, Doppler ultrasonography of the sacroiliac joint was performed to compare the Doppler parameters before and after treatment, and the correlation between baseline Doppler ultrasonography and clinical characteristics was analyzed, along with its diagnostic performance. The pre-treatment and post-treatment parameters were compared to the measured data followed by paired t-test for normal distribution, and the counting data were paired with Chi- square test. Pearson correlation test was used to analyze the correlation between pretreatment ultrasound parameters and pre-treatment disease activity. All statistical tests were bilateral, with a statistically significant difference of P<0.05. Results:After treatment, the overall score [(1.4±1.0) points vs (6.0±1.8) points, t=17.80, P<0.001], night pain score [(1.6±1.2) points vs (5.7±1.5) points, t=15.80, P<0.001], back pain score [(1.9±1.3) points vs (5.5±1.2) points, t=16.39, P<0.001], morning stiffness [(12±6) min vs (38±21) min points, t=8.93, P<0.001], Bath ankylosing spondylitis disease activity index (BASDAI) [(1.1±0.6) vs (4.6±1.3), t=12.41, P<0.001], ankylosing spondylitis disease activity score-C-reactive protein (ASDAS-CRP) [(1.0±0.4) points vs (3.7±0.9) points, t=22.01, P<0.001] and ASDAS-erythrocyte sedimentation rate (ESR) [(1.0±0.7) points vs (4.0±0.8) points, t=20.10, P<0.001] of patients with ankylosing spondylitis were lower than those before treatment, and the differences were statistically significant ( P<0.001). Compared with AS patients before treatment, the color blood flow grading score was significantly lower after treatment [(1.7±0.8) points vs (3.9±1.1) points, t= 12.86, P<0.001). The post-treatment proportion of AS patients with bilateral sacroiliac joint blood flow signal was 67% (40/60), which was lower than 87% (52/60) before treatment, but the difference was not statistically significant ( P=0.251). After treatment, the peak systolic velocity (PSV), pulsatile index (PI) and resistance index (RI) were significantly higher than those before treatment [(30±17) cm/s vs (19±8) cm/s, t=-5.42, P<0.001; (1.55±0.69) vs (1.00±0.45), t=0.45, P<0.001; (0.81±0.11) vs (0.55±0.14), t=11.20, P<0.001)]. The end diastolic velocity (EDV) before and after treatment had no statistical significant differences [(6.7±2.5) cm/s vs (6.3±1.9) cm/s, t=0.80, P=0.428]. Baseline Doppler ultrasound parameters and pre-treatment clinical indicators showed that PI and RI were negatively correlated with BASDAI ( r=-0.49, P=0.005; r=-0.51, P<0.001) , and blood flow grades were positively correlated with BASDAI ( r=0.46, P=0.028). However, there were no significant correlation between PSV, EDV and BASDAI ( r=-0.12, P=0.176; r=0.03, P=0.756). Baseline Doppler ultrasound parameters were correlated with ASDAS-CRP ( r=-0.45, P=0.012; r=0.29, P<0.048; r=-0.52, P<0.035; r=-0.76, P<0.001; r=0.61, P<0.001). There was no correlation between EDV and ASDAS-ESR ( r=0.30, P=0.110), the other ultrasound Doppler parameters were correlated with ASDAS-ESR ( r=-0.36, P<0.001; r=-0.54, P<0.001; r=-0.61, P=0.021; r=0.41, P=0.028). The receiver operating characteristic curve was drawn with the baseline RI value as a variable. According to the ASDAS-CRP value, the diagnostic threshold for determining the presence or absence of AS activity after 12 weeks of treatment was 0.49, with an area under the curve of 0.817, sensitivity of 88.1%, specificity of 61.1%, positive predictive value of 66.7%, and negative predictive value of 86.1%. Conclusion:Baseline Doppler ultrasound correlates well with clinical indicators, among which baseline RI values is a good predictor of inflammatory activity status after rhTNFR:Fc treatment.

Application of continuing nursing care based on Wechat platform in patients with psoriasis by injecting tumor necrosis factor-α antagonist at home / 中国实用护理杂志

Objective:To observe the effect of continuous nursing care based on Wechat platform on the drug safety and compliance in patients with psoriasis at home injection of tumor necrosis factor α (TNF-α) antagonists, so as to provide guidance for patients to use biological agents safely and effectively at home.Methods:A total of 86 patients with moderate to severe psoriasis who were discharged from Dalian Dermatology Hospital from January to December 2020, injected with TNF-α antagonist at home were selected as the study subjects. They were divided into control group and observation group by random digits table method with 43 cases in each group. The control group received routine injection guidance and telephone follow-up; the observation group used continuous nursing care based on Wechat platform on the basis of the control group. Three months after discharge, the medication compliance of the two groups was evaluated by Morisky Medication Adherence Scale-8 (MMAS-8). Before discharge and three months after discharge, the efficacy of the two groups was evaluated by psoriasis area and severity index (PASI). One month after discharge, the adverse reactions of the two groups were counted.Results:The MMAS-8 score was 7.26 ± 1.28 in the observation group and 5.13 ± 1.42 in the control group three months after discharge, the difference was statistically significant ( t = 7.31, P<0.01). There was no significant difference in PASI score between the two groups before discharge ( P>0.05). Three months after discharge, the PASI score was 2.69 ± 1.45 in the observation group and 5.74 ± 1.32 in the control group, the difference was statistically significant ( t = 10.12, P<0.01). The total effective rate was 97.67% (42/43) in the observation group and 93.02% (40/43) in the control group, the difference was statistically significant ( χ2 = 2.35, P<0.05). The incidence of adverse reactions was 6.98% (3/43) in the observation group and 18.60% (8/43) in the control group, the difference was statistically significant ( χ2 = 6.05, P<0.05). Conclusions:In the treatment of patients with psoriasis who inject TNF-α antagonists at home, supplemented with continuous nursing based on Wechat platform can effectively reduce adverse reactions, improve their medication compliance, and improve the safety of home injections Sexuality and effectiveness.

Combination of CD47-based nanoparticles and αPD-L1 for antitumor immunotherapy / 国际生物医学工程杂志

Objective:To investigate the therapeutic efficacy of the combination therapy with CD47-based nanoparticles and anti-PD-L1 monoclonal antibody (αPD-L1) for preventing tumor recurrence and metastasis in vivo.Methods:BALB/c mice were used to construct 4T1 tumor-bearing mouse models. The mouse model was treated with the combination therapy to analyze the effects on local tumor recurrence, tumor growth volume, survival time and lung metastasis in the 4T1 mammary tumor-bearing mouse model.Results:The combination therapy could effectively inhibit local tumor recurrence and prolong the survival time of tumor-bearing mice ( P<0.001). Compared with the αPD-L1 group, the combination therapy can increase the expression of cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mouse serum (all P<0.05) and effector memory T cells in mouse spleen ( P<0.001). In addition, the results on the 4T1-Luc mammary tumor-bearing mouse lung metastasis model showed that the combination therapy could effectively inhibit tumor lung metastasis. Conclusions:The results strongly suggested that combination therapy with CD47-based nanoparticles and αPD-L1 can effectively elicit the memory immune response, and prevent tumor recurrence and lung metastasis.

Effects of traditional Chinese Songchi ointment combined with treadmill training on PI3K/Akt/mTOR signal pathway and inflammation in rats with disused muscles atrophy / 中华物理医学与康复杂志

Objective:To observe any effect of supplementing treadmill training with applications of the traditional Chinese Songchi ointment in the rehabilitation of gastrocnemius muscles atrophied through disuse.Methods:Forty-five Wistar rats were randomly divided into a normal control group ( n=8) and a model group ( n=37). The rats in the model group had their left hind limbs immobilized by the Nagai method to induce disused muscle atrophy (DMA). That group was then randomly subdivided into a model control (MC) group, a treadmill training group (the EX group), a Songchi ointment group (SC group) and a comprehensive rehabilitation group (the CR group), each of 8. The EX and SC groups were given treadmill training at 18m/min or topical application of Songchi ointment once a day, 6 days a week for 6 weeks. The CR group was given both treatments. After the 6 weeks, hematoxylin and eosin staining was used to evaluate the pathological changes in the gastrocnemius of each rat′s left hind limb. Serum levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) were detected using enzyme-linked immunosorbent assays. PI3K, Akt and mTOR mRNA and protein were assayed using real-time quantitative PCR and western blotting. Results:The arrangement of muscle fibers in the MC group was disordered and there was a large number of infiltrated inflammatory cells. Such conditions were significantly relieved in the CR group. After the intervention the levels of inflammatory factors TNF-α and IL-1β in the CR group were, on average, significantly lower than those observed in the MC group, the EX group or the SC group, while the level of anti-inflammatory factor IL-10 was significantly higher. The average PI3K, Akt and mTOR mRNA and protein levels of group CR were significantly higher than those of the MC and EX groups.Conclusions:The traditional Chinese Songchi ointment can usefully supplement treadmill training to relieve DMA. It upregulates IL-10, activates the PI3K Akt/mTOR signaling pathway and promotes the synthesis of muscle fiber protein while down-regulating TNF-α and IL-1β and muscle fiber inflammatory response.

Effects of foraging exercise on depressive-like behaviors and expression of transforming growth factor-β1 in hippocampus of rats with ischemic stroke after chronic stress / 中华行为医学与脑科学杂志

Objective:To explore the effects of foraging exercise (FE) on depressive-like behaviors and expression of transforming growth factor-β1 (TGF-β1) in hippocampus of rats with ischemic stroke after chronic stress.Methods:The right middle cerebral artery occlusion (MCAO) model was used in 30 male adult clean grade SD rats by suture method.According to the body weight, rats were evenly divided into stroke group ( n=10) and chronic unpredictable mild stimulation (CUMS) group ( n=20). Rats of CUMS group received stress induction 1 week after operation and lasted for 3 weeks. Then, according to random number generator of SPSS 24.0 software, the depression rats were divided into post-stroke depression (PSD) group( n=10) and FE groups ( n=10). The FE group received free FE intervention for 4 weeks. Body weight, water maze test, novelty inhibition feeding test (NSFT) and sucrose preference test (SPT) were performed at the end of the 1st, 4th and 8th week, respectively. The expression of TGF-β1 in hippocampus was detected by Immunohistochemistry (IHC) and Western blot (WB), and the levels of TGF-β1 and TNF-α in serum were detected by ELISA. SPSS 24.0 software was used for statistical analysis. The behavioral data were compared by two factor repeated measurement analysis of variance. One way ANOVA was used for comparison among groups, and LSD test was used for further pairwise comparison. Results:(1) The interaction between group and time had statistical significance on body weight, latency and food intake of NSFT and sucrose preference index(SPI) ( F=2.936-12.098, all P<0.05). After 4 weeks, compared with the stroke group((343.80±19.34)g, (12.10±6.97)s, (0.75±0.09)%), the body weight((307.80±17.23)g, (305.30±24.39)g), and SPI((0.52±0.06)%, (0.53±0.07)%) of PSD group and FE group were lower and the NSFT latency((21.70±7.02)s, (22.40±0.84)s) was longer (all P<0.05). After 8 weeks, SPI in FE group was higher than that in PSD group ( P=0.045). There were significant differences in body weight of three groups, NSFT latency and SPI of PSD group and FE group, and food intake of stroke and FE group ( F=8.478-196.548, all P<0.05). There was no interaction between group and time in the water maze test. Main effect of time ( P=0.034) and main effect of group ( P<0.01) had statistical significance on escape latency. The escape latency after 4 weeks was longer than that after 1 week ( P=0.003). The latency of PSD group was longer than that of stroke group ( P=0.005), and latency of FE group was shorter than that of the PSD group ( P<0.01). The main effect of group had statistical significance in the number of crossing quadrant ( P<0.01). The number of crossing quadrant of FE group was less than that of PSD group ( P<0.01). (2) Immunohistoche mistry staining showed that compared with the stroke group, the expression of TGF-β1 was down-regulated in 3 areas of hippocampus of PSD group (CA1, CA3 and DG) ( t=5.449-9.353, all P<0.01). Compared with stroke group, the expression of TGF-β1 of CA1 ( t=7.433, P<0.01) in FE group was down-regulated, but was up-regulated in CA3 ( t=3.342, P<0.05) of FE group. Compared with the PSD group, the expression of TGF-β1 was up-regulated in CA3 and DG of FE group ( t=7.811, 8.790, both P<0.01). (3) Western blot results: Compared with stroke group, the expression of TGF-β1 in hippocampus of PSD group was down-regulated ( t=3.255, P<0.01). Compared with the PSD group, the expression of TGF-β1 in hippocampus of FE group was up-regulated ( t=2.906, P<0.05). (4) ELISA detection showed that compared with the stroke group, the levels of TGF-β1 decreased ( t=2.224, P<0.05), but TNF-α increased ( t=6.127, P<0.01) in PSD group.Compared with the PSD group, the expression of TGF-β1 in FE group increased significantly ( t=4.417, P<0.01). Conclusion:Foraging exercise can improve the depressive behavior symptoms of ischemic stroke rats after chronic stress, and its mechanism may be related to the increasing expression of TGF-β1, which can alleviate the inflammatory reaction in hippocampus.

Effect of Haikunshenxi capsule combined with losartan potassium tablets on renal function and inflammatory factors in patients with chronic kidney disease / 中国医师进修杂志

Objective:To investigate the curative effect of Haikunshenxi capsule combined with losartan potassium tablets on chronic kidney disease (CKD) and its effect on renal function and inflammatory factors.Methods:One hundred patients with chronic kidney disease in Shaoxing Central Hospital from January 2018 to December 2019 were selected and randomly divided into observation group (50 cases) and control group (50 cases). The control group was treated with losartan potassium tablets based on conventional therapy, and the observation group was treated with Haikunshenxi capsulebase on control group. The treatment course of the two groups was 12 weeks. The curative effect, renal function, inflammatory factors, 24h urinary protein (24 h Upro) and glomerular filtration rate (GFR) were compared between the two groups before and after treatment.Results:The total effective rate in the observation group was higher than that in the control group: 90.0%(45/50) vs. 72.0%(36/50), χ2 = 5.26, P<0.05. After treatment, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in the two groups were decreased and the levels of Scr and BUN in the observation group were lower than those in the control group: (63.27 ± 2.89) μmol/L vs. (67.89 ± 2.35) μmol/L, (5.23 ± 0.19) mmol/L vs. (5.56 ± 0.16) mmol/L, the differences were statistically significant ( P<0.05). After treatment, the levels of serum C-reactive protein (CRP) , interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the two groups were decreased and the levels of CRP, IL-6 and TNF-α in the observation group were lower than those in the control group: (2.97 ± 0.34) mg/L vs. (3.58 ± 0.42) mg/L, (3.64 ± 0.68) ng/L vs. (4.97 ± 0.96) ng/L, (14.32 ± 2.17) ng/L vs. (17.86 ± 2.06) ng/L, the differences were statistically significant ( P<0.05). After treatment, the level of 24 h Upro in two groups was decreased, while the level of GFR was increased, and the level of 24 h Upro in the observation group was lower than that in the control group: (0.87 ± 0.09) g vs. (1.15 ± 0.13) g , but the level of GFR in the observation group was higher than that in the control group: (101.73 ± 3.12) ml/(min·m 2) vs. (96.75 ± 2.35) ml/(min·m 2), the differences were statistically significant ( P<0.05). Conclusions:Haikunshenxi capsule combined with losartan potassium tablets has obvious curative effect on patients with chronic kidney disease, and can improve renal function and micro inflammation.

Effect of Maxing Shigantang on Airway Injury and EGFR Expression in Asthma Model Rats / 中国实验方剂学杂志

ObjectiveTo explore the optimal formula of Maxing Shigantang in regulating epidermal growth factor receptor（EGFR）expression and alleviating airway injury in asthmatic rats and to reveal the underlying mechanism. MethodSD male rats were randomly divided into normal group, model group, dexamethasone group (5×10-4 g·kg-1) and Maxing Shigantang 1∶0.5, 1∶1, 1∶2 groups (group A, B, C, 10 g·kg-1), with 8 rats in each group. The other groups except the normal group received nebulization of 2% acetylcholine chloride and 0.4% histamine phosphate for the modeling of asthma. One hour before modeling， the normal group and the model group were given the same amount of normal saline， and the other groups were given the same amount of corresponding drugs， once a day for 7 days. On the 7th day， the model was established and the incubation period of asthma was recorded. The rats were then immediately anesthetized， and arterial blood and tracheal tissue were collected. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the levels of interleukin-2 （IL-2）， interleukin-4 （IL-4）， and tumor necrosis factor-α （TNF-α） in serum. Pathological sections were prepared for the observation of the pathological changes of tracheal tissues and the ultrastructure of epithelial cells in each group. Terminal-deoxynucleotidyl transferase-mediated nick-end labeling （TUNEL） was adopted to detect epithelial cell apoptosis， and in situ hybridization and Western blot were employed to determine the mRNA and protein levels of epidermal growth factor receptor （EGFR）， respectively. ResultCompared with the model group， groups A， B and C prolonged the incubation period of asthma （P<0.05，P<0.01）. Compared with the control group， the model group showed declined IL-2 level （P<0.01）， risen IL-4 and TNF-α levels （P<0.05，P<0.01）， increased airway pathology score， collagen volume fraction， and airway epithelial cell apoptosis index （P<0.01）， and up-regulated mRNA and protein levels of EGFR in trachea tissue （P<0.01）. Compared with the model group， group A showed increased IL-2 level （P<0.05） and declined IL-4 （P<0.05，P<0.01） level， and group B showed declined IL-4 level （P<0.05）. The level of TNF-α in groups A， B， and C declined compared with that in the model group （P<0.01）. Maxing Shigantang repaired the tracheal tissue to different degrees （P<0.05）. Among the three groups， group A inhibited tracheal fibrosis （P<0.05） and had the most significant effect of repairing the ultrastructural changes of airway epithelial cells. Groups A， B and C all inhibited the apoptosis of airway epithelial cells （P<0.05）. All the three groups inhibited the up-regulation of EGFR mRNA level （P<0.05，P<0.01）， and groups B and C inhibited the up-regulation of EGFR protein level （P<0.05，P<0.01）. ConclusionMaxing Shigantang can inhibit the abnormal changes of airway epithelial structure， alleviate airway injury， and can down-regulate the expression of EGFR in the tracheal tissue of asthma model rats. In this study， the optimal compatibility of Maxing Shigantang to repair airway epithelial injury in asthmatic rats was group A， with the Ephedrae Herba-Armeniacae Semen Amarum-Glycyrrhizae Radix et Rhizoma-Gypsum Fibrosum ratio of 1∶0.5∶4∶1.

Tumor necrosis factor-α inhibitor-induced psoriasis / 中华皮肤科杂志

Tumor necrosis factor-α (TNF-α) inhibitors have been widely used and proven to be effective in the treatment of various inflammatory disorders in recent years, but there is a noteworthy and paradoxical adverse drug reaction that cannot be ignored, that is, TNF-α inhibitor-induced psoriasis. Its pathological manifestations could be psoriasiform or spongiotic changes, and its pathogenesis may be related to the imbalance between TNF-α and type Ⅰinterferon, the involvement of interleukin-23/T helper 17 axis, or infection. This review elaborates the epidemiological, histopathological features and possible pathogenesis of TNF-α inhibitor-induced psoriasis, and provides a basis for recognition and treatment of TNF-α inhibitor-induced psoriasis.

Hyperactivation of PI3K/AKT/mTOR signal pathway impairs TNF-α-induced autophagy in mesenchymal stem cells from patients with ankylosing spondylitis / 南方医科大学学报

OBJECTIVE@#To investigate the changes in autophagy of mesenchymal stem cells (MSCs) from patients with ankylosing spondylitis and explore the mechanism for decreased autophagy in ASMSCs.@*METHODS@#MSCs collected from 14 patients with AS (ASMSCs) and from 15 healthy donors (HDMSCs) were cultured in the absence or presence of 25 ng/mL TNF-α for 6 h. Autophagy of the cells was determined by immunofluorescence staining of GFP-LC3B, and the results were confirmed by detecting the protein expressions of autophagy markers LC3 II/LC3 I and P62. The mRNA expressions of the related genes were detected using qRT-PCR, and the protein expressions of the autophagy markers and signaling pathway-related molecules were determined with Western blotting. TG100713 was used to block the PI3K/AKT/mTOR signal pathway, and its effect on autophagy of ASMSCs was evaluated.@*RESULTS@#ASMSCs showed significantly weaker GFP-LC3B puncta staining and lower protein expression levels of LC3 II/LC3 I but higher levels of P62 protein (P < 0.05), indicating a decreased autophagy capacity as compared with HDMSCs. TNF-α-induced ASMSCs showed significantly higher protein expressions of p-PI3K/ PI3K, p-AKT/AKT and p-mTOR/mTOR than HDMSCs (P < 0.05), suggesting hyperactivation of the PI3K/AKT/mTOR signaling pathway in ASMSCs. Blocking PI3K/AKT/mTOR signaling with TG100713 eliminated the difference in TNF-α-induced autophagy between HDMSCs and ASMSCs.@*CONCLUSION@#In patients with AS, hyperactivation of the PI3K/AKT/mTOR signaling pathway results in decreased autophagy of the MSCs and potentially contributes to chronic inflammation.

ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism.@*METHODS@#Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats.@*RESULTS@#BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05).@*CONCLUSION@#ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.

Association of single nucleotide polymorphism of TNF-α gene G308A with obesity and metabolic disorder in children / 中华内分泌代谢杂志

Objective:To investigate the association of tumor necrosis factor-α(TNF-α)gene G308A single nucleotide polymorphism(SNP)with childhood obesity and metabolic disorders.Methods:A total of 620 obese children admitted to our pediatric department from January 2015 to December 2019 were selected as research subjects, who were divided into metabolic non-healthy group( n=267)and metabolic healthy group( n=353), and 260 healthy children were selected as the control group. Single nucleotide polymorphism of TNF-α gene G308A was detected, serum TNF-α level, obesity indicators, glucose and lipid metabolism indicators were compared among the children in various groups. Results:No significant differences in body mass index(BMI), waist circumference, hip circumference, and serum TNF-α level were found between metabolic non-healthy group and metabolic healthy group( P>0.05), but higher than those in control group( P<0.05). There were no significant differences in fasting plasma glucose(FPG)and total cholesterol(TC) levels among the three groups( P>0.05). The levels of fasting insulin(FINS), fasting glucagon(FGC), HbA 1C, triglyceride(TG), and low density lipoprotein-cholesterol(LDL-C)in metabolic non-health group and metabolic health group were significantly higher than those in control group, higher in metabolic non-health group compared with metabolic healthy group( P<0.05). HDL-C level in two obese groups was significantly lower than that in control group, lower in metabolic non-health group compared with metabolic healthy group( P<0.05). The frequencies of GG genotype and allele G in metabolic non-healthy group and metabolic healthy group were significantly lower than those in control group, lower in metabolic non-health group compared with metabolic healthy group. The frequencies of AA, GA genotypes and allele A were significantly higher in metabolic non-health group than those in metabolic healthy group( P<0.05). There were no significant differences in TNF-α, FPG, and TC among AA, GA and GG groups( P>0.05). BMI, waist circumference, hip circumference, FINS, FGC, HbA 1C, TG, HDL-C and LDL-C were comparable between AA type and GA type( P>0.05), but revealed a significant difference compared with GG type( P<0.05). Pearson correlation analysis showed that the level of TNF-α was positively correlated with BMI, waist circumference, hip circumference, FPG, FINS, FGC, HbA 1C, TC, TG, and LDL-C( P<0.05), but negatively correlated with HDL-C( P<0.05). Conclusion:TNF-α gene G308A single nucleotide polymorphism is associated with obesity and metabolic disorders in children.

Clinical observation of sodium hyaluronate in the treatment of chronic periodontitis and its influence on serum inflammatory factors / 中国医师进修杂志

Objective:To investigate the effect of sodium hyaluronate on chronic periodontitis and its influence on serum hyper sensitive C-reactive protein(hs-CRP), interleukin 8(IL-8) and tumor necrosis factor-α(TNF-α).Methods:Using the random number table method, 98 patients with chronic periodontitis from March 2017 to March 2019 in Hangzhou Xixi Hospital were randomly divided into observation group (49 cases) and control group (49 cases). The control group was treated with tinidazole tablets, and the observation group was treated with sodium hyaluronate on the basis of the control group. The course of treatment was 4 weeks. The total effective rate was compared and the gingival index(GI), sulcus bleeding index (SBI), plaque index (PLI), and the levels of serum hs-CRP, IL-8, TNF-α before and 4 weeks after treatment were compared between the two groups.Results:The total effective rate of the observation group was higher than that of the control group:93.88%(46/49) vs. 71.43%(35/49), the difference was statistically significant ( χ2=8.612, P<0.05). After treatment of 4 weeks, the scores of GI, SBI and PLI in the observation group were lower than those in the control group: (1.10 ± 0.23 vs. 1.63 ± 0.36, 0.38 ± 0.10 vs.0.71 ± 0.15, 0.83 ± 0.29 vs. 1.36 ± 0.21), the differences were statistically significant ( P<0.05). After treatment of 4 weeks, the levels of hs-CRP, IL-8 and TNF-α in the observation group were lower than those in the control group: (4.53 ± 1.29) mg/L vs. (7.65 ± 1.82) mg/L, (6.17 ± 1.08) ng/L vs. (9.98 ± 1.56) ng/L, (2.27 ± 0.26) μg/L vs. (3.98 ± 0.32) μg/L, the differences were statistically significant ( P<0.05). No obvious adverse reactions occurred in the two groups. Conclusions:Sodium hyaluronate has a significant clinical effect on chronic periodontitis. It can reduce the levels of hs-CRP, IL-8, TNF-α and alleviate the inflammatory reaction.

Pay attention to the risk of infection and tumor progression during application of TNF-α inhibitors in uveitis / 中华实验眼科杂志

Adalimumab, one of the tumor necrosis factor-α (TNF-α) inhibitors, has been approved as a therapeutic drug for non-infectious intermediate, posterior and pan-uveitis by FDA.Due to the good efficacy, TNF-α inhibitors are being applied widely in ophthalmology.However, some researches based on the application of TNF-α inhibitor in treating inflammatory bowel diseases and rheumatoid arthritis, etc.have showed that it can bring out some adverse effects such as infection and tumor occurrence and/or progression.The main safety problems in the application of TNF-α inhibitors lie in its increased risk of serious infection, postoperative infection, the occurrence or progression of tuberculosis and hepatitis, as well as the tumorigenesis and tumor progression.With the wider application of adalimumab in refractory uveitis, ophthalmologists should not only focus on its therapeutic effect, but also get to know the adverse effects of the drug, so as to standardize the examination, prevention and control of primary diseases before and after the administration of adalimumab and observe closely clinical manifestations of patients with administration of adalimumab, select the treating method and timing reasonably to reduce and avoid the adverse drug reactions, and improve the therapeutic outcome.

Maxing xiongting mixture regulates factors relevant to lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats / 中国组织工程研究

BACKGROUND: Hypoxic pulmonary hypertension is a key link in the progression from chronic obstructive pulmonary disease to cor pulmonale. Its severity is closely related to disease development and prognosis. Current treatments cannot prevent or reverse disease progression. Maxing Xiongting Mixture has significant effect on hypoxic pulmonary hypertension with the syndrome of intermingled phlegm and blood stasis. OBJECTIVE: To study how the Maxing Xiongting Mixture regulates relevant factors of lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats with the syndrome of intermingled phlegm and blood stasis. METHODS: Seventy Sprague-Dawley rats, 5 weeks old, were randomly divided into normal group (n=10) and model group (n=60), where acute cor pulmonale model was prepared by injecting 50 mg/kg monocrotaline solution (1%) intraperitoneally, followed by forced smoking and swimming 6 days a week lasting for 4 weeks. Except for 10 rats in the normal group, there were 46 model rats in the model group. According to the normal distribution of body mass, 40 rats were selected and randomly divided into 4 groups: model group, high-dose Maxing Xiongting Mixture group (MH), low-dose Maxing Xiongting Mixture group (ML) and fasudil group, with 10 rats in each group. Rats in MH and ML groups were respectively given Maxing Xiongting Mixture at 20 g/(kg·d) and 5 g/(kg·d), respectively and those in the fasudil group were given fasudil at a dose of 10 mg/(kg·d). Other groups were given equal amount of saline. Administration was given intraperitoneally and intragastrically, once a day for 14 days in total. RT-PCR was used to test the expression of factors related to lung reshaping and vascular remodeling, including RhoA, stromelysin 1 and tumor necrosis factor-α mRNAs. An approval for the study was obtained from the Ethics Committee of Chengdu University of Traditional Chinese Medicine (approval No. 2017-03). RESULTS AND CONCLUSION: Compared with the model group, the expressions of RhoA, stromelysin 1, and tumor necrosis factor-α mRNAs were significantly lowered in the MH group (all P 0.05). To conclude, Maxing Xiongting Mixture, which is similar to fasudil, intervenes lung reshaping and vascular remodeling of hypoxic pulmonary hypertension rats with the syndrome of intermingled phlegm and blood stasis by inhibiting the expressions of RhoA, stromelysin 1, and tumor necrosis factor-α mRNAs.