GPCRs are the largest membrane protein receptor superfamily in the human body, with more than 800 isoforms, and approximately 35% of Food and Drug Administration-approved and marketed drugs currently target GPCRs for the treatment of a wide range of diseases, for heart failure (beta-adrenergic receptors), peptic ulcer (histamine receptors), prostate cancer (gonadotropin receptors), hypertension (adrenergic and angiotensin receptors), pain (opioid receptors), and bronchial asthma (beta2-adrenergic receptors) examples. Although the number of GPCRs is enormous, the signaling proteins downstream of them are limited, heterotrimeric G proteins (GPs) are key proteins that signal GPCRs, translate extracellular stimuli into intracellular responses by coupling to GPCRs and initiate multiple signaling events via downstream cascades. Podocytes are an important component of the glomerular filtration barrier, and their damage is a central event in proteinuria formation and progressive glomerulosclerosis. This article reviews the regulation of GPs, their signaling and their role in podocyte injury to provide a theoretical basis for scientific research and clinical treatment of this disease.

Objective To investigate the interventional effects of Icariin(IC A)combined with prednisone acetate tablets(PAT)in rats with steroid-resistant nephrotic syndrome(SRNS)model.Methods Male SD rats were used to construct the SRNS model with 2 injections of adriamycin(ADR),and were randomly divided into the model group,PAT group,ICA group,and the combined group,with 10 rats in each group after successful modeling;another 10 rats were taken as the blank group.The blank and model groups were given 0.9％NaCl;the PAT group was given 6.3 mg·kg-1·d-1 PAT;the ICA group was given 50 mg·kg-1·d-1 ICA;and the combined group was given 6.3 mg·kg-1·d-1 PAT+50 mg·kg-1·d-1 ICA.The volume of gavage of the five groups of rats was 1 mL·100 g-1,and the drug was administered once a day for 6 weeks.The renal function and blood lipid level of rats in each group were compared;the expression of calcium/calmodulin dependent protein kinase Ⅱ α(CaMK Ⅱα),cofilin-1 and F-actin were detected by Western blotting.Results Urinary protein quantification values at 8 weeks in blank,model,PAT,ICA and combined groups were(6.66±1.48),(178.38±8.96),(161.56±5.49),(157.13±8.32)and(96.90±5.05)mg·24 hi-1;serum creatinine levels were(30.90±1.79),(41.10±2.77),(34.90±2.03),(35.10±2.18)and(31.90±2.47)μmol·L-1;triglycerides levels were(0.87±0.14),(2.30±0.41),(1.94±0.44),(1.17±0.59)and(0.89±0.30)mmol·L-1;total cholesterol levels were(1.54±0.08),(2.53±0.22),(2.14±0.59),(2.27±0.31)and(1.93±0.32)mmol·L-1;the relative expression levels of CaMK Ⅱ α proteins were 0.88±0.09,0.65±0.06,0.71±0.08,0.76±0.07 and 0.88±0.08;the p-Cofilin-1/Cofilin-1 ratios were 0.56±0.27,2.52±0.04,0.75±0.02,0.91±0.20 and 0.53±0.05;the relative expression levels of F-actin protein were 0.93±0.01,0.64±0.01,0.75±0.02,0.80±0.01 and 0.85±0.00,respectively.The differences of the above indexes in the model group were statistically significant compared with those in the blank group and the combined group(all P＜0.05).Conclusion ICA combined with PAT can improve renal function,lipid levels,improve renal histopathological structure,and promote skeletal protein remodeling in SRNS rats by regulating CaMK Ⅱ α/Cofilin-1/F-actin pathway.

Renal fibrosis is a common pathological manifestation of all chronic kidney diseases.Ferroptosis is closely related to the pathogenesis of renal fibrosis and can influence the onset of renal fibrosis,and it is the most critical step in the development of renal fibrosis.The paper describes the relationship between ferroptosis and renal fibrosis,discusses the research progress of ferroptosis on renal fibrosis,and further summarizes,analyzes,and describes the effective and highly targeted natural active ingredients of traditional Chinese medicines against ferroptosis,and concludes that the reversal of renal fibrosis is achieved through the regulation of the key targets of ferroptosis,with a view to providing a broad new direction for its prospects in the field of renal fibrotic disease prevention and treatment;and to provide a scientific guide for clinical treatment and basis for clinical treatment.

Objective To study the common basis and association between sickness behaviour and occurrence of classical symptoms of kidney yang deficiency of rats with adriamycin nephropathy.Methods The SD rats were given adriamycin by tail-vein injection for 2 times(4.0 and 3.5 mg·kg-1,one week apart)to construct the model of nephrotic syndrome with Chinese medicine symptom of kidney yang deficiency.After successful modeling,the model rats were randomly divided into adriamycin group(ADR group),corticosterone group(CORT group)and hydrocortisone group(HYD group),with 12 rats per group;another 12 normal rats were taken as normal group.In the HYD group,25 mg·kg-1·d-1 HYD was administered for 14 d to establish kidney yang deficiency model with simple hypothalamus-pituitary-adrenal cortex(HPA)axis inhibition.CORT group was adding 25 μg·mL-1 corticosterone to the water for 6 weeks,and the others drinking water supplied.The levels of urinary 17-hydroxy steroid were measured by enzyme linked immunosorbent assay.Glucocorticoid receptor(GR)and nuclear factor-kappa B(NF-κB)protein expression levels in kidney and hypothalamus were detected by Western blotting.Results In the normal,ADR,CORT and HYD groups,the urinary 17-hydroxysteroid levels were(19.14±1.94),(10.07±1.62),(20.30±1.55)and(14.23±2.37)μg·L-1;the relative expression levels of GR protein in hypothalamic were 0.63±0.05,0.11±0.05,0.85±0.08 and 0.35±0.06;the relative expression levels of NF-κB protein in hypothalamic were 0.06±0.03,0.96±0.03,0.59±0.01 and 0.23±0.04;the relative expression levels of GR protein in kidney tissue were 0.94±0.06,0.06±0.02,0.40±0.02 and 0.09±0.08;the relative expression levels of NF-κB protein in kidney tissue were 0.07±0.05,0.81±0.12,0.72±0.07 and 0.49±0.08,respectively.Compared with the ADR and HYD groups,the above indexes in the normal group were statistically significant(P＜0.05,P＜0.01).And compared with the ADR group,the relative expression levels of NF-κB protein in renal tissue with CORT group were not statistically significant(P＞0.05),but the other indexes in CORT group were statistically significant(all P＜0.01).Conclusion HPA axis dysfunction with GR damaged and activated inflammatory levels are the common basis for the combination of typical symptoms of kidney yang deficiency and sickness behaviour which characterised by"deficiency and cold syndrome".

Taking Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology as an example,it discusses the basic ideas and innovative practices of project organization from"passive order taking"to"active planning",platform construction from"free growth"to"directional cultivation",team construction from"wearing hats"to"focusing on actual combat",and achievement transformation from"resource guidance"to"comprehensive policy".It puts forward some suggestions that hospitals should play the leading role of"national team"in organizing scientific research and innovation practice,pay attention to the docking of national strategy,the linkage of university resources.

ObjectivesTo investigate the effect of acupuncture intervention at different time during the acute phase of ischemic stroke on limb motor dysfunction 6 months after onset. MethodsThe enrolled ischemic stroke patients from four tertiary hospitals all received western basic treatment for ≥14 days； additionally， they were given the cleaning-mind and opening-orifices acupuncture method， with acupuncture at bilateral Neiguan （PC 6）， Shuigou （GV 26）， and Sanyinjiao （SP 6） of the affected side， once a day for at least 2 times. Three cohorts were formed by the timing of acupuncture intervention of the onset of the disease within 10 days， namely， the acupuncture group of 1-3 days after onset of the disease （195 cases）， the acupuncture group of 4-7 days after onset of the disease （171 cases）， and the acupuncture group of 8-10 days after onset of the disease （96 cases）. Propensity score matching was performed using R4.3.3 software， and there were 89 patients in each of the three groups after matching. Modified Rankin Scale （mRS） score， Fugl-Meyer Scale （FMA） score， EuroQoL 5-Dimension 5-Level （EQ-5D-5L） score and the proportion of good functional outcome were observed in the 3 groups of patients before treatment and 6 months after onset. A logistic regression model was constructed to analyse the effect of the timing of acupuncture intervention on the effectiveness of acupuncture treatment for limb motor dysfunction in ischaemic stroke. ResultsCompared with the pre-treatment of this group， mRS and EQ-5D-5L scores decreased and FMA increased in all three groups 6 months after onset （P＜0.01）， and all the indexes of the onset 1-3 days acupuncture group and the onset 4-7 days acupuncture group were better than those of the onset 8-10 days acupuncture group （P＜0.05）. The proportions of good functional outcome in the onset 1-3 days acupuncture group， the onset 4-7 days acupuncture group， and the onset 8-10 days acupuncture group were 76.40%， 80.90%， and 57.30%， respectively， and the proportions of good functional outcome in the onset 1-3 days acupuncture group and the onset 4-7 days acupuncture group were significantly higher than those in the onset 8-10 days acupuncture group （P＜0.05）. Multifactorial logistic analysis showed that compared with the group with 8-10 days of onset， the group with 1-3 days of onset （OR=2.796， 95%CI： 1.340~5.836， P = 0.006）， and the group with 4-7 days of onset （OR=3.482， 95%CI： 1.647~7.362， P = 0.001） increased the likelihood that patients would be nondisabled 6 months after onset. ConclusionThe intervention of cleaning-mind and opening-orifices acupuncture within 1-7 days of onset for patients with acute ischemic stroke can reduce the rate of disability 6 months after onset， improve limb motor function， and enhance the quality of life.

AIM:To explore the therapeutic effect and possible molecular mechanisms of prednisone combined with icariin(ICA)on hormone resistant nephrotic syndrome(SRNS).METHODS:In the in vi-vo experiment,rats were divided into control group,SRNS group,prednisone group,and P+I group.Each group was given corresponding drugs for 6 weeks.Detection of 24-hour urinary protein in rats using CBB;The blood biochemistry analyzer de-tects rat albumin,total cholesterol,triglycerides,creatinine,and urea nitrogen;HE and Masson were used to detect morphological changes in rat kidney tissue;Immunohistochemical detection of GR-α,GR-β,NLRP3,caspase-1,GSDMD,IL-1β.In the in vi-tro experiment,HK-2 cell injury model with doxoru-bicin,divided into control group,SRNS group,pred-nisone group,P+l group.GR-α,GR-β,NLRP3,cas-pase-1,GSDMD were detected by Rt-PCR and West-ern blot.RESULTS:In the in vivo experiment,com-pared with the control group,the SRNS group showed weight loss,increased 24-hour urine pro-tein,decreased albumin,increased total cholester-ol,triglycerides,creatinine,and urea nitrogen,renal tubular atrophy,increased renal interstitial area,sig-nificant infiltration of inflammatory cells,fibrous tis-sue proliferation,and GR-β,NLRP3,caspase-1,GSD-MD,IL-1 β in renal tissue decreased(P＜0.01);Com-pared with the SRNS group,the combined group showed weight gain,decreased 24-hour urine pro-tein,increased albumin,decreased total cholester-ol,triglycerides,creatinine,and urea nitrogen,re-duced renal tubular atrophy,reduced interstitial in-flammatory cell infiltration,reduced fibrosis,and and GR-α,NLRP3,caspase-1,GSDMD in renal tissue decreased increased(P＜0.01).In vitro experiments,compared with the control group,the model group showed GR-β,NLRP3,caspase-1,and GSDMD in-creased(P＜0.01),GR-α decreased(P＜0.01);Com-pared with the SRNS group,GR-β,NLRP3,caspase-1,and GSDMD decreased(P＜0.01),GR-α increased in the P+I group.CONCLUSION:The combination of prednisone and ICA has a protective effect on the kidneys of SRNS rats and can improve the therapeu-tic effect.The mechanism may be related to the NL-RP3/Caspase-1/GSDMD pathway.

Aim To study the effects of Taohong Siwu Tang(TSD)on serum lipid metabolites in rats with abnormal uterine bleeding(AUB),and to analyze the mechanism of action of TSD in improving lipid metabo-lism disorders in AUB.Methods The rat model of AUB was replicated by the method of incomplete abor-tion with drugs,and the lipid metabolites of serum were detected by applying UPLC-Q-Exactive Orbitrap/MS technology,and combined with the principal com-ponent analysis and orthogonal partial least squares-discriminant analysis to screen for differential lipids,the changes of lipids in serum before and after the in-tervention of TSD were clarified.Results A total of 11 differential lipids were screened,mainly phosphati-dyl inositol,phosphatidic acid,phosphatidyl ethanola-mine,phosphatidyl serine,sterol lipids,ceramide,acrylolipids and fatty acids.The screened differential lipids all tended to regress to normal after the adminis-tration of TSD intervention.Conclusion Improvement of AUB by TSD may be related to lipid metabolism such as phosphatidic acid,phosphatidyl inositol,phos-phatidyl ethanolamine,phosphatidyl serine,and ce-ramide.

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.
Humans ; Tumor Necrosis Factor-alpha ; DNA-Binding Proteins/metabolism* ; Ubiquitin-Specific Peptidase 7 ; Cisplatin ; Temozolomide ; Transcription Factors ; Glioma ; Cell Proliferation ; Melanoma ; Cell Line, Tumor ; Apoptosis ; Nuclear Proteins/genetics*

Objective To investigate the pharmacodynamic effects of Poria triterpenes on tumor suppression in mice with ascites tumors,and to detect and identify the chemical components of Poria triterpenes using HPLC-LTQ-Orbitrap method,and to explore the potential mechanism of action of Poria triterpenes on tumor suppression in mice with ascites tumors based on both of them using non-labeled definitive proteomics techniques.Methods Poria triterpene parts were extracted by solvent method,and the main components were detected and identified by HPLC-LTQ-Orbitrap liquid mass spectrometer;mice were randomly divided into model group,Poria triterpene group and positive control group(mushroom polysaccharide group),after 21 days of continuous administration,to establish After continuous administration for 21 days,the H22 ascites tumor mouse model was established,and the effect of each drug group on the amount of ascites,spleen index,thymus index,liver index,serum TNF-Alpha and IL-2 in H22 ascites tumor mice was observed after one week of continued administration;then H22 cells were extracted from the ascites of mice,and the H22 cells in the model group and Poria triterpene group were detected by non-lable-free quantitative proteomics technique.The differentially expressed proteins(DEPs)were screened out by using GO,KEGG and other analyses.Results The abdominal water volume in the mouse Poria triterpene group was significantly lower than that in the model group(P<0.05);the thymus index in the mouse Poria triterpene group was significantly higher than that in the model group(P<0.05);the serum levels of TNF-Alpha in the mouse Poria triterpene group were significantly different from those in the model group(P<0.01),and the serum levels of IL-2 in the mouse Poria triterpene group were significantly different from those in the model group(P<0.01).Through the analysis of the chemical composition of Poria triterpene parts,a total of 19 triterpenoids were identified,with four main structural types.A total of 188 differentially expressed proteins were identified in the Poria triterpene group compared with the model group,of which 86 differentially expressed proteins were up-regulated and 102 differentially expressed proteins were down-regulated;GO database analysis showed that the differentially expressed proteins in the Poria triterpene group were mainly involved in the regulation of interleukin-1 production The KEGG database analysis showed that the differentially expressed proteins in the Poria triterpene group were involved in signaling pathways closely related to tumor,mainly MAPK,Apoptosis,mTOR,Wnt and p53 pathways,etc.The genes coding for the seven representative differential proteins were validated at the mRNA level by RT-qPCR.Conclusion The pharmacodynamic study found that Poria triterpenes had tumor suppressive effect on H22 ascites tumor mice,then by proteomics found Poria triterpenes group ascites H22 cell protein compared to the model group changed significantly,the study thus showed that Poria triterpenes for mice ascites tumor mechanism of tumor suppressive effect mainly involves apoptosis,inflammatory response and immune process.