SGK3 promotes vascular calcification via Pit-1 in chronic kidney disease.

Rationale: Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation of VC remains unclear despite extensive research. Although serum- and glucocorticoid-induced kinase 3 (SGK3) regulate the sodium-dependent phosphate cotransporters in the intestine and kidney, its effect on VC in CKD remains unknown. Additionally, type III sodium-dependent phosphate cotransporter-1 (Pit-1) plays a significant role in VC development induced by high phosphate in vascular smooth muscle cells (VSMCs). However, it remains unclear whether SGK3 regulates Pit-1 and how exactly SGK3 promotes VC in CKD via Pit-1 at the molecular level. Thus, we investigated the role of SGK3 in the certified outflow vein of arteriovenous fistulas (AVF) and aortas of uremic mice. Methods and Results: In our study, using uremic mice, we observed a significant upregulation of SGK3 and calcium deposition in certified outflow veins of the AVF and aortas, and the increase expression of SGK3 was positively correlated with calcium deposition in uremic aortas. In vitro, the downregulation of SGK3 reversed VSMCs calcification and phenotype switching induced by high phosphate. Mechanistically, SGK3 activation enhanced the mRNA transcription of Pit-1 through NF-κB, downregulated the ubiquitin-proteasome mediated degradation of Pit-1 via inhibiting the activity of neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase. Moreover, under high phosphate stimulation, the enhanced phosphate uptake induced by SGK3 activation was independent of the increased protein expression of Pit-1. Our co-immunoprecipitation and in vitro kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Conclusion: Thus, it is justifiable to conclude that SGK3 promotes VC in CKD by enhancing the expression and activities of Pit-1, which indicate that SGK3 could be a therapeutic target for VC in CKD.

The Physiopathologic Roles of Calcium Signaling in Podocytes.

Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into podocytes, after activation of Ca2+ channels (such as transient receptor potential canonical (TRPC) channels and N-type calcium channels) by different stimuli. In addition, the type 2 ryanodine receptor (RyR2) and the voltage-dependent anion channel 1 (VDAC1) on mitochondrial store-operated calcium channels (SOCs) on the endoplasmic reticulum maintain the Ca2+ homeostasis of the organelle. Ca2+ signaling is transmitted through multiple downstream signaling pathways and participates in the morphogenesis, structural maintenance, and survival of podocytes. When Ca2+ is dysregulated, it leads to the occurrence and progression of various diseases, such as focal segmental glomerulosclerosis, diabetic kidney disease, lupus nephritis, transplant glomerulopathy, and hypertensive renal injury. Ca2+ signaling is a promising therapeutic target for podocyte-related diseases. This review first summarizes the role of Ca2+ sensing, Ca2+ channels, and different Ca2+-signaling pathways in the biological functions of podocytes, then, explores the status of Ca2+ signaling in different podocyte-related diseases and its advances as a therapeutic target.

Curcumin ameliorates focal segmental glomerulosclerosis by inhibiting apoptosis and oxidative stress in podocytes.

Focal segmental glomerulosclerosis (FSGS), a podocyte disease, is the leading cause of end-stage renal disease (ESRD). Nevertheless, the current effective treatment for FSGS is deficient. Curcumin (CUR) is a principal curcuminoid of turmeric, which is a member of the ginger family. Previous studies have shown that CUR has renoprotective effects. However, the mechanism of CUR in anti-FSGS is not clear. This study aimed to explore the mechanism of CUR against FSGS through a combination of network pharmacological methods and verification of experiments. The analysis identified 98 shared targets of CUR against FSGS, and these 98 targets formed a network of protein-protein interactions (PPI). Of these 98 targets, AKT1, TNF, IL-6, VEGFA, STAT3, MAPK3, HIF1A, CASP3, IL1B, and JUN were identified as the hub targets. Molecular docking suggested that the best binding to CUR is MAPK3 and AKT1. Apoptotic process and cell proliferation were identified as the main biological processes of CUR against FSGS by gene ontology (GO) analysis. The most enriched signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was the PI3K-AKT signaling pathway. Western blots and flow cytometry showed that CUR could inhibit adriamycin (ADR) induced apoptosis, oxidative stress damage, and attenuate podocyte epithelial-mesenchymal transition (EMT) by repressing the AKT signaling pathway. Collectively, our study demonstrates that CUR can attenuate apoptosis, oxidative stress damage, and EMT in FSGS in vitro. These results supply a compelling basis for future studies of CUR for the clinical treatment of FSGS.

Role of the SLIT-ROBO signaling pathway in renal pathophysiology and various renal diseases.

SLIT ligand and its receptor ROBO were initially recognized for their role in axon guidance in central nervous system development. In recent years, as research has advanced, the role of the SLIT-ROBO signaling pathway has gradually expanded from axonal repulsion to cell migration, tumor development, angiogenesis, and bone metabolism. As a secreted protein, SLIT regulates various pathophysiological processes in the kidney, such as proinflammatory responses and fibrosis progression. Many studies have shown that SLIT-ROBO is extensively involved in various aspects of kidney development and maintenance of structure and function. The SLIT-ROBO signaling pathway also plays an important role in different types of kidney disease. This article reviews the advances in the study of the SLIT-ROBO pathway in various renal pathophysiological and kidney disorders and proposes new directions for further research in this field.

Effects of electroacupuncture on rats with cognitive impairment: An iTRAQ-based proteomics analysis / 中西医结合学报

OBJECTIVE@#The study explores the effects of electroacupuncture (EA) at the governing vessel (GV) on proteomic changes in the hippocampus of rats with cognitive impairment.@*METHODS@#Healthy male rats were randomly divided into 3 groups: sham, model and EA. Cognitive impairment was induced by left middle cerebral artery occlusion in the model and EA groups. Rats in the EA group were treated with EA at Shenting (GV24) and Baihui (GV20) for 7 d. Neurological deficit was scored using the Longa scale, the learning and memory ability was detected using the Morris water maze (MWM) test, and the proteomic profiling in the hippocampus was analyzed using protein-labeling technology based on the isobaric tag for relative and absolute quantitation (iTRAQ). The Western blot (WB) analysis was used to detect the proteins and validate the results of iTRAQ.@*RESULTS@#Compared with the model group, the neurological deficit score was significantly reduced, and the escape latency in the MWM test was significantly shortened, while the number of platform crossings increased in the EA group. A total of 2872 proteins were identified by iTRAQ. Differentially expressed proteins (DEPs) were identified between different groups: 92 proteins were upregulated and 103 were downregulated in the model group compared with the sham group, while 142 proteins were upregulated and 126 were downregulated in the EA group compared with the model group. Most of the DEPs were involved in oxidative phosphorylation, glycolipid metabolism and synaptic transmission. Furthermore, we also verified 4 DEPs using WB technology. Although the WB results were not exactly the same as the iTRAQ results, the expression trends of the DEPs were consistent. The upregulation of heat-shock protein β1 (Hspb1) was the highest in the EA group compared to the model group.@*CONCLUSION@#EA can effect proteomic changes in the hippocampus of rats with cognitive impairment. Hspb1 may be involved in the molecular mechanism by which acupuncture improves cognitive impairment.

Asthma management and asthma control level in children / 中国当代儿科杂志

OBJECTIVES@#To investigate the influencing factors for asthma management and asthma control level in children.@*METHODS@#A total of 202 children with a confirmed diagnosis of asthma were enrolled. The questionnaire of asthma control level and family management was used to investigate the influencing factors for asthma control level and the indicators of family management. The awareness of childhood asthma and its management was analyzed among the parents, as well as the influence on asthma control level in children, and the association between them was analyzed.@*RESULTS@#Compared with the non-complete control group, the complete control group had significantly longer course of asthma and treatment time (P<0.05). The proportions of asthma attacks ≥3 times and aerosol treatment for asthma attacks >3 times in one year in the complete control group were significantly lower than those in the non-complete control group (P<0.05). The complete control group had a significantly lower proportion of children with frequent respiratory infection, wheezing during respiratory infection, or a family history of allergic diseases (P<0.05). The parents in the complete control group had significantly stronger awareness of short-term escalation to asthma medication after respiratory infection and significantly enhanced management of maintenance medication (P<0.05). Compared with the complete control group, the non-complete control group had a significantly higher proportion of children with abnormal pulmonary function at the initial stage (P<0.05). The level of asthma control in children was associated with short-term escalation to asthma medication during respiratory infection and initial lung function (P<0.05).@*CONCLUSIONS@#The level of asthma control in children is closely associated with the severity of asthma and the comprehensive management of childhood asthma. Early treatment and family management, especially escalation to asthma medication during the early stage of respiratory infection, are of great importance in asthma control. Citation:Chinese Journal of Contemporary Pediatrics, 2023, 25(1): 73-79.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study / 亚洲男科学杂志(英文版)

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Integrated strategy for biomarkers of stable coronary heart disease with phlegm and blood stasis syndrome based on RNA-seq and network pharmacology / 中国中药杂志

This study aimed to analyze the biological foundation and biomarkers of stable coronary heart disease(CHD) with phlegm and blood stasis(PBS) syndrome based on RNA-seq and network pharmacology. Peripheral blood nucleated cells from five CHD patients with PBS syndrome, five CHD patients with non-PBS syndrome, and five healthy adults were collected for RNA-seq. The specific targets of CHD with PBS syndrome were determined by differential gene expression analysis and Venn diagram analysis. The active ingredients of Danlou Tablets were screened out from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the "component-target" prediction was completed through PubChem and SwissTargetPrediction. The "drug-ingredient-target-signaling pathway" network of Danlou Tablets against CHD with PBS syndrome was optimized by Cytoscape software. After the target biomarkers were identified, 90 participants were enrolled for diagnostic tests, and 30 CHD patients with PBS syndrome were included in before-and-after experiment to determine the therapeutic effect of Danlou Tablets on those targets. As revealed by RNA-seq and Venn diagram analysis, 200 specific genes were identified for CHD with PBS syndrome. A total of 1 118 potential therapeutic targets of Danlou Tablets were predicted through network pharmacology. Through integrated analysis of the two gene sets, 13 key targets of Danlou Tablets in the treatment of CHD with PBS syndrome were screened out, including CSF1, AKR1C2, PDGFRB, ARG1, CNR2, ALOX15B, ALDH1A1, CTSL, PLA2G7, LAP3, AKR1C3, IGFBP3, and CA1. They were presumably the biomarkers of CHD with PBS syndrome. The ELISA test further showed that CSF1 was significantly up-regulated in the peripheral blood of CHD patients with PBS syndrome, and was significantly down-regulated after Danlou Tablets intervention. CSF1 may be a biomarker for CHD with PBS syndrome, and it is positively correlated with the severity of the disease. The diagnostic cut-off of CSF1 for CHD with PBS syndrome was 286 pg·mL~(-1).

HbA1c comparison and diagnostic efficacy analysis of multi center different glycosylated hemoglobin detection systems / 中华预防医学杂志

Objective: Compare and analyze the results of the domestic Lanyi AH600 glycated hemoglobin analyzer and other different detection systems to understand the comparability of the detection results of different detectors, and establish the best cut point of Lanyi AH600 determination of haemoglobin A1c (HbA1c) in the diagnosis of diabetes. Methods: Multi center cohort study was adopted. The clinical laboratory departments of 18 medical institutions independently collected test samples from their respective hospitals from March to April 2022, and independently completed comparative analysis of the evaluated instrument (Lanyi AH600) and the reference instrument HbA1c. The reference instruments include four different brands of glycosylated hemoglobin meters, including Arkray, Bio-Rad, DOSOH, and Huizhong. Scatter plot was used to calculate the correlation between the results of different detection systems, and the regression equation was calculated. The consistency analysis between the results of different detection systems was evaluated by Bland Altman method. Consistency judgment principles: (1) When the 95% limits of agreement (95% LoA) of the measurement difference was within 0.4% HbA1c and the measurement score was≥80 points, the comparison consistency was good; (2) When the measurement difference of 95% LoA exceeded 0.4% HbA1c, and the measurement score was≥80 points, the comparison consistency was relatively good; (3) The measurement score was less than 80 points, the comparison consistency was poor. The difference between the results of different detection systems was tested by paired sample T test or Wilcoxon paired sign rank sum test; The best cut-off point of diabetes was analyzed by receiver operating characteristic curve (ROC). Results: The correlation coefficient R2 of results between Lanyi AH600 and the reference instrument in 16 hospitals is≥0.99; The Bland Altman consistency analysis showed that the difference of 95% LoA in Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180) was -0.486%-0.325%, and the measurement score was 94.6 points (473/500); The difference of 95% LoA in the Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant II) was -0.727%-0.612%, and the measurement score was 89.8 points; The difference of 95% LoA in the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT) was -0.231%-0.461%, and the measurement score was 96.6 points; The difference of 95% LoA in the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT) was -0.469%-0.479%, and the measurement score was 91.9 points. The other 14 hospitals, Lanyi AH600, were compared with 4 reference instrument brands, the difference of 95% LoA was less than 0.4% HbA1c, and the scores were all greater than 95 points. The results of paired sample T test or Wilcoxon paired sign rank sum test showed that there was no statistically significant difference between Lanyi AH600 and the reference instrument Arkray HA8180 (Z=1.665,P=0.096), with no statistical difference. The mean difference between the measured values of the two instruments was 0.004%. The comparison data of Lanyi AH600 and the reference instrument of all other institutions had significant differences (all P<0.001), however, it was necessary to consider whether it was within the clinical acceptable range in combination with the results of the Bland-Altman consistency analysis. The ROC curve of HbA1c detected by Lanyi AH600 in 985 patients with diabetes and 3 423 patients with non-diabetes was analyzed, the area under curve (AUC) was 0.877, the standard error was 0.007, and the 95% confidence interval 95%CI was (0.864, 0.891), which was statistically significant (P<0.001). The maximum value of Youden index was 0.634, and the corresponding HbA1c cut point was 6.235%. The sensitivity and specificity of diabetes diagnosis were 76.2% and 87.2%, respectively. Conclusion: Among the hospitals and instruments currently included in this study, among these four hospitals included Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180), Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant Ⅱ), the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT), and the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT), the comparison between Lanyi AH600 and the reference instruments showed relatively good consistency, while the other 14 hospitals involved four different brands of reference instruments: Arkray, Bio-Rad, DOSOH, and Huizhong, Lanyi AH600 had good consistency with its comparison. The best cut point of the domestic Lanyi AH600 for detecting HbA1c in the diagnosis of diabetes is 6.235%.

Correlating nerve conduction studies with cross-sectional area measured using ultrasound in patients with neuromuscular disease / 中华神经科杂志

Objective:To determine whether there is a correlation between the cross-sectional area (CSA) and the parameters as measured on nerve conduction studies.Methods:Twenty-one patients with neuromuscular diseases in Beijing Tiantan Hospital from March 3, 2022 to May 4, 2023 underwent ultrasound measurement of the CSA of the median nerves and ulnar nerves at the wrist, elbow and the upper arm, followed by nerve conduction studies (NCS). A linear regression model was performed to compare NCS and CSA.Results:A total of 180 sets of motor nerve conduction velocity (MCV) and CSA at the different sites including 102 sets of median nerve and 78 sets of ulnar nerve, 220 sets of compound muscle action potential (CMAP) amplitude and CSA at the different sites including 104 sets of median nerve and 116 sets of ulnar nerve, 60 sets of sensory nerve conduction velocity (SCV) and CSA and sensory nerve action potential (SNAP) amplitude and CSA at the wrist including 32 sets of median nerve and 28 sets of ulnar nerve were recorded. The linear correlation between MCV and CSA was statistically significant both in median nerve ( r2=0.10,adjusted r2=0.09, P=0.001) and in ulnar nerve ( r2=0.18,adjusted r2=0.17, P<0.001).When CSA>10 mm 2, the linear correlation between CMAP amplitude and CSA was statistically significant both in median nerve ( r2=0.09,adjusted r2=0.08, P=0.024) and ulnar nerve ( r2=0.19,adjusted r2=0.17, P=0.004). The correlation between CMAP and CSA was not statistically significant when CSA≤10 mm 2. And the correlations between SCV and CSA and between SNAP and CSA were not statistically significant. Conclusions:CSA can better show the characteristics of changes in motor nerve conduction especially in motor conduction velocity. It is suggested that its application prospect in demyelinating peripheral neuropathy with motor nerve damage may be more extensive.

Contributions of SGK3 to transporter-related diseases.

Serum- and glucocorticoid-induced kinase 3 (SGK3), which is ubiquitously expressed in mammals, is regulated by estrogens and androgens. SGK3 is activated by insulin and growth factors through signaling pathways involving phosphatidylinositol-3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1 (PDK-1), and mammalian target of rapamycin complex 2 (mTORC2). Activated SGK3 can activate ion channels (TRPV5/6, SOC, Kv1.3, Kv1.5, Kv7.1, BKCa, Kir2.1, Kir2.2, ENaC, Nav1.5, ClC-2, and ClC Ka), carriers and receptors (Npt2a, Npt2b, NHE3, GluR1, GluR6, SN1, EAAT1, EAAT2, EAAT4, EAAT5, SGLT1, SLC1A5, SLC6A19, SLC6A8, and NaDC1), and Na+/K+-ATPase, promoting the transportation of calcium, phosphorus, sodium, glucose, and neutral amino acids in the kidney and intestine, the absorption of potassium and neutral amino acids in the renal tubules, the transportation of glutamate and glutamine in the nervous system, and the transportation of creatine. SGK3-sensitive transporters contribute to a variety of physiological and pathophysiological processes, such as maintaining calcium and phosphorus homeostasis, hydro-salinity balance and acid-base balance, cell proliferation, muscle action potential, cardiac and neural electrophysiological disturbances, bone density, intestinal nutrition absorption, immune function, and multiple substance metabolism. These processes are related to kidney stones, hypophosphorous rickets, multiple syndromes, arrhythmia, hypertension, heart failure, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, glaucoma, ataxia idiopathic deafness, and other diseases.

TOPK Activation Exerts Protective Effects on Cisplatin-induced Acute Kidney Injury.

OBJECTIVE: T-LAK-cell-originated protein kinase (TOPK), a PSD95-Disc large-ZO1 (PDZ) binding kinase (PBK), is a novel member of the mitogen-activated protein kinase (MAPK) family. Studies have shown that TOPK plays a critical role in the function of tumor cells, including apoptosis and mitosis. However, little is known on the effect of TOPK in cisplatin-induced acute kidney injury (CP-AKI). This study aimed to investigate the role and mechanism of TOPK in CP-AKI. METHODS: Cisplatin was administered to C57BL/6 mice and cultured kidney tubular epithelial cells (TECs) to establish the CP-AKI murine or cellular models. TECs were then stimulated with the specific inhibitor of TOPK OTS514 or transfected with the recombinant-activated plasmid TOPK-T9E to inhibit or activate TOPK. The TECs were treated with AKT inhibitor VIII following stimulation with OTS514 or cisplatin. Western blotting and flow cytometry were used to evaluate the cell cycle and apoptosis of TECs. RESULTS: The analysis revealed that the TOPK activity was significantly suppressed by cisplatin, both in vivo and in vitro. Furthermore, the pharmacological inhibition of TOPK by OTS514, a specific inhibitor of TOPK, exacerbated the cisplatin-induced cell cycle arrest in the G2/M phase and apoptosis of cultured TECs. Moreover, the TOPK activation via the TOPK-T9E plasmid transfection could partially reverse the cell cycle arrest at the G2/M phase and apoptosis of cisplatin-treated TECs. In addition, AKT/protein kinase B (PKB), as a TOPK target protein, was inhibited by cisplatin in cultured TECs. The pharmaceutical inhibition of AKT further aggravated the apoptosis of TECs induced by cisplatin or TOPK inhibition. TOPK systematically mediated the apoptosis via the AKT pathway in the CP-AKI cell model. CONCLUSION: These results indicate that TOPK activation protects against CP-AKI by ameliorating the G2/M cell cycle arrest and cell apoptosis.

Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids / 生理学报

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

Effects of Interactive Dynamic Scalp Acupuncture on Motor Function and Gait of Lower Limbs after Stroke: A Multicenter, Randomized, Controlled Clinical Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate the effects of interactive dynamic scalp acupuncture (IDSA), simple combination therapy (SCT), and traditional scalp acupuncture (TSA) on motor function and gait of the lower limbs in post-stroke hemiplegia patients.@*METHODS@#A total of 231 patients with post-stroke hemiplegia was randomly divided into IDSA (78 cases), SCT (78 cases), and TSA (75 cases) groups by a random number table. Scalp acupuncture (SA) and lower-limb robot training (LLRT) were both performed in the IDSA and SCT groups. The patients in the TSA group underwent SA and did not receive LLRT. The treatment was administered once daily and 6 times weekly for 8 continuous weeks, each session lasted for 30 min. The primary outcome measures included Fugl-Meyer assessment of the lower extremity (FMA-LE), berg balance scale (BBS), modified barthel index (MBI), and 6-min walking test (6MWT). The secondary outcome measures included stride frequency (SF), stride length (SL), stride width (SW), affected side foot angle (ASFA), passive range of motion (PROM) of the affected hip (PROM-H), knee (PROM-K) and ankle (PROM-A) joints. The patients were evaluated before treatment, at 1- and 2-month treatment, and 1-, and 2-month follow-up visits, respectively. Adverse events during 2-month treatment were observed.@*RESULTS@#Nineteen patients withdrew from the trial, with 8 in the IDSA and 5 in the SCT groups, 6 in the TSA group. The FMA-LE, BBS, 6MWT and MBI scores in the IDSA group were significantly increased after 8-week treatment and 2 follow-up visits compared with the SCT and TSA groups (P<0.05 or P<0.01). Compared with pre-treatment, the grade distribution of BBS and MBI scores in the 3 groups were significantly improved at 1, 2-month treatment and 2 follow-up visits (P<0.05 or P<0.01). The SF, PROM-H, PROM-K and PROM-A in the IDSA group was significantly increased compared with the SCT and TSA groups after 8-week of treatment (P<0.05 or P<0.01). Compared with the SCT group, ASFA of the IDSA group was significantly reduced after 8-week of treatment (P<0.05). SF, SL, PROM-K and PROM-A were significantly increased at the 2nd follow-up visit whereas the ASFA was significantly reduced in the IDSA group compared with the SCT groups at 1st follow-up visit (P<0.05 or P<0.01). The SF was significantly increased in the SCT group compared with the TSA group after 8-week treatment (P<0.05). Compared with the TSA group, PROM-K, PROM-A were significantly increased at the 2nd follow-up visit (P<0.05).@*CONCLUSIONS@#The effects of IDSA on lower-limb motor function and walking ability of post-stroke patients were superior to SCT and TSA. The SCT was comparable to TSA treatment, and appeared to be superior in improving the motion range of the lower extremities. (Registration No. ChiCTR1900027206).

Mechanism of Anti-tuberculosis Particles （Kanglao Granule） Based on Network Pharmacology and Experimental Research / 中国实验方剂学杂志

ObjectiveTo explore the potential anti-tuberculosis mechanism of Kanglao granule through network pharmacology. MethodThe active components of Kanglao granule were retrieved from related databases and the potential targets of the components from SwissTargetPrediction. Targets of the tuberculosis were screened from GeneCards and National Center for Biotechnology Information （NCBI）， and the anti-tuberculosis targets of the prescription were further identified. STRING and Cytoscape 3.8.0 were employed to construct the Chinese medicinal-disease target-signaling pathway network and screen core targets. Then gene ontology （GO） term enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were performed. Finally， AutoDock Vina was used for molecular docking between the active components of the prescription and key proteins and Western blotting for verifying the interaction between them. ResultA total of 29 important chemical components in the prescription were screened out， including β-sitosterol， sesamin， and kaempferol. A total of 28 key anti-tuberculosis targets were retrieved， such as protein kinase B1 （Akt1）， epidermal growth factor receptor （EGFR）， hypoxia inducible factor-1A （HIF-1A）， proto-oncogene tyrosine-protein kinase （SRC）， and matrix metalloproteinase-9 （MMP-9）. Bioinformatics analysis showed the 28 targets were involved in 41 GO terms such as oxygen metabolism， nucleic acid transcription， and metabolic enzyme pathway， and 28 key KEGG pathways， including Mycobacterium tuberculosis signaling pathway and phosphatidylinositol 3 kinase/protein kinase B pathway. Molecular docking results showed that Akt1 had the strongest binding affinity to sesamin. In vitro experiment indicated that sesamin inhibited the growth of M. tuberculosis by suppressing the phosphorylation of Akt1. ConclusionKanglao granule improved the sterilization level and immune response through multi-component， multi-target， and multi-pathway interactions， thereby achieving therapeutic effect on tuberculosis. Akt1 is one of the important targets involved in the treatment of tuberculosis.

Effect of Interactive Dynamic Scalp Acupuncture on Post-Stroke Cognitive Function, Depression, and Anxiety: A Multicenter, Randomized, Controlled Trial / 中国结合医学杂志

OBJECTIVE@#To compare the clinical effects of interactive dynamic scalp acupuncture (IDSA), simple combination therapy (SCT), and traditional scalp acupuncture (TSA) on cognitive function, depression and anxiety in patients with post-stroke cognitive impairment.@*METHODS@#A total of 660 patients with post-stroke cognitive impairment who were admitted to 3 hospitals in Shenzhen City between May 2017 and May 2020 were recruited and randomly assigned to the IDSA (218 cases), SCT (222 cases) and TSA groups (220 cases) according to a random number table. All the patients received conventional drug therapy for cerebral stroke and exercise rehabilitation training. Scalp acupuncture and computer-based cognitive training (CBCT) were performed simultaneously in the IDSA group, but separately in the morning and in the afternoon in the SCT group. The patients in the TSA group underwent scalp acupuncture only. The course of treatment was 8 weeks. Before treatment (M0), 1 (M1) and 2 months (M2) after treatment, as well as follow-up at 1 (M3) and 2 months (M4), the cognitive function of patients was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA) Scales; depression, anxiety, sleep quality, and self-care ability of patients were assessed using Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Pittsburgh Sleep Quality Index (PSQI), and Modified Barthel Index (MBI), respectively. During this trial, all adverse events (AEs) were accurately recorded.@*RESULTS@#There were no significant differences in the MMSE, MoCA, HAMD, HAMA, PSQI, and MBI scores among the 3 groups at M0 (all P>0.05). In the IDSA group, the MMSE, MoCA and MBI scores from M2 to M4 were significantly higher than those in the SCT and TSA groups, while the HAMD, HAMA and PSQI scores were significantly reduced (all P<0.01). The changes of all above scores (M2-M0, M4-M0) were significantly superior to those in the SCT and TSA groups (all P<0.01, except M4-M0 of HAMD). At M2, the severity of MMSE, HAMD, HAMA, PSQI and MBI in the IDSA group was significantly lower than that in the SCT and TSA groups (all P<0.01). There was no serious AE during this trial.@*CONCLUSIONS@#IDSA can not only significantly improve cognitive function, but also reduce depression, anxiety, which finally improves the patient's self-care ability. The effect of IDSA was significantly better than SCT and TSA. (Trial registration No. ChiCTR1900027206).

The electrophysiological features of patients with anti-neurofascin 155 IgG4 antibodies positive chronic inflammatory demyelinating polyradiculoneuropathy / 中华神经科杂志

Objective:To investigate the electrophysiological features of patients with anti-neurofascin 155 (NF155) IgG4 antibodies positive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Methods:The electrophysiological data of 6 anti-NF155 IgG4 antibodies positive CIDP patients in Beijing Tiantan Hospital, Capital Medical University from September 2018 to May 2021 were retrospectively analyzed. Parameters studies included standard motor and sensory nerve conduction studies, electromyography (EMG) and F waves studies. Correlation analysis was made to explore the relationships between clinical indicators and electrophysiological data.Results:There was statistically significant difference in the motor nerve conduction study on abnormal rate of tibial nerve (χ 2=11.08, P=0.011). Motor nerve conduction abnormalities were presented in a majority of patients with decreased motor conduction velocity (MCV) and prolonged distal motor latency (DML). There was no statistically significant difference in the overall abnormal rate between lower limbs and upper limbs (30/32, 93.8% vs 22/22, 100.0%; χ 2=1.43, P=0.508), sensory nerve conduction and motor nerve conduction (52/54, 96.3% vs 42/42, 100.0%; χ 2=1.59, P=0.503). There was statistically significant difference in the overall abnormal rate in median nerve, ulnar nerve and sural nerve (χ 2=14.96, P=0.001;χ 2=10.00, P=0.007; χ 2=9.95, P=0.008),and absent sensory nerve action potential was the most common abnormality in sensory nerve conduction abnormalities. The abnormal rate of EMG was 9/14, which was constituted by upper limbs (4/8) and lower limbs (5/6), and the spontaneous activity accompanied with prolonged duration and increased amplitude of motor unit action potential was common. Significant negative correlations were established between disease duration and compound muscle action potential (CMAP) amplitude and negative area of ulnar nerve ( r=-0.84, P=0.036; r =-0.76, P=0.011), and the correlations between age and MCV of median nerve and ulnar nerve were also found ( r=0.89, P=0.019; r=0.95, P=0.003). The DML of median nerve was negatively correlated with CMAP amplitude ( r=-0.63, P=0.049). Moreover, the correlation analysis revealed associations of the F wave latency with the DML, CMAP amplitude and MCV of tibial nerve ( r= 0.90, P=0.039; r=-0.96, P=0.012; r=-0.96, P=0.010). Conclusions:The motor nerve and sensory nerve, the myelin sheath and axon of peripheral nerves in anti-NF155 IgG4 CIDP patients were largely affected. The CMAP amplitude and negative area of ulnar nerve might be of certain clinical value in reflecting the disease duration.The younger the patients, the more severe the demyelination degree of the upper limbs. The F wave latency of tibial nerve not only reflected the abnormal proximal conduction, but also the distal damage degree of myelin sheath and axon.

Mechanistic insights into the renoprotective role of curcumin in cisplatin-induced acute kidney injury: network pharmacology analysis and experimental validation.

Cisplatin-induced acute kidney injury (CP-AKI) is a severe complication in patients receiving CP chemotherapy. However, effective therapies for CP-AKI are currently lacking. Curcumin (CUR), a natural polyphenol, is extracted from the rhizome of turmeric and has been reported to have nephroprotective activity. However, the role of CUR in CP-AKI remains unclear. This study aimed to explore the mechanism of CUR in CP-AKI by combining a network pharmacology approach with experimental validations. The analysis revealed 176 potential targets of CUR based on the HERB database and 1,286 related targets of CP-AKI from the GeneCards, DrugBank, and OMIM databases. Further, 106 common targets of CUR against CP-AKI were obtained, and these common targets constructed a protein-protein interaction (PPI) network. In addition, the core targets were screened from the PPI network using Cytoscape. Molecular docking revealed that CUR displayed the best binding to AKT1. Gene Ontology (GO) analysis indicated that the primary biological processes of CUR against CP-AKI included cellular response to chemical stress and apoptotic regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the PI3K-Akt signaling pathway was most significantly enriched in CUR against CP-AKI. Western blotting and flow cytometry showed that CUR inhibited apoptosis induced by CP by activating the Akt signaling pathway in human kidney tubular epithelial cells (HK-2). Altogether, our findings demonstrated that CUR alleviated apoptosis by activating the Akt signaling pathway in CP-AKI in vitro. These data provide a scientific basis for future investigations into the clinical application of CUR against CP-AKI.

Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin.

Serum and glucocorticoid-inducible kinase 3 (SGK3) is involved in maintaining podocyte function by regulating the protein levels of podocin and CD2-associated protein. Nephrin is also one of the slit diaphragm proteins of podocytes, but whether SGK3 participates in podocyte injury by regulating the levels of nephrin remains unclear. In this study, we focused on whether SGK3 affects nephrin levels and the mechanisms involved in the same. In the kidneys of adriamycin (ADR)-induced podocyte injury mouse model, the protein levels of SGK3 and nephrin were significantly decreased. Furthermore, the expression of SGK3 was negatively correlated with the output of proteinuria, and positively correlated with the levels of nephrin. In ADR-treated conditionally immortalized mouse podocyte cells (MPCs), the protein levels of nephrin and SGK3 were inhibited, while the constitutive expression of SGK3 reversed the ADR-induced decline in nephrin protein levels. Furthermore, ADR treatment or SGK3 inactivation enhanced the ubiquitin-proteasome degradation of nephrin in MPCs, and dramatically activated downstream effector proteins of SGK3, neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2) and glycogen synthase kinase-3 ß (GSK3ß). Similarly, Nedd4-2 or GSK3ß overexpression resulted in increased activity of Nedd4-2 or GSK3ß, and significantly downregulated nephrin levels. Interestingly, ubiquitin-mediated protein degradation of nephrin was regulated by Nedd4-2, rather than by GSK3ß. In summary, SGK3 inactivation downregulated the levels of nephrin by increasing Nedd4-2 and GSK3ß activity in ADR-induced podocyte injury model; in particular, the SGK3/Nedd4-2 signaling pathway was found to be involved in ubiquitin-mediated proteasome degradation of nephrin.