Chronic kidney disease(CKD)is a chronic disease characterized by renal structural damage and dysfunction.At present,there is still a lack of effective therapeutic drugs and prevention and treatment methods for CKD in clinical practice.More and more studies have shown that necroptosis,as a new type of programmed cell death,plays a vital role in the onset and progression of CKD.Targeting key molecules in the necroptosis pathway,such as RIPK1,RIPK3 and MLKL,the development of small molecule inhibitors has become an emerging strategy for the treatment of CKD,and has shown significant potential to pro-tect the kidneys and alleviate renal fibrosis in a variety of in vitro and in vivo models.Therefore,this article summarizes the re-search progress of the mechanism of necroptosis in recent years,and focuses on the potential role of necroptosis in the pathogene-sis of CKD and the therapeutic potential of targeting this path-way,providing a new perspective and research direction for the prevention and treatment of CKD in the future.

AIM To observe the effects of Yiqi Jiedu Tongluo Formula(YQJDTL)on renal microvascular endothelial function and prevention of renal injury in a rat model of type 2 diabetes mellitus(T2DM).METHODS The SD rats were randomly divided into a normal group and a model group.The model group was administered with high-fat diet combined with a single intraperitoneal injection of STZ to establish the T2DM model.The successfully modeled rats were randomly divided into the model group,the canagliflozin group(9 mg/kg),and the low-dose and high-dose YQJDTL groups(4.77,9.45 g/kg).The corresponding doses of the drug were administered by gavage for a total of 12 weeks,during which the rats underwent observation of their general condition and blood glucose changes.After the end of administration,the rats had their levels of renal index,24-hour UP,serum SCr,BUN,TC,TG,HDL-C,LDL-C,ET-1 and NOS measured;their changes in renal microvasculature and the degree of renal fibrosis observed using HE staining,Masson staining,PAS staining,and PASM staining;their ultrastructure of the glomeruli observed using transmission electron microscopy;their renal protein expressions of TGF-β,SMAD2,SMAD3,Col-1,VEGFA and PKC detected by immunohistochemical staining and Western blot;and their renal mRNA expressions of VEGFA,TGF-β,SMAD2 determined by RT-qPCR.RESULTS Compared with the model group,the high-dose YQJDTL group showed decreased levels of renal index,blood glucose,TG,TC,HDL,24 h UP,BUN,SCr and ET-1(P＜0.05,P＜0.01);increased LDL and NOS levels(P＜0.05,P＜0.01);reduced renal inflammatory infiltration and fibrosis degree,inhibited fusion of foot processes and thickening of basement membrane;decreased renal protein expressions of TGF-β,SMAD2,SMAD3,VEGFA,PKC and Col-1(P＜0.05,P＜0.01);and decreased mRNA expressions of VEGFA,TGF-β and SMAD2(P＜0.01).CONCLUSION In the rat models of T2DM,YQJDTL can reduce their levels of blood glucose and lipids by improving the renal indices levels and the renal microvascular endothelial functions to alleviate renal fibrosis and microangiopathy as well,and the mechanism may be associated with the down-regulated expressions of TGF-β/SMAD and VEGF pathway-related proteins.

Objective To explore the value of phase contrast(PC)MRI intracranial hemodynamic parameters for predicting acute mountain sickness(AMS).Methods Totally 72 healthy young volunteers were prospectively recruited.Intracranial hemodynamic parameters of internal carotid artery(ICA)and internal jugular vein(IJV)were measured using PC MRI under normal breathing,as well as mild,moderate and severe Valsalva maneuvers(VM)in plain area.The subjects were divided into AMS group(n=9)and non-AMS group(n=63)according to results of Lake Louise score(LLS)10 h after a rapid ascent to plateau area with altitude of 4 411 m.Univariate and multivariate logistic regression analyses were performed to screen independent predictors of AMS under different states and then construct single and combined VM states prediction models.Receiver operating characteristic curves were plotted,and the area under the curve(AUC)was calculated to evaluate the predictive efficacy of each model.Results ICA pulsatility index(PIICA)under mild VM,IJV cross-sectional area(SIJV)under moderate VM and IJV resistance index(RIIJV)under severe VM were all independent predictors of AMS(all P＜0.05).The efficacy of combined VM states model(AUC=0.869)for predicting AMS was higher than each single VM state model(AUC=0.698-0.738).Conclusion The model constructed based on PIICA under mild VM,SIJV under moderate VM and RIIJV under severe VM could be used to effectively predict AMS.

Chronic kidney disease(CKD)is a chronic disease characterized by renal structural damage and dysfunction.At present,there is still a lack of effective therapeutic drugs and prevention and treatment methods for CKD in clinical practice.More and more studies have shown that necroptosis,as a new type of programmed cell death,plays a vital role in the onset and progression of CKD.Targeting key molecules in the necroptosis pathway,such as RIPK1,RIPK3 and MLKL,the development of small molecule inhibitors has become an emerging strategy for the treatment of CKD,and has shown significant potential to pro-tect the kidneys and alleviate renal fibrosis in a variety of in vitro and in vivo models.Therefore,this article summarizes the re-search progress of the mechanism of necroptosis in recent years,and focuses on the potential role of necroptosis in the pathogene-sis of CKD and the therapeutic potential of targeting this path-way,providing a new perspective and research direction for the prevention and treatment of CKD in the future.

AIM:To explore the regulatory mecha-nism of pinoresinol diglucoside(PDG)on angiogen-esis during osteoporotic fracture healing in vivo and in vitro.METHODS:Fifty male C57BL/6J mice were randomly divided into five groups:normal group,model group,PDG 0.005,0.015 g/kg groups,and parathyroid hormone 1-34(PTH1-34)4×10-5 g/kg group.The osteoporotic fracture model of ovariec-tomized combined with femoral fracture was estab-lished,the PDG group was given intragastric admin-istration every other day and the PTH1-34 group was given subcutaneous injection of PTH1-34 every other day for 8 weeks.Micro-CT scanning,immunofluo-rescence and immunohistochemical staining were used to detect the related parameters and protein expressions.Human umbilical vein endothelial cells(HUVECs)were cultured,normal group,PDG 1,10,100 μmol/L groups and PTH1-341 ng/mL group were set up.CCK-8 assay,scratch experiment,tubule for-mation experiment,immunofluorescence and Western blot were used to detect the related pa-rameters and protein expressions.RESULTS:In vivo experiments found,compared with the normal con-trol group,a small amount of bone callus volume of fracture site were increased in the model control group,while BMD of non-callus site of femur,tra-becular bone fraction(BV/TV),trabecular thickness(Tb.Th)and trabecular number(Tb.N)were de-creased(P＜0.01),and trabecular separation(Tb.Sp)was increased(P＜0.01).The positive expression of vascular endothelial marker vascular endothelial markers(CD31)was decreased(P＜0.01).Compared with mice in the model control group,bone callus volume,index of BMD and BV/TV were increased in the PDG 0.005 g/kg group(P＜0.05),index of BMD,BV/TV,Tb.Th,Tb.N were increased,and index of Tb.Sp was decreased in the PDG 0.015 g/kg group(P＜0.05),the positive expression of CD31 was in-creased in the PDG administration groups(P＜0.01),the protein expressions of vascular endothelial growth factor(VEGF-A)(P＜0.01),Yes-associated protein 1(YAP1)(P＜0.01),PDZ-binding motif(TAZ)(P＜0.05)and TEA domain transcription factor 2(TEAD2)(P＜0.01)were increased in callus in the PDG 0.015 g/kg groups.Cell experiments found,compared with the normal control group,PDG groups promoted the proliferation,migration and tubule formation activity of HUVECs to varying de-grees(P＜0.05),at the same time,the expression of endothelial cadherin(E-cadherin)was decreased(P＜0.01),and VEGF-A,TEAD2,TAZ and YAP1 protein expression were increased(P＜0.05).CONCLUSION:PDG may accelerate osteoporotic fracture healing by promoting bone angiogenesis through regulat-ing Hippo signal pathway.

The plants of the genus Caragana Fabr. are desert plants of the Leguminosae family, which are widely used in traditional ethnomedicine, with the effects of nourishing Yin and nourishing blood, dispelling wind and removing dampness, clearing heat and detoxifying toxins. The anti-inflammatory effect of Caragana Fabr. has attracted much attention, the research on the related mechanism has made some progress, but it lacks systematic collation. By summarising the anti-inflammatory effects of the active ingredients of Caragana Fabr., the authors found that they have good anti-inflammatory activities on different inflammatory cell models in vitro, and have good improvement effects on rheumatoid arthritis, colitis, complex nephritis, and acute lung injury and other disease models. The anti-inflammatory effects of the active components of this genus mainly include the reduction of the levels of a variety of pro-inflammatory factors, and the signalling pathways involved mainly include TLR4/NF-κB, TLR4/MAPK, TLR4/NF-κB/IRF3, JAK/STAT-1, ERK/STAT-1 and so on. Therefore, the paper mainly reviews the research progress on the anti-inflammatory effects and mechanisms of the Caragana Fabr. plants and their active components according to disease types, with a view to providing reference for the in-depth study of their anti-inflammatory activities and the development of new products with related functions.

AIM:To explore the regulatory mecha-nism of pinoresinol diglucoside(PDG)on angiogen-esis during osteoporotic fracture healing in vivo and in vitro.METHODS:Fifty male C57BL/6J mice were randomly divided into five groups:normal group,model group,PDG 0.005,0.015 g/kg groups,and parathyroid hormone 1-34(PTH1-34)4×10-5 g/kg group.The osteoporotic fracture model of ovariec-tomized combined with femoral fracture was estab-lished,the PDG group was given intragastric admin-istration every other day and the PTH1-34 group was given subcutaneous injection of PTH1-34 every other day for 8 weeks.Micro-CT scanning,immunofluo-rescence and immunohistochemical staining were used to detect the related parameters and protein expressions.Human umbilical vein endothelial cells(HUVECs)were cultured,normal group,PDG 1,10,100 μmol/L groups and PTH1-341 ng/mL group were set up.CCK-8 assay,scratch experiment,tubule for-mation experiment,immunofluorescence and Western blot were used to detect the related pa-rameters and protein expressions.RESULTS:In vivo experiments found,compared with the normal con-trol group,a small amount of bone callus volume of fracture site were increased in the model control group,while BMD of non-callus site of femur,tra-becular bone fraction(BV/TV),trabecular thickness(Tb.Th)and trabecular number(Tb.N)were de-creased(P＜0.01),and trabecular separation(Tb.Sp)was increased(P＜0.01).The positive expression of vascular endothelial marker vascular endothelial markers(CD31)was decreased(P＜0.01).Compared with mice in the model control group,bone callus volume,index of BMD and BV/TV were increased in the PDG 0.005 g/kg group(P＜0.05),index of BMD,BV/TV,Tb.Th,Tb.N were increased,and index of Tb.Sp was decreased in the PDG 0.015 g/kg group(P＜0.05),the positive expression of CD31 was in-creased in the PDG administration groups(P＜0.01),the protein expressions of vascular endothelial growth factor(VEGF-A)(P＜0.01),Yes-associated protein 1(YAP1)(P＜0.01),PDZ-binding motif(TAZ)(P＜0.05)and TEA domain transcription factor 2(TEAD2)(P＜0.01)were increased in callus in the PDG 0.015 g/kg groups.Cell experiments found,compared with the normal control group,PDG groups promoted the proliferation,migration and tubule formation activity of HUVECs to varying de-grees(P＜0.05),at the same time,the expression of endothelial cadherin(E-cadherin)was decreased(P＜0.01),and VEGF-A,TEAD2,TAZ and YAP1 protein expression were increased(P＜0.05).CONCLUSION:PDG may accelerate osteoporotic fracture healing by promoting bone angiogenesis through regulat-ing Hippo signal pathway.

OBJECTIVE: Pseudomonas aeruginosa( P. aeruginosa) is a prevalent pathogenic bacterium involved in meningitis; however, the virulence factors contributing to this disease remain poorly understood. METHODS: The virulence of the P. aeruginosa A584, isolated from meningitis samples, was evaluated by constructing in vitro blood-brain barrier and in vivo systemic infection models. qPCR, whole-genome sequencing, and drug efflux assays of A584 were performed to analyze the virulence factors. RESULTS: Genomic sequencing showed that A584 formed a phylogenetic cluster with the reference strains NY7610, DDRC3, Pa58, and Pa124. Its genome includes abundant virulence factors, such as hemolysin, the Type IV secretion system, and pyoverdine. A584 is a multidrug-resistant strain, and its wide-spectrum resistance is associated with enhanced drug efflux. Moreover, this strain caused significantly more severe damage to the blood-brain barrier than the standard strain, PAO1. qPCR assays further revealed the downregulation of the blood-brain barrier-associated proteins Claudin-5 and Occludin by A584. During systemic infection, A584 exhibited a higher capacity of brain colonization than PAO1 (37.1 × 10 ⁶ CFU/g brain versus 2.5 × 10 ⁶ CFU/g brain), leading to higher levels of the pro-inflammatory factors IL-1β and TNF-α. CONCLUSION This study sheds light on the virulence factors of P. aeruginosa involved in meningitis.
Pseudomonas aeruginosa/genetics* ; Virulence Factors/metabolism* ; Animals ; Virulence ; Mice ; Pseudomonas Infections/microbiology* ; Blood-Brain Barrier/microbiology* ; Humans ; Female

OBJECTIVE: To investigate the biological behavior, differentiation ability, and differential gene expression of lymph node mesenchymal stem cells (MSCs) in patients with diffuse large B-cell lymphoma (DLBCL) and reactive lymphoid hyperplasia (RLH), providing a theoretical basis for clinical chemotherapy resistance. METHODS: Lymph node MSCs from patients with DLBCL and RLH were separated, passaged and cultured. The cell morphology and growth status were observed. Flow cytometry was performed to detect the immune phenotype of MSCs. The in vitro directed differentiation ability of the two types of MSCs was observed. High-throughput sequencing was used to analyze the differential gene expression and enrichment of two groups of MSCs. RESULTS: The lymph node MSCs of patients with DLBCL and RLH had similar cell morphology and growth characteristics, and both groups of MSCs expressed CD90, CD105, and CD73 on the cell surface. Compared with lymph node MSCs derived from patients with RLH, lymph node MSCs derived from DLBCL patients showed stronger osteogenic and adipogenic differentiation abilities. High-throughput sequencing results displayed that lymph node MSCs derived from DLBCL patients significantly upregulated some genes such as TOP2A, LFNG, GRIA3, SEC14L2, SPON2, AURKA, LRRC15, FOXD1, HOXC9, CDC20 and remarkably downregulated some genes such as TBC1D8, LDLR, PCDHAC2, POLH, PKP2, ANKRD37, DMKN, HSD11B1, ARHGAP20, PTGS1,etc. CONCLUSION Lymph node MSCs in DLBCL patients exhibit unique biological behavior and gene expression profiles, which may be closely related to clinical chemotherapy resistance.
Humans ; Mesenchymal Stem Cells/cytology* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Cell Differentiation ; Lymph Nodes/pathology* ; Pseudolymphoma/pathology*

Abuse of amphetamine-based stimulants is a primary public health concern. Recent studies have underscored a troubling escalation in the inappropriate use of prescription amphetamine-based stimulants. However, the neurophysiological mechanisms underlying the impact of acute methamphetamine exposure (AME) on sleep homeostasis remain to be explored. This study employed non-human primates and electroencephalogram (EEG) sleep staging to evaluate the influence of AME on neural oscillations. The primary focus was on alterations in spindles, delta oscillations, and slow oscillations (SOs) and their interactions as conduits through which AME influences sleep stability. AME predominantly diminishes sleep-spindle waves in the non-rapid eye movement 2 (NREM2) stage, and impacts SOs and delta waves differentially. Furthermore, the competitive relationships between SO/delta waves nesting with sleep spindles were selectively strengthened by methamphetamine. Complexity analysis also revealed that the SO-nested spindles had lost their ability to maintain sleep depth and stability. In summary, this finding could be one of the intrinsic electrophysiological mechanisms by which AME disrupted sleep homeostasis.
Animals ; Methamphetamine ; Electroencephalography ; Male ; Sleep/drug effects* ; Central Nervous System Stimulants ; Delta Rhythm/drug effects* ; Sleep Stages/drug effects*