Screening of active components in Astragalus mongholicus Bunge and Panax notoginseng formula for anti-fibrosis in CKD: nobiletin inhibits Lgals1/PI3K/AKT signaling to improve renal fibrosis.

The Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) has been clinically shown to effectively slow down the progression of chronic kidney disease (CKD) and has demonstrated significant anti-fibrosis effects in experimental CKD model. However, the specific active ingredients and underlying mechanism are still unclear. The active ingredients of A&P were analyzed by Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-HR-MS). A mouse model of CKD was constructed by 5/6 nephrectomy. Renal function was assessed by creatinine and urea nitrogen. Real-time PCR and Western Blot were performed to detect the mRNA and protein changes in kidney and cells. An in vitro fibrotic cell model was constructed by TGF-ß induction in TCMK-1 cells. The results showed that thirteen active ingredients of A&P were identified by UPLC-HR-MS, nine of which were identified by analysis with standards, among which the relative percentage of NOB was high. We found that NOB treatment significantly improved renal function, pathological damage and reduced the expression level of fibrotic factors in CKD mice. The results also demonstrated that Lgals1 was overexpressed in the interstitial kidney of CKD mice, and NOB treatment significantly reduced its expression level, while inhibiting PI3K and AKT phosphorylation. Interestingly, overexpression of Lgals1 significantly increased fibrosis in TCMK1 cells and upregulated the activity of PI3K and AKT, which were strongly inhibited by NOB treatment. NOB is one of the main active components of A&P. The molecular mechanism by which NOB ameliorates renal fibrosis in CKD may be through the inhibition of Lgals1/PI3K/AKT signaling pathway.

Critical role of checkpoint kinase 1 in spinal cord injury-induced motor dysfunction in mice.

Spinal cord injury (SCI) is a devastating neurotraumatic condition characterized by severe motor dysfunction and paralysis. Accumulating evidence suggests that DNA damage is involved in SCI pathology. However, the underlying mechanisms remain elusive. Although checkpoint kinase 1 (Chk1)-regulated DNA damage is involved in critical cellular processes, its role in SCI regulation remains unclear. This study aimed to explore the role and potential mechanism of Chk1 in SCI-induced motor dysfunction. Adult female C57BL/6J mice subjected to T9-T10 spinal cord contusions were used as models of SCI. Western blotting, immunoprecipitation, histomorphology, and Chk1 knockdown or overexpression achieved by adeno-associated virus were performed to explore the underlying mechanisms. Levels of p-Chk1 and γ-H2AX (a cellular DNA damage marker) were upregulated, while ferroptosis-related protein levels, including glutathione peroxidase 4 (GPX4) and x-CT were downregulated, in the spinal cord and hippocampal tissues of SCI mice. Functional experiments revealed increased Basso Mouse Scale (BMS) scores, indicating that Chk1 downregulation promoted motor function recovery after SCI, whereas Chk1 overexpression aggravated SCI-induced motor dysfunction. In addition, Chk1 downregulation reversed the SCI-increased levels of GPX4 and x-CT expression in the spinal cord and hippocampus, while immunoprecipitation assays revealed strengthened interactions between p-Chk1 and GPX4 in the spinal cord after SCI. Finally, Chk1 downregulation promoted while Chk1 overexpression inhibited NeuN cellular immunoactivity in the spinal cord after SCI, respectively. Collectively, these preliminary results imply that Chk1 is a novel regulator of SCI-induced motor dysfunction, and that interventions targeting Chk1 may represent promising therapeutic targets for neurotraumatic diseases such as SCI.

Effectiveness of teriparatide in in improving healing rates and bone-turnover markers of osteoporotic hip fracture: a meta-analysis.

Objective: To evaluate the effect of subcutaneous teriparatide therapy on fracture healing rate and change in bone mass density in osteoporotic hip fractures. METHODS: The meta-analysis was done from September to December 2022, and comprised literature search on Wanfang, CNKI, VIP, PubMed, Embase, Cochrane Library, and Web of Science databases from the establishment of the respective database till December 2022. The relevant journals of the library of Macao University of Science and Technology, China, were manually searched for randomised controlled trials of teriparatide in the treatment of osteoporotic hip fractures. The shortlisted studies were subjectd to Cochrane Risk of Bias tool and the Jadad Rating Scale. Meta-analysis was done using the RevMan 5.4 software provided by the Cochrane Collaboration Network. Fracture healing rate and bone mineral density were the primary outcome measures, while mortality, adverse events, malformations, complications, subsequent fractures, timed-up-and-go test, visual analogue scale score, and procollagen type I N-terminal propeptide were the secondary outcome measures. RESULTS: Of the 1,094 articles retrieved, 8(0.7%) randomised controlled trials were analysed. There were 744 patients; 372(50%) in the teriparatide group and 372(50%) in the control group. Fracture healing rate was not significantly different (p=0.82), while bone mineral density was significantly different between the groups (p<0.001). Mortality, adverse events, deformity, and complications were not significantly different (p>0.05), while subsequent fractures, timed-up-and-go score, visual analogue scale score and procollagen type I N-terminal propeptide were significantly different between the groups (p<0.05). Conclusion: The literature did not support teriparatide's ability to improve the healing rate of osteoporotic hip fractures, or to reduce mortality, adverse events, malformations, and complications. In addition, teriparatide could increase bone mineral density of osteoporotic hip fractures and the procollagen type I N-terminal propeptide value, alleviate hip pain, and reduce subsequent fracture rates. This trial is registered with PROSPERO with registration number CRD42022379832.

Extracellular vesicles in chronic kidney disease: diagnostic and therapeutic roles.

Chronic kidney disease (CKD) is a progressive disorder characterized by structural and functional changes in the kidneys, providing a global health challenge with significant impacts on mortality rates. Extracellular vesicles (EVs), are vital in the physiological and pathological processes associated with CKD. They have been shown to modulate key pathways involved in renal injury, including inflammation, fibrosis, apoptosis, and oxidative stress. Currently, the application research of EVs in the diagnosis and treatment of CKD is highly prevalent. However, there is currently a lack of standardized guidelines for their application, and various methodologies have advantages and limitations. Consequently, we present an comprehensive summary elucidating the multifaceted involvement of EVs in both physiological and pathological aspects in CKD. Furthermore, we explore their potential as biomarkers and diverse therapeutic roles in CKD. This review provides an overview of the current state of research on application of EVs in the diagnosis and therapeutic management of CKD.

Hydrogen sulfide ameliorates lipopolysaccharide-induced anxiety-like behavior by inhibiting checkpoint kinase 1 activation in the hippocampus of mice.

Hydrogen sulfide (H2S), an endogenous gasotransmitter, exhibits the anxiolytic roles through its anti-inflammatory effects, although its underlying mechanisms remain largely elusive. Emerging evidence has documented that cell cycle checkpoint kinase 1 (Chk1)-regulated DNA damage plays an important role in the neurodegenerative diseases; however, there are few relevant reports on the research of Chk1 in neuropsychiatric diseases. Here, we aimed to investigate the regulatory role of H2S on Chk1 in lipopolysaccharide (LPS)-induced anxiety-like behavior focusing on inflammasome activation in the hippocampus. Cystathionine γ-lyase (CSE, a H2S-producing enzyme) knockout (CSE-/-) mice displayed anxiety-like behavior and activation of inflammasome-mediated inflammatory responses, manifesting by the increase levels of interleukin-1ß (IL-1ß), IL-6, and ionized calcium-binding adaptor molecule-1 (Iba-1, microglia marker) expression in the hippocampus. Importantly, expression of p-Chk1 and γ-H2AX (DNA damage marker) levels were also increased in the hippocampus of CSE-/- mice. LPS treatment decreased the expression of CSE and CBS while increased p-Chk1 and γ-H2AX levels and inflammasome-activated neuroinflammation in the hippocampus of mice. Moreover, p-Chk1 and γ-H2AX protein levels and cellular immunoactivity were significantly increased while CSE and CBS were markedly decreased in cultured BV2 cells followed by LPS treatment. Treatment of mice with GYY4137, a donor of H2S, inhibited LPS-induced increased in p-Chk1 and γ-H2AX levels, mitigated inflammasome activation and inflammatory responses as well as amelioration of anxiety-like behavior. Notably, SB-218078, a selective Chk1 inhibitor treatment attenuated the effect of LPS on inflammasome activation and inflammatory responses and the induction of anxiety-like behavior. Finally, STAT3 knockdown with AAV-STAT3 shRNA alleviated LPS-induced anxiety-like behavior and inhibited inflammasome activation in the hippocampus, and blockade of NLRP3 with MCC950 attenuated neuroinflammation induction and ameliorated LPS-induced anxiety-like behavior. Overall, this study indicates that downregulation of Chk1 activity by H2S activation may be considered as a valid strategy for preventing the progression of LPS-induced anxiety-like behavior.

Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycin-induced focal segmental glomerulosclerosis.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (MSCs) show podocyte-protective effects in chronic kidney disease. Calycosin (CA), a phytoestrogen, is isolated from Astragalus membranaceus with a kidney-tonifying effect. CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion. However, the protective effect and underlying mechanism of CA-pretreated MSCs (MSCsCA) on podocytes in adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) mice remain unclear. AIM: To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved. METHODS: ADR was used to induce FSGS in mice, and MSCs, CA, or MSCsCA were administered to mice. Their protective effect and possible mechanism of action on podocytes were observed by Western blot, immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction. In vitro, ADR was used to stimulate mouse podocytes (MPC5) to induce injury, and the supernatants from MSC-, CA-, or MSCsCA-treated cells were collected to observe their protective effects on podocytes. Subsequently, the apoptosis of podocytes was detected in vivo and in vitro by Western blot, TUNEL assay, and immunofluorescence. Overexpression of Smad3, which is involved in apoptosis, was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells. RESULTS: CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells. Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells, which was reversed by MSCCA treatment more significantly than by MSCs or CA alone. When Smad3 was overexpressed in MPC5 cells, MSCsCA could not fulfill their potential to inhibit podocyte apoptosis. CONCLUSION: MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis. The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.

VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model.

BACKGROUND: We have shown that Hippo-YAP signaling pathway plays an important role in endothelial cell differentiation. Vestigial-like family member 4 (VGLL4) has been identified as a YAP inhibitor. However, the exact function of VGLL4 in vascular endothelial cell development remains unclear. In this study, we investigated the role of VGLL4, in human endothelial lineage specification both in 3D vascular organoid and 2D endothelial cell differentiation. METHODS AND RESULTS: In this study, we found that VGLL4 was increased during 3D vascular organoids generation and directed differentiation of human embryonic stem cells H1 towards the endothelial lineage. Using inducible ectopic expression of VGLL4 based on the piggyBac system, we proved that overexpression of VGLL4 in H1 promoted vascular organoids generation and endothelial cells differentiation. In contrast, VGLL4 knockdown (heterozygous knockout) of H1 exhibited inhibitory effects. Using bioinformatics analysis and protein immunoprecipitation, we further found that VGLL4 binds to TEAD1 and facilitates the expression of endothelial master transcription factors, including FLI1, to promote endothelial lineage specification. Moreover, TEAD1 overexpression rescued VGLL4 knockdown-mediated negative effects. CONCLUSIONS: In summary, VGLL4 promotes EC lineage specification both in 3D vascular organoid and 2D EC differentiation from pluripotent stem cell, VGLL4 interacts with TEAD1 and facilitates EC key transcription factor, including FLI1, to enhance EC lineage specification.

Assessment of prognostic role of a novel 7-lncRNA signature in HCC patients.

Background: Hepatocellular carcinoma (HCC) is characterized by extensive risk factors, high morbidity and mortality. Clinical prognostic evaluation assay assumes a nonspecific quality. Better HCC prognostics are urgently needed. Long noncoding RNAs (lncRNAs) exerts a crucial role in tumorigenesis and development. Excavating specific lncRNAs signature to ameliorate the high-risk survival prediction in HCC patients is worthwhile. Methods: Differentially expressed lncRNAs (DElncRNAs) profile was acquired from The Cancer Genome Atlas database (TCGA). Then, the lncRNAs high-risk survival prognostic model was established using the least absolute shrinkage and selection operator (LASSO)-Cox regression algorithm. The lncRNAs were evaluated in clinical specimen by PCR. The receiver operating characteristic curve (ROC) analysis was further conducted to assess the potential prognostic value of the model. Moreover, a visible nomogram containing clinicopathological features and prognostic model was developed for prediction of survival property. Potential molecular mechanism was assessed by GO, KEGG, GSEA enrichment analysis and CIBERSORT immune infiltration analysis. Results: A novel 7-lncRNA risk model (AL161937.2, LINC01063, AC145207.5, POLH-AS1, LNCSRLR, MKLN1-AS, AC105345.1) was constructed and validated for HCC prognosis prediction. Kaplan-Meier analysis revealed that patients in the high-risk group suffered a poor prognosis (p = 1.813 × 10-8). These genes were detected by PCR, and the expression trend was in accordance with TCGA database. Interestingly, the risk score served as an independent risk factor for HCC patients (HR: 1.166, 95% CI:1.119-1.214, p < 0.001). The nomogram was established, and the predictive accuracy in the nomogram was prior to the TNM stage according to the ROC curve analysis. Cell proliferation related pathway, decreased CD4+ T cell, CD8+ T cell, NK cell and elevated Neutrophil, Macrophage M0 were observed in high-risk group. Besides, suppression of MKLN1-AS expression inhibited cell proliferation of HCC cells by CCK8 assay in vitro. Conclusion: The 7-lncRNA signature may exert a particular prognostic prediction role in HCC and provide new insight in HCC carcinogenesis.

Panax Notoginseng Saponins Alleviate LPS-induced Fibrosis of HK-2 Cells by Inhibiting the Activation of NLRP3 Inflammasome and Pyroptosis.

BACKGROUND: Renal fibrosis is related to impaired kidney function and can eventually lead to end-stage renal disease, for which no effective treatment is available. Panax notoginseng saponins (PNS), as a commonly used traditional Chinese medicine, is considered a possible alternative for the treatment of fibrosis. OBJECTIVE: The purpose of the present study was to investigate the effects and possible mechanisms of PNS on renal fibrosis. METHODS: HK-2 cells were used to induce renal fibrosis cell model by lipopolysaccharide (LPS), and the cytotoxicity of PNS on HK-2 cells was investigated. Cell damage, pyroptosis, and fibrosis were analyzed to investigate the effects of PNS on LPS-induced HK-2 cells. NLRP3 agonist Nigericin was used further to explore the inhibitory effect of PNS on LPS-induced pyroptosis so as to clarify the possible mechanism of PNS on renal fibrosis. RESULTS: PNS had no cytotoxicity on HK-2 cells, and could reduce the apoptosis and the release of lactate dehydrogenase (LDH) and inflammatory cytokines of LPS-induced HK-2 cells, showing an alleviating effect on cell damage. PNS also reduced the expression of pyroptosis proteins NLRP3, IL-1ß, IL-18, and Caspase-1, as well as fibrosis proteins α-SMA, collagen Ⅰ and p-Smad3/Smad3, which showed an inhibitory effect on LPS-induced pyroptosis and fibrosis. In addition, LPS-induced cell damage, pyroptosis, and fibrosis were aggravated after Nigericin treatment, while PNS alleviated the aggravation caused by Nigericin. CONCLUSION: PNS inhibits pyroptosis by inhibiting the activation of NLRP3 inflammasome in LPS-induced HK-2 cells, which ultimately alleviates renal fibrosis and plays a good role in the treatment of kidney diseases.

VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2.

The Hippo signaling pathway plays a critical role in cardiovascular development and stem cell differentiation. Using microarray profiling, we found that the Hippo pathway components vestigial-like family member 4 (VGLL4) and TEA domain transcription factor 1 (TEAD1) were upregulated during vascular smooth muscle cell (VSMC) differentiation from H1 ESCs (H1 embryonic stem cells). To further explore the role and molecular mechanisms of VGLL4 in regulating VSMC differentiation, we generated a VGLL4-knockdown H1 ESC line (heterozygous knockout) using the CRISPR/Cas9 system and found that VGLL4 knockdown inhibited VSMC specification. In contrast, overexpression of VGLL4 using the PiggyBac transposon system facilitated VSMC differentiation. We confirmed that this effect was mediated via TEAD1 and VGLL4 interaction. In addition, bioinformatics analysis revealed that Ten-eleven-translocation 2 (TET2), a DNA dioxygenase, is a target of TEAD1, and a luciferase assay further verified that TET2 is the target of the VGLL4-TEAD1 complex. Indeed, TET2 overexpression promoted VSMC marker gene expression and countered the VGLL4 knockdown-mediated inhibitory effects on VSMC differentiation. In summary, we revealed a novel role of VGLL4 in promoting VSMC differentiation from hESCs and identified TET2 as a new target of the VGLL4-TEAD1 complex, which may demethylate VSMC marker genes and facilitate VSMC differentiation. This study provides new insights into the VGLL4-TEAD1-TET2 axis in VSMC differentiation and vascular development.

KCNQ1OT1 Influences HK-2 Apoptosis and Inflammation in LPS-Induced Acute Renal Injury via Modulating miR-30a-5p/NLRP3 Axis.

Objective: To investigate the influence of KCNQ1OT1 on HK-2 apoptosis and inflammation in ARI and its molecular mechanism. Methods: Normal cultivated HK-2 cells were used as negative control (NC) group. Three different concentrations of lipopolysaccharide (LPS) were used to treat the cells (5 µg/mL, 10 µg/mL, and 20 µg/mL). The groups included si-KCN1OT1+ LPS, si-NC + LPS, miR-30a-5p + LPS, pcDNA-NLRP3+si-KCNQ1OT1 + LPS group, miR-NC + LPS group, and pcDNA + si-KCNQ1OT1 + LPS group. CCK-8 and flow cytometry are used to measure cell viability and apoptosis, while RT-qPCR and Western blotting are used to detect KCNQ1OT1, miR-30a-5p, and NLRP3 mRNA. ELISA was used to detect the levels of TNF-α, IL-6, and IL-1ß in HK-2 cells. The targeting relationship among KCNQ1OT1, miR-30a-5p, and NLRP3 was verified. Results: After the intervention of LPS, the viability of HK-2 cells was decreased, while the apoptosis rates were increased. The mRNA and protein expressions of NLRP3 and KCNQ1OT1 were increased, while the mRNA and protein levels of miR-30a-5p were decreased (P < 0.05). The expressions of Bax and Cleaved-caspase-3 were downregulated after silencing KCNQ1OT1 and overexpressed miR-30a-5p. In addition, the viability of HK-2 cells was improved, and the apoptosis was reduced by inhibiting KCNQ1OT1 and overexpressed miR-30a-5p. Thus, KCNQ1OT1 modulated NLRP3 via targeting miR-30a-5p. Overexpression of NLRP3 reverses KCNQ1OT1 inhibition of LPS-induced apoptosis, activity, and inflammation in HK-2 cells. Conclusions: Through modulating the miR-30a-5p/NLRP3 axis, inhibition of KCNQ1OT1 may reduce HK-2 apoptosis and inflammation in LPS-induced ARI.

Panax notoginseng saponins alleviate damage to the intestinal barrier and regulate levels of intestinal microbes in a rat model of chronic kidney disease.

OBJECTIVES: Chronic kidney disease (CKD) is a long-term condition characterized by poor prognosis and a high mortality rate. Panax notoginseng saponins (PNS) are the main active ingredient of the traditional Chinese herb Panaxnotoginseng(Burk.)F.H.Chen, which has been widely reported to have various pharmacological effects. Here, we examined the effect of PNS on renal function and the modulation of intestinal flora and intestinal barrier in a rat model of adenine-induced CKD. METHODS: Adenine was used to establish a rat model of CKD, biochemical testing, histopathologic examination, ELISA, immunohistochemical assay, western blot assay, and fecal microbiota 16s rRNA analysis was used to test the effect of PNS on CKD rats. RESULTS: Adenine induced a significant decrease in glomerular filtration rate, an increase in urinary protein excretion rate, and pathological damage to renal tissue in CKD rats. TNF-α, MCP-1, IL-1ß, IL-18, TMAO, and endotoxin levels were increased in the blood of the model rats. Application of PNS countered the effects of adenine, restoring the above parameters to the level observed in healthy rats. In addition, activation of the inflammatory proteins NF-κB (p65) and NLRP3 and the fibrosis-associated proteins α-SMA and smad3 were inhibited in the kidneys of CKD rats. Furthermore, PNS promoted the expression of the tight junction proteins Occludin and ZO-1, increased SIgA levels, strengthened intestinal immunity, reduced mechanical damage to the intestine, was reduced levels of DAO and D-LA. Our data suggest PNS may delay CKD by restoring gut microbiota, and through the subsequent generation of a microbial barrier and modulation of microbiota metabolites. CONCLUSIONS: In conclusion, PNS may inhibit the development of inflammation and fibrosis in the kidney tissue through regulation of intestinal microorganisms and inhibition of the activation of pro-inflammatory and pro-fibrotic proteins in the kidney.

Role of Ero1α in cognitive impairment induced by chronic hypoxia.

Recent reports suggested the endoplasmic reticulum stress (ERS)-associated pathway is involved with cognitive impairment in hypoxia condition. ERO1-like protein alpha (Ero1α), an endoplasmic reticulum membrane-bound N-glycoprotein, has been reported to promote oxidative protein folding. However, no studies have reported whether the Ero1α is trapped in hypoxia-induced neuronal loss through the ERS-associated pathways. In our study, this effect of Ero1α was investigated using C57BL/6J mice, the HT22 cells and primary rat neurons. C57BL/6J mice were modeled in a hypoxic chamber for 4 weeks. Behavioral tests were then carried out to test cognitive functions, including the Morris water maze and fear conditioning test. Proteomics showed that Ero1α distinctly upregulated compared with normoxia group and verified using western blotting. Flow cytometry and immunofluorescence were used to analyze the neuroprotective effect of inhibitor EN460 of Ero1α in the HT22 cells. In C57BL/6J mice, hypoxia significantly caused cognitive decline. Brain slice staining results were also used to confirm this effect. Western blot analysis demonstrated that Ero1α, ERS-associated proteins and apoptosis-associated proteins significantly increased in the hypoxia treated groups, further proliferation-related marker protein decreased. EN460, a selective endoplasmic reticulum oxidation 1 (ERO1) inhibitor, counteracted neuronal apoptosis and ameliorated neuronal cell proliferation in the HT22 cells. Taken together, our data indicate that hypoxia induces cognitive impairment, at least in part, by upregulating Ero1α which contributes to neuronal apoptosis through ERS signaling pathway, providing preliminary experimental evidence that the Ero1α is a promising therapeutic target in hypoxia-induced cognitive deficits.

The Apelin-APJ axis alleviates LPS-induced pulmonary fibrosis and endothelial mesenchymal transformation in mice by promoting Angiotensin-Converting Enzyme 2.

Fibrotic alterations resulting from abnormal tissue repair after lung injury are responsible for the high mortality observed after acute respiratory distress syndrome. Therefore, the prevention and treatment of pulmonary fibrosis has been widely concerned. The Apelin-APJ axis plays an important role in the prevention and treatment of respiratory diseases and organ fibrosis. However, its underlying mechanism remains to be further studied. The aim of this study was to investigate whether the anti-pulmonary fibrosis effect of apelin-APJ axis is related to the activation of angiotensin-converting Enzyme 2 (ACE2). Here, we found that exogenous activation of the Apelin-APJ axis alleviates lipopolysaccharide (LPS)-induced pulmonary fibrosis in mice. In vitro studies revealed that Apelin-13 inhibited LPS-induced endothelial mesenchymal transition in lung microvascular endothelial cells, whereas [Ala13]-Apelin-13 (Apelin-APJ axis inhibitor) accelerated LPS-induced endothelial interstitial transformation in lung microvascular endothelial cells. Notably, angiotensin-converting enzyme 2 (ACE2) inhibitor blocks the beneficial effect of the Apelin-APJ axis activation on LPS-induced pulmonary fibrosis. This finding suggests that the Apelin-APJ axis inhibits pulmonary fibrosis by activating ACE2. Simultaneously, accumulating evidence suggests that ubiquitination may contribute to pulmonary fibrosis. Our study found that LPS increased the ubiquitination of ACE2 protein, whereas Apelin-13 inhibited it. In conclusion, exogenous activation of the Apelin-APJ axis improves LPS-induced pulmonary fibrosis in mice and may be a viable therapeutic target for pulmonary fibrosis.

Vascular Calcification in Chronic Kidney Disease: An Update and Perspective.

Chronic kidney disease is a devastating condition resulting from irreversible loss of nephron numbers and function and leading to end-stage renal disease and mineral disorders. Vascular calcification, an ectopic deposition of calcium-phosphate salts in blood vessel walls and heart valves, is an independent risk factor of cardiovascular morbidity and mortality in chronic kidney disease. Moreover, aging and related metabolic disorders are essential risk factors for chronic kidney disease and vascular calcification. Marked progress has been recently made in understanding and treating vascular calcification in chronic kidney disease. However, there is a paucity of systematic reviews summarizing this progress, and investigating unresolved issues is warranted. In this systematic review, we aimed to overview the underlying mechanisms of vascular calcification in chronic kidney diseases and discuss the impact of chronic kidney disease on the pathophysiology of vascular calcification. Additionally, we summarized potential clinical diagnostic biomarkers and therapeutic applications for vascular calcification with chronic kidney disease. This review may offer new insights into the pathogenesis, diagnosis, and therapeutic intervention of vascular calcification.

Long-segment restrictive tear of radial artery under ultrasound guide for arteriovenous fistula by PTA: A case report.

Considerable calcification and stenosis frequently occur in the radial artery (RA) in diabetic nephropathy. PTA was performed successfully using a balloon to expand and restrictively tear the longitudinal axis of the RA. This approach seems to be a useful measure of promoting the maturation of AVF in diabetic nephropathy.

Mechanical Behavior of Polyethylene Pipes under Strike-Slip Fault Movements.

The present paper addresses the mechanical behaviors and failure mechanisms of buried polyethylene (PE) pipes crossing active strike slip tectonic faults based on numerical simulation of the nonlinear response of the soil-pipeline system. The developed finite element (FE) model is first verified through comparing the simulation results with those from large-scale tests and good agreement between simulation and experimental measurements is obtained. The FE model is then applied to investigate the effects of fault crossing angle, pipe and soil properties on the mechanical behavior of PE pipe. The results indicate that the PE pipe crossing negative fault angles is primarily subjected to compression and bending, thus exhibits the phenomenon of buckling. With the increase of crossing angle, there is an increase of the axial strain and the maximum Mises stress in the buckled cross section, and a decrease of the distance between the buckling position and the fault plane. While for positive crossing angles, the PE pipe is mainly subjected to tension and relatively small bending. Increasing the crossing angle causes an increase in bending strain and a decrease in the axial strain. In addition, when the fault moving speed is slower, the axial strain and bending strain are larger, whereas the maximum Mises stress in the buckled cross section and the distance between the buckled position and the fault plane are reduced. Furthermore, the most severe deformation of the pipe is observed when it is buried in the sandy soil, followed by cohesive soil and loess soil.

Shenweifang-containing serum inhibits transforming growth factor-ß1 induced myofibroblast differentiation in normal rat kidney interstitial fibroblast cell.

OBJECTIVE: To investigate the efficacy of Shenweifang (SWF)-containing serum on transforming growth factor (TGF)-ß1-induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells (NRK-49F). METHODS: Sprague-Dawley rats were gavaged with one of five solutions: (a) saline; (b) saline plus low-dose SWF; (c) saline plus medium-dose SWF; (d) saline plus highdose SWF; and (e) saline plus valsartan. NRK-49F cells were treated with TGF-ß1 and cultured using serum from the gavaged rats. RESULTS: TGF-ß1 treatment increased the expression of α-smooth muscle actin, proliferating cell nuclear antigen, collagen I, Smad3, mitogen-activated protein kinase (MAPK) 10, and c-Jun N-terminal kinase (JNK) 3 and induced abnormalities in cell morphology, cell cycle progression, and cell proliferation. CONCLUSIONS: SWF- or valsartan-containing serum corrected (or partially corrected) TGF-ß1-induced abnormal changes in this in vitro system. SWF-containing serum reversed abnormalities in morphology, cell cycle progression, and proliferation in TGF-ß1-treated NRK49F cells, probably by blocking the TGF-ß1/Smads and TGF-ß1/MAPK/JNK pathways.

ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.