Publications by authors named "Lining Wang"

99 Publications

Automated detection of hippocampal sclerosis: Comparison of a composite MRI-based index with conventional MRI measures.

Epilepsy Res 2021 Aug 9;174:106638. Epub 2021 Apr 9.

Department of Radiology, Sanbo Brain Hospital, Capital Medical University, China. Electronic address:

Purpose: This study aims to compare the performance of an MRI-based composite index (HSI) with conventional MRI-based measures in hippocampal sclerosis (HS) detection and postoperative outcome estimation.

Methods: Seventy-two temporal lobe epilepsy (TLE) patients with pathologically confirmed HS and fifteen TLE patients without HS were included retrospectively. The T1-weighted and FLAIR images of these patients were processed with AccuBrain to quantify the hippocampal volume (HV) and the hippocampal FLAIR signal. The HSI index that considered both HV and hippocampal FLAIR signal was also calculated. Two experienced neuropathologists rated the HS severity with the resected tissue and reached an agreement for all cases. The asymmetry indices of the MRI measures were used to lateralize the sclerotic side, and the original MRI measures were applied to detect HS vs. normal hippocampi. Operating characteristic curve (ROC) analyses were performed for these predictions. We also investigated the sensitivity of the ipsilateral MRI measures in characterizing the pathological severity of HS and the associations of the MRI measures with postoperative outcomes (Engel class categories).

Results: With the optimal cutoffs, the asymmetry indices of HSI and HV both achieved excellent performance in differentiating left vs. right HS (accuracy = 100 %), and the absolute value of the asymmetry index of HSI performed best in differentiating unilateral vs. bilateral HS (accuracy = 91.7 %). Regarding the detection of HS, HSI performed better in sensitivity (94.4 % vs. 87.5 %) while HV performed better in specificity (93.6 % vs. 89.4 %) when the contralateral site of unilateral HS and both sides of non-HS patients were considered as the normal reference, and HSI performed even better than HV when only both sides of non-HS patients were considered as the normal reference (AUC: 0.956 vs. 0.934, p = 0.038). The ipsilateral HSI presented the strongest association with the pathological rating of HS severity (r = 0.405, p < 0.001). None of the ipsilateral or contralateral MRI measures was associated with the postoperative outcomes. Among the asymmetry indices, only the absolute value of the asymmetry index of HV presented a significant association with the Engel classifications for the Year 2∼3 visit (r = -0.466, p = 0.004) or the latest visit with >1 year follow-up (r = -0.374, p = 0.003) while controlling for disease duration and follow-up duration.

Conclusion: The HSI index and HV presented comparable good performance in HS detection, and HSI may have better sensitivity than HV in differentiating pathological HS severity. Higher magnitude of HV dissymmetry may indicate better post-surgical outcomes for HS patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106638DOI Listing
August 2021

IL-6/STAT3-mediated autophagy participates in the development of age-related glomerulosclerosis.

J Biochem Mol Toxicol 2021 Apr 3;35(4):e22698. Epub 2021 Jan 3.

Department of Nephrology, The First Hospital of China Medical University, Shenyang, China.

The standard of age-related glomerulosclerosis is unclear. Both signal transducer and activator of transcription 3 (STAT3) and autophagy are involved in age-related kidney disease. Therefore, we aimed to explore the standard, as well as the potential mechanism(s). A total of 44 patients who underwent radical nephrectomy were enrolled. Pearson analysis was performed to investigate the parameters with ages. The patients were divided into the young- and aged-kidney groups. Kidney morphological changes were evaluated by histology staining, senescence was evaluated by senescence-associated-β-galactosidase (SA-β-gal) staining, and autophagosome was measured by transmission electron microscopy. Moreover, Western blot and/or immunohistochemistry were accomplished to assess the expression of p16, STAT3, and glycoprotein130 (GP130) and autophagy-related proteins. Furthermore, human glomerular mesangial cells were administrated with tocilizumab (TCZ) and/or IL-6, and then the above indexes were tested again. Sclerotic glomerular density and glomerular sclerosis rate were significantly higher in individuals more than 40 years old, and they were strongly correlated with ages. Moreover, the expression of p16, STAT3, GP130, and p62 was significantly increased, while LC3II and autophagosome were statistically decreased in the aged-kidney. Glomeruli were hardly to stain with SA-β-gal. For the in vitro experiments, we observed that IL-6 significantly increased p16, STAT3, GP130, and p62, induced higher SA-β-gal staining, while downregulated LC3II and autophagosome. Furthermore, TCZ statistically reversed the effects of IL-6 on the above expression of proteins. Glomerular sclerosis rate might be one standard for natural renal aging, and IL-6/STAT3-mediated autophagy may participate in the development of age-related glomerulosclerosis.
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http://dx.doi.org/10.1002/jbt.22698DOI Listing
April 2021

Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens.

Front Pharmacol 2020 15;11:563321. Epub 2020 Dec 15.

Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Busulfan (BU) is widely used in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). The exposure-escalated BU directed by therapeutic drug monitoring (TDM) is extremely necessary for the patients with high-risk hematologic malignancies in order to diminish relapse, but it increases the risk of drug-induced toxicity. BU exposure, involved in the glutathione- (GSH-) glutathione S-transferases (GSTs) pathway and proinflammatory response, is associated with clinical outcomes after HSCT. However, the expression of genes in the GSH-GSTs pathway is regulated by NF-E2-related factor 2 (Nrf2) that can also alleviate inflammation. In this study, we evaluated the influence of polymorphisms on BU exposure, proinflammatory cytokine levels, and clinical outcomes in HSCT patients. A total of 87 Chinese adult patients receiving twice-daily intravenous BU were enrolled. Compared with the patients carrying wild genotypes, those with genotypes showed higher plasma interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α levels, poorer overall survival (OS; RR = 3.91), and increased transplant-related mortality (TRM; HR = 4.17). High BU exposure [area under the concentration-time curve (AUC) > 9.27 mg/L × h)] was related to BU toxicities. Furthermore, genotypes could significantly impact TRM (HR = 4.04; = 0.0142) and OS (HR = 3.69; = 0.0272) in the patients with high BU AUC. , we found that high exposure of endothelial cell (EC) to BU, in the absence of Nrf2, elicited the hyperstimulation of NF-κB-p65, accompanied with the elevated secretion of proinflammatory cytokines, and led to EC death. These results showed that genotypes, correlated with high proinflammatory cytokine levels, could predict inferior outcomes in HSCT patients with high BU AUC. Thus, genotyping combined with TDM would further optimize personalized BU dosing for sufficient efficacy and safety endpoint.
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http://dx.doi.org/10.3389/fphar.2020.563321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770105PMC
December 2020

Higher environmental composite quality index score and risk of asthma and allergy in Northeast China.

Allergy 2021 Jun 7;76(6):1875-1879. Epub 2020 Dec 7.

Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, China.

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http://dx.doi.org/10.1111/all.14672DOI Listing
June 2021

Predicting the presence and mechanism of busulfan drug-drug interactions in hematopoietic stem cell transplantation using pharmacokinetic interaction network-based molecular structure similarity and network pharmacology.

Eur J Clin Pharmacol 2021 Apr 11;77(4):595-605. Epub 2020 Nov 11.

Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Purpose: This study aimed to predict the presence and mechanism of busulfan drug-drug interactions (DDIs) in hematopoietic stem cell transplantation (HSCT) using pharmacokinetic interaction (PKI) network-based molecular structure similarity and network pharmacology.

Methods: Logistic function models were established to predict busulfan DDIs based on the assumption that an approved drug tends to interact with the drug used in HSCT (DH) if structurally similar to the drugs in the PKI network of the DH. The PKI network of the DH represented the association between drugs and the proteins related to the PK of the DH. The most appropriate model was applied to predict busulfan DDIs in HSCT. Candidate targets for busulfan DDIs and their interacting were identified by network pharmacology.

Results: Six of the top ten predicted busulfan DDIs were clinically relevant and involved voriconazole, fludarabine, itraconazole, cyclophosphamide, metronidazole, and melphalan. Candidate targets for these DDIs were CYP450s (3A4, 2B6, 2C9, and 2C19), GSTs (GSTA1, GSTP1, GSTT1, and GSTM1), and ABC transporters (ABCB1, ABCC1, ABCC2, and ABCC3), in the targets of drug-induced liver injury (DILI). The networks of interacting proteins and candidate targets indicated the regulatory potential of pregnane X receptor (PXR), as a nuclear receptor. Enrichment analysis showed the metabolism of drugs and xenobiotics, glutathione metabolism, and bile secretion associated with busulfan DDIs and DILI.

Conclusions: This study has successfully predicted busulfan DDIs in HSCT through PKI-based molecular structure similarity. The mechanism of busulfan DDI and DILI was attributed mostly to CYP450s, GSTs, and ABC transporters, and PXR was identified as a potential target.
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http://dx.doi.org/10.1007/s00228-020-03034-4DOI Listing
April 2021

Melatonin Reverses 10-Hydroxycamptothecin-Induced Apoptosis and Autophagy in Mouse Oocyte.

Reprod Sci 2021 Jul 26;28(7):1839-1849. Epub 2020 Oct 26.

College of Life Science, The Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Weijin Road 94, Tianjin, 300071, China.

10-Hydroxycamptothecin (HCPT) is a widely used anticancer drug that induces cytotoxicity by triggering the cell apoptotic pathway. Studies have shown that HCPT has harmful effects on normal cells, but whether HCPT affects the development of mouse oocytes in vitro has not been reported. First, this study investigated the development of oocytes exposed to 60 μM HCPT in vitro. In the HCPT-treated group, the first polar body extrusion (PBE) rate of oocytes decreased, spindle morphology was abnormal, DNA double-strand break, oxidative stress level increased, and mitochondrial distribution was abnormal. The apoptosis and autophagy levels of oocytes in the HCPT-treated group were detected by qRT-PCR and western blot. Compared with the control group, the expressions of key regulators of oocyte apoptosis (bax, caspase-3) and autophagy (lc3, beclin, ATG12) pathway were increased in the HCPT-treated group. HCPT treatment induced apoptosis and autophagy in oocytes. Melatonin (MT) can protect cell structure, prevent DNA damage, and reduce the content of peroxides. So we wondered whether MT could ameliorate the harmful effects of mouse oocytes induced by HCPT. Interestingly, the addition of 1 mM MT can protect oocytes from HCPT toxicity to some extent. Compared with the HCPT group, the addition of 1 mM MT increased the PBE ratio of oocytes, decreased ROS levels, and decreased spindle abnormalities and DNA breakage ratio. In summary, these results revealed that HCPT exhibited adverse effects on mouse oocyte maturation and quality, and MT administration alleviated the negative influence of HCPT.
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http://dx.doi.org/10.1007/s43032-020-00359-4DOI Listing
July 2021

Implications of near-term mitigation on China's long-term energy transitions for aligning with the Paris goals.

Energy Econ 2020 Aug 13;90:104865. Epub 2020 Jul 13.

Institute of Energy, Environment and Economy, Tsinghua University, Beijing 100084, China.

In the international community, there are many appeals to ratcheting up the current nationally determined contributions (NDCs), in order to narrow the 2030 global emissions gap with the Paris goals. Near-term mitigation has a direct impact on the required efforts beyond 2030 to control warming within 2°C or 1.5°C successfully. In this study, implications of near-term mitigation on China's long-term energy transitions until 2100 for aligning with the Paris goals, are quantified using a refined Global Change Assessment Model (GCAM) with six mitigation scenarios. Results show that intensifying near-term mitigation will alleviate China's transitional challenges during 2030-2050 and long-term reliance on carbon dioxide removal technologies (CDR). Each five-year earlier peaking of CO allows almost a five-year later carbon neutrality of China's energy system. To align with 2°C (1.5°C), peaking in 2025 instead of 2030 reduces the requirement of CDR over the century by 17% (13%). Intensifying near-term mitigation also tends to have economic benefits to China's Paris-aligned energy transitions. Under 2°C (1.5°C), peaking in 2025 instead of 2030, with larger near-term mitigation costs by 1.3 (1.6) times, has the potential to reduce China's aggregate mitigation costs throughout the century by 4% (6%). Although in what way China's NDC is to be updated is determined by decision-makers, transitional and economic benefits suggest China to try its best to pursue more ambitious near-term mitigation in accordance with its latest national circumstances and development needs.
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http://dx.doi.org/10.1016/j.eneco.2020.104865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357467PMC
August 2020

Prevention and infection control of COVID-19 in nursing homes: experience from China.

Age Ageing 2020 10;49(6):894-895

School of Nursing, Harbin Medical University (Daqing) 163319, China.

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http://dx.doi.org/10.1093/ageing/afaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449334PMC
October 2020

Gene Expression in Human Polymorphonuclear Neutrophils (PMNs) Stimulated by Bacillus Calmette-Guérin (BCG).

Inflammation 2020 Dec;43(6):2098-2108

Department of Urology, Tianjin Nankai hospital, Tianjin, 300100, People's Republic of China.

Neutrophils are the most abundant leukocytes in the blood. Moreover, neutrophils form the first line of host immune defense against bacterial and fungal invasion, and also play an important part in inflammatory and immune system responses. Intravesical bacillus Calmette-Guérin (BCG) has been shown to reduce and delay tumor progression to muscle-invasive disease after transurethral resection of bladder tumors (TRUBTs). Following intravesical BCG, neutrophils gather around tissues infected by BCG in the early stage of inflammatory and immune responses. In our previous study, we reported that BCG induced the formation of neutrophil extracellular traps (NETs), which play an important role in tumor treatment. Therefore, in the present study, we analyzed the gene expression profile of neutrophils stimulated by BCG through high-throughput arrays, which helped us determine the potential roles of neutrophils in BCG immunotherapy. The results showed that the expression of neutrophil genes led to changes in the early stage of BCG stimulation. The changed genes were involved in many functions of neutrophils such as mobility, proliferation, and secretion of cytokines, chemokines, and adhesion molecules. These changes in neutrophil biological functions may play an essential role in BCG induction of inflammatory and immune responses, and in anti-tumor processes.
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http://dx.doi.org/10.1007/s10753-020-01277-yDOI Listing
December 2020

Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies: a prospective single-arm phase II study.

Front Med 2021 Feb 10;15(1):108-115. Epub 2020 Jun 10.

Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group (P = 0.03 and P = 0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%-86.7%) and 58.4% (95% CI: 41.9%-81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%-35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%-38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.
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http://dx.doi.org/10.1007/s11684-019-0730-8DOI Listing
February 2021

Genome-Wide Characterization and Comparative Analysis of MYB Transcription Factors in Species.

G3 (Bethesda) 2020 08 5;10(8):2653-2660. Epub 2020 Aug 5.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

Numerous studies in plants have shown the vital roles of MYB transcription factors in signal transduction, developmental regulation, biotic/abiotic stress responses and secondary metabolism regulation. However, less is known about the functions of in In this study, five medicinal macrofungi of genus were subjected to a genome-wide comparative analysis of genes. A total of 75 genes were identified and classified into four types: 1R-MYBs (52), 2R-MYBs (19), 3R-MYBs (2) and 4R-MYBs (2). Gene structure analysis revealed varying exon numbers (3-14) and intron lengths (7-1058 bp), and noncanonical GC-AG introns were detected in and In a phylogenetic analysis, 69 out of 75 genes were clustered into 15 subgroups, and both single-copy orthologous genes and duplicated genes were identified. The promoters of the genes harbored multiple -elements, and specific genes were co-expressed with the genes, indicating the potential roles of these genes in stress response, development and metabolism. This comprehensive and systematic study of MYB family members provides a reference and solid foundation for further functional analysis of genes in species.
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http://dx.doi.org/10.1534/g3.120.401372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407476PMC
August 2020

Joint effect of surfactants and cephalexin on the formation of Escherichia coli filament.

Ecotoxicol Environ Saf 2020 Aug 20;199:110750. Epub 2020 May 20.

State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin, 300071, China. Electronic address:

Both antibiotics and surfactants commonly exist in natural environment and have generated great concerns due to their biological influence on the ecosystem. A major concern lies in the capacity of antibiotics to induce bacterial filaments formation, which has potential health risks. However, their joint effect is not clear so far. Here, we studied the joint effect of cephalexin (Cex), a typical antibiotic, and differently charged surfactants on the formation of E. coli filaments. Three kinds of surfactants characterized by different charges were used: cationic surfactant (CTAB), anionic surfactant (SDS) and nonionic surfactant (Tween). Data showed that Cex alone caused the formation of E. coli filaments, elongating their maximum profile from ca. 2 μm (a single E. coli cell) to tens of micrometers (an E. coli filament). A joint use of surfactants with Cex could produce even longer E. coli filaments, elongating the maximum length of the bacteria to larger than 100 μm. The capacity order of different surfactants under their optimum concentrations to produce elongated E. coli filaments was Tween > SDS > CTAB. The E. coli filaments were characterized with a normal DNA distribution and a good cell membrane integrity. We measured the stiffness of bacterial cell wall by atomic force microscopy and correlated the elongation capacity of the E. coli filaments to the stiffness of cell wall. Zeta potential measurement indicated that inserting into or being bound to the cell surface in a large quantity was tested not to be the major way that surfactants interacted with bacteria.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110750DOI Listing
August 2020

Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST) inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats.

J Cell Mol Med 2020 04 3;24(7):4105-4117. Epub 2020 Mar 3.

Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China.

Osthole (OST), a derivative of Fructus Cnidii, has been proved to have potential anti-osteoporosis effects in our recent studies. However, its pharmacological effects are limited in the human body because of poor solubility and bioavailability. Under the guidance of the classical theory of Chinese medicine, Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST), which has not previously been reported in the literature, was synthesized in order to overcome the defects and obtain better efficacy. In this study, we found that NSC-OST inhibited on the formation and resorption activity of osteoclasts through using a bone marrow macrophage (BMM)-derived osteoclast culture system in vitro, rather than affecting the viability of cells. We also found that NSC-OST inhibited osteoclast formation, hydroxyapatite resorption and RANKL-induced osteoclast marker protein expression. In terms of mechanism, NSC-OST suppressed the NFATc1 transcriptional activity and the activation of NF-κB signalling pathway. In vivo, ovariectomized (OVX) rat models were established for further research. We found that NSC-OST can attenuate bone loss in OVX rats through inhibiting osteoclastogenesis. Consistent with our hypothesis, NSC-OST is more effective than OST in parts of the results. Taken together, our findings suggest that NSC-OST can suppress RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats and could be considered a safe and more effective anti-osteoporosis drug than OST.
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http://dx.doi.org/10.1111/jcmm.15064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171421PMC
April 2020

Protocol for a prospective, cluster randomized trial to evaluate routine and deferred dialysis initiation (RADDI) in Chinese population.

BMC Nephrol 2019 12 9;20(1):455. Epub 2019 Dec 9.

Department of Nephrology, Peking University People's Hospital, Beijing, China.

Background: The timing of when to initiate dialysis for progressive chronic kidney disease (CKD) patients has not been well established. There has been a strong trend for early dialysis initiation for these patients over the past decades. However, the perceived survival advantage of early dialysis has been questioned by a series of recent observational studies. The only randomized controlled trial (RCT) research on this issue found the all-cause mortality, comorbidities, and quality of life showed no difference between early and late dialysis starters. To better understand optimal timing for dialysis initiation, our research will evaluate the efficacy and safety of deferred dialysis initiation in a large Chinese population.

Methods: The trial adopts a multicenter, cluster randomized, single-blind (outcomes assessor), and endpoint-driven design. Eligible participants are 18-80 years old, in stable CKD stages 4-5 (eGFR > 7 ml/min /1.73 m), and with good heart function (NYHA grade I or II). Participants will be randomized into a routine or deferred dialysis group. The reference eGFR at initiating dialysis for asymptomatic patients is 7 ml/min /1.73 m (routine dialysis group) and 5 ml/min/1.73 m or less (deferred dialysis group) in each group. The primary endpoint will be the difference of all-cause mortality and acute nonfatal cerebro-cardiovascular events between the two groups. The secondary outcomes include hospitalization rate and other safety indices. The primary and secondary outcomes will be analyzed by appropriate statistical methods.

Discussion: This study protocol represents a large, cluster randomized study evaluating deferred and routine dialysis intervention for an advanced CKD population. The reference eGFR to initiate dialysis for both treatment groups is targeted at less than 7 ml/min/1.73m. With this design, we aim to eliminate lead-time and survivor bias and avoid selection bias and confounding factors. We acknowledge that the study has limitations. Even so, given the low-targeted eGFR values of both arms, this study still has potential economic, health, and scientific implications. This research is unique in that such a low targeted eGFR value has never been studied in a clinical trial.

Trial Registration: The trial has been approved by ClinicalTrials.gov (Trial registration ID NCT02423655). The date of registration was April 22, 2015.
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http://dx.doi.org/10.1186/s12882-019-1627-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902500PMC
December 2019

Expression patterns of two pal genes of Pleurotus ostreatus across developmental stages and under heat stress.

BMC Microbiol 2019 10 26;19(1):231. Epub 2019 Oct 26.

Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences, Beijing, China.

Background: Phenylalanine ammonia-lyase (PAL, EC 4.3.1.24) is the first key enzyme in the phenylpropanoid pathway. The pal gene has been widely studied in plants and participates in plant growth, development and defense systems. However, in Pleurotus ostreatus, the biological functions of pal during organismal development and exposure to abiotic stress have not been reported.

Results: In this study, we cloned and characterized the pal1 (2232 bp) and pal2 (2244 bp) genes from the basidiomycete P. ostreatus CCMSSC 00389. The pal1 and pal2 genes are interrupted by 6 and 10 introns, respectively, and encode proteins of 743 and 747 amino acids, respectively. Furthermore, prokaryotic expression experiments showed that PAL enzymes catalyzed the conversion of L-phenylalanine to trans-cinnamic acid. The function of pal1 and pal2 was determined by constructing overexpression (OE) and RNA interference (RNAi) strains. The results showed that the two pal genes had similar expression patterns during different developmental stages. The expression of pal genes was higher in the reproductive growth stage than in the vegetative growth stage. And the interference of pal1 and pal2 delayed the formation of primordia. The results of heat stress assays showed that the RNAi-pal1 strains had enhanced mycelial tolerance to high temperature, while the RNAi-pal2 strains had enhanced mycelial resistance to HO.

Conclusions: These results indicate that two pal genes may play a similar role in the development of P. ostreatus fruiting bodies, but may alleviate stress through different regulatory pathways under heat stress.
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http://dx.doi.org/10.1186/s12866-019-1594-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815457PMC
October 2019

Prognostic value of miR-221 in human malignancy: evidence from 3041 subjects.

BMC Cancer 2019 Aug 30;19(1):867. Epub 2019 Aug 30.

Department of Urology, Tianjin institute of urology, The 2nd Hospital of Tianjin Medical University, No 23, PingJiang Road, Hexi District, Tianjin, 300211, People's Republic of China.

Background: MiR-221, acting as onco-miR or oncosuppressor-miR, plays an important role in tumor progression; however, the prognostic value of miR-221 in human carcinomas is controversial and inconclusive. The objective of our study was to conducted a systematic review and meta-analysis of miR-221 in various types of human cancers.

Methods: An online search of up-to-date electronic databases, including PubMed and Embase, was conducted to identify as many relevant papers as possible. 32 papers involving 3041 patients with different carcinomas were included in the analysis. Hazard ratios (HRs) of miR-221 were used to evaluate prognostic values.

Results: Thirty-two papers involving 15 cancers were included. MiR-221 was associated with a worse overall survival (OS) in patients, and a combined HR was 1.93 (95% CI of 1.43-2.60, 2080 patients, 22 studies, I-squared = 80.4%, P = 0.000); however, the combined HR for relapse-free survival (RFS) was 1.37 (95% CI of 0.75-2.48, 625 patients, 7 studies, I-squared = 78.8%, P = 0.000), and disease-free survival (DFS) was 1.24 (95% CI of 0.60-2.56, 539 patients, 5 studies, I-squared = 81.8%, P = 0.000).

Conclusion: MiR-221 was shown to be associated with a poor OS in human carcinomas, and thus may serve as a useful predictor of clinical outcomes.
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http://dx.doi.org/10.1186/s12885-019-6079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717359PMC
August 2019

Weak ferromagnetic insulator with huge coercivity in monoclinic double perovskite LaCuIrO.

J Phys Condens Matter 2019 Oct 8;31(43):435601. Epub 2019 Jul 8.

College of Electronic and Optical Engineering, Nanjing University of Posts and Telecommunications (NJUPT), Nanjing, Jiangsu 210023, People's Republic of China.

Insulating ferromagnets with high T are required for many new magnetic devices. More complexity arises when strongly correlated 3d ions coexist with strongly spin-orbit coupled 5d ones in a double perovskite. Here, we perform the structural, magnetic, and density functional theory (DFT) study of such double perovskite LaCuIrO. A new P2/n polymorph is found according to the comprehensive analysis of x-ray, Raman scattering and phonon spectrum. The magnetization reveals a weak ferromagnetic (FM) transition at T   =  62 K and short range FM order in higher temperature range. A huge coercivity is found as high as H ~ 11.96 kOe at 10 K, which, in combination with the negative trapped field, results in the magnetization reversal in the zero field cooling measurement. The first principle calculations confirm the observed FM state and suggest LaCuIrO of this polymorph is a Mott insulating ferromagnet assisted by the spin-orbit coupling.
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http://dx.doi.org/10.1088/1361-648X/ab2ff8DOI Listing
October 2019

The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells.

Cell Signal 2019 10 31;62:109334. Epub 2019 May 31.

Department of Nephrology, The First Hospital of China Medical University, No.155 NanjingBei Rd., Heping District, Shenyang, Liaoning 110001, China. Electronic address:

Renal aging and associated functional decline are associated with an increase in cellular senescence. Previous studies show a direct correlation between advanced glycation end products (AGEs) accumulation and renal aging, chronic kidney disease (CKD) and other nephropathies, although the underlying molecular mechanisms remain largely unclear. We found elevated levels of the receptor of advanced glycation end product (RAGE) as well as STAT5 in aged human kidneys, as well as in human mesangial cells aged artificially through AGEs. Furthermore, genetic and pharmacological ablation of STAT5 significantly downregulated p16 levels and the percentage of β-Gal-positive senescent cells in mesangial cells and kidneys of SD rats, indicating that AGEs-induced senescence depends on STAT5 signaling. The aged kidney tissues (both in patients and SD rats) and mesangial cells show low levels of LC3 (both LC3-II and LC3-II/I), and cultured mesangial cells also show fewer autolysosomes, autophagosomes, and autophagic vacuoles, which can be partially restored upon STAT5 inhibition. This indicates that AGEs accumulation also obliterates the protective effects of autophagy against aging via the RAGE/STAT5 axis. Direct inhibition of autophagy via 3-methyladenine (3-MA) increases the phenotype of renal aging without activating RAGE, it is inhibition of autophagy caused by RAGE/STAT5 that leads to mesangial aging. In conclusion, we found AGEs induced inhibition of autophagy and cellular senescence in mesangial cells via the RAGE/STAT5 pathway. Moreover, we found that RAGE/STAT5 acts as a key link between autophagy and senescence in the process of mesangial aging in vivo and in vitro.
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http://dx.doi.org/10.1016/j.cellsig.2019.05.019DOI Listing
October 2019

Isolation, Purification, and Differentiation of Osteoclast Precursors from Rat Bone Marrow.

J Vis Exp 2019 05 19(147). Epub 2019 May 19.

Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine; TCM Nursing Intervention Laboratory of Chronic Disease Key Laboratory, Nanjing University of Chinese Medicine; Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine;

Osteoclasts are large, multinucleated, and bone-resorbing cells of the monocyte-macrophage lineage that are formed by the fusion of monocytes or macrophage precursors. Excessive bone resorption is one the most significant cellular mechanisms leading to osteolytic diseases, including osteoporosis, periodontitis, and periprosthetic osteolysis. The main physiological function of osteoclasts is to absorb both the hydroxyapatite mineral component and the organic matrix of bone, generating the characteristic resorption appearance on the surface of bones. There are relatively few osteoclasts compared to other cells in the body, especially in adult bones. Recent studies have focused on how to obtain more mature osteoclasts in less time, which has always been a problem. Several improvements in the isolation and culture techniques have developed in laboratories in order to obtain more mature osteoclasts. Here, we introduce a method that isolates bone marrow in less time and with less effort compared to the traditional procedure, using a special and simple device. With the use of density gradient centrifugation, we obtain large amounts of fully differentiated osteoclasts from rat bone marrow, which are identified by classical methods.
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http://dx.doi.org/10.3791/58895DOI Listing
May 2019

Thiotepa, Fludarabine, and Busulfan Conditioning Regimen before T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia: A Bicentric Experience of 100 Patients.

Biol Blood Marrow Transplant 2019 09 22;25(9):1803-1809. Epub 2019 May 22.

Department of Hematology, Institut Paoli-Calmettes, Marseille, France; Centre de Recherche en Cancérologie de Marseille, Inserm U1068, UMR 7258, Marseille, France; Aix-Marseille University, UM 105, Marseille, France. Electronic address:

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.014DOI Listing
September 2019

Fluorene-9-bisphenol exposure induces cytotoxicity in mouse oocytes and causes ovarian damage.

Ecotoxicol Environ Saf 2019 Sep 10;180:168-178. Epub 2019 May 10.

State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin, 300 071, China. Electronic address:

Fluorene-9-bisphenol (BHPF), a substitute for bisphenol A, is a chemical component of plastics for industrial production. There is evidence that BHPF exerts an antioestrogenic effect on mice, induces endometrial atrophy and leads to adverse pregnancy outcomes. However, the effects of BHPF on oocyte maturation and ovary development as well as its possible mechanisms remain unclear. The objective of this study was to investigate the toxicity and mechanism of BHPF exposure in mouse oocytes in vitro and in vivo. Our results showed that BHPF could inhibit the maturation of oocytes in vitro by reducing the protein level of p-MAPK and destroying the meiotic spindle. We found that in vitro, BHPF-treated oocytes showed increased ROS levels, DNA damage, mitochondrial dysfunction, and expression of apoptosis- and autophagy-related genes, such as Bax, cleaved-caspase 3, LC 3 and Atg 12. In addition, in vivo experiments showed that BHPF exposure could induce the expression of oxidative stress genes (Cat, Gpx 3 and Sod 2) and apoptosis genes (Bax, Bcl-2 and Cleaved-caspase 3) and increase the number of atresia follicles in the ovaries. Our data showed that BHPF exposure affected the first polar body extrusion of oocytes, increased oxidative stress, destroyed spindle assembly, caused DNA damage, altered mitochondrial membrane potentials, induced apoptosis and autophagy, and affected ovarian development.
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http://dx.doi.org/10.1016/j.ecoenv.2019.05.019DOI Listing
September 2019

Osthole inhibits osteoclasts formation and bone resorption by regulating NF-κB signaling and NFATc1 activations stimulated by RANKL.

J Cell Biochem 2019 09 13;120(9):16052-16061. Epub 2019 May 13.

Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Chinese herbal medicine Fructus Cnidii has an outstanding effect on chronic lumbar pain and impotence, also has been used against osteoporosis with high frequency. Yet, the mechanisms of osthole, a derivative of Fructus Cnidii, on osteoclasts remains barely known. In this study, it was found out that osthole (10 mol/L, 10 mol/L) had the influence of inhibiting osteoclast formation and bone resorptive activities induced by receptor activator of nuclear factor κB ligand (RANKL), rather than affecting the viability of osteoclast-like cells. Furthermore, osthole could also inhibit the messenger RNA expressions of c-Src, tartrate-resistant acid phosphatase, β3-Integrin, matrix metallopeptidase 9, and cathepsin K. The results of the mechanistic study indicated that osthole regulated the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and nuclear factor-κB (NF-κB) activations following the RANKL stimulation. These findings suggested that the inhibitory effects of osthole were associated with restraining the activations of NFATc1 and NF-κB induced by RANKL. Thus osthole can be used as a potential treatment for abnormal bone-resorption related diseases.
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http://dx.doi.org/10.1002/jcb.28886DOI Listing
September 2019

Trehalose induced by reactive oxygen species relieved the radial growth defects of Pleurotus ostreatus under heat stress.

Appl Microbiol Biotechnol 2019 Jul 8;103(13):5379-5390. Epub 2019 May 8.

Institute of Agricultural Resources and Regional Planning, Chinese Academy of Agricultural Sciences; Key Laboratory of Microbial Resources, Ministry of Agriculture and Rural Affairs, 12 Zhongguancun South Street, Beijing, 100081, China.

Trehalose is a nonreducing disaccharide, and it plays an intracellular protective role in organisms under various stress conditions. In this study, the trehalose synthesis and its protective role in Pleurotus ostreatus were investigated. As a signal in metabolic regulation, reactive oxygen species (ROS) accumulated in the mycelia of P. ostreatus under heat stress (HS). Furthermore, mycelial growth was significantly inhibited, and the malondialdehyde (MDA) level significantly increased under HS. First, exogenous addition of HO inhibited mycelial growth and elevated the MDA level, while N-acetyl cysteine (NAC) and vitamin C (VC) reduced the MDA level and recovered mycelial growth under HS by scavenging ROS. These results indicated that the mycelial radial growth defect under HS might be partly caused by ROS accumulation. Second, adding NAC and VC to the media resulted in rescued trehalose accumulation, which indicated that ROS has an effect on inducing trehalose synthesis. Third, the mycelial growth was recovered by addition of trehalose to the media after HS, and the MDA level was reduced. This effect was further verified by the overexpression of genes for trehalose-6-phosphate synthase (TPS) and neutral trehalase (NTH), which led to increased and reduced trehalose content, respectively. In addition, adding validamycin A (NTH inhibitor) to the media promoted trehalose accumulation and the recovered mycelial growth after HS. In conclusion, trehalose production was partly induced by ROS accumulation in the mycelia under HS, and the accumulated trehalose could promote the recovery of growth after HS, partly by reducing the MDA level in the mycelia.
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http://dx.doi.org/10.1007/s00253-019-09834-8DOI Listing
July 2019

[Research progress on signaling molecules involved in articular cartilage repair].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2019 Apr;36(2):343-348

Nanjing University of Chinese Medicine, Nanjing 210023, P.R.China;Department of Traumatology & Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, P.R.China.

After the articular cartilage injury, the metabolic level is increased during the progressive degeneration, the chondrocytes secrete a variety of inflammatory factors, and the original cell phenotype is gradually changed. For a long time, a large number of researchers have done a lot of researches to promote anabolism of chondrocytes and to maintain the stability of chondrocyte phenotype. There are many molecular signaling pathways involved in the process of promoting cartilage repair. This review focuses on the key signaling molecules in articular cartilage repair, such as transforming growth factor-beta and bone morphogenetic protein, and reveals their roles in the process of cartilage injury and repair, so that researchers in related fields can understand the molecular mechanism of cartilage injury and repair widely and deeply. Based on this, they may find promising targets and biological methods for the treatment of cartilage injury.
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http://dx.doi.org/10.7507/1001-5515.201806021DOI Listing
April 2019

Glomerular Proteomic Profiles in the NZB/W F1 Hybrid Mouse Model of Lupus Nephritis.

Med Sci Monit 2019 Mar 22;25:2122-2131. Epub 2019 Mar 22.

Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).

BACKGROUND Lupus nephritis is one of the most serious complications of systemic lupus erythematosus (SLE) and is associated with patient mortality. This study aimed to investigate the proteomic profiles of the glomerulus in the NZB/W F1 hybrid mouse model of mild and severe lupus nephritis using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). MATERIAL AND METHODS Female NZB/WF1 mice (n=60) at 28 weeks of age were divided into the mild proteinuria group (+1), the moderate proteinuria group (+2), and the severe proteinuria group (+3) using paper strip urine testing, and then later divided into a mild (≤1+) and severe (≥3+) proteinuria group to allow comparison of upregulation and down-regulation of proteins between the two groups. Renal glomeruli were isolated following renal perfusion with magnetic beads. Protein expression was determined by Western blot, immunohistochemistry, 2D-DIGE, and MALDI-TOF-MS. RESULTS A total of 56 differentially expressed proteins were identified from 133 protein spots, of which 18 were upregulated and 23 were down-regulated between groups 1 and 2. Expression of the proteins Ras-related GTP-binding protein B (RRAGB), serine/threonine-protein kinase 1 (SMG1), angiopoietin 2 (ANGP2), methylmalonate semialdehyde (MMSA), and ATP beta chain (ATPB) were identified by Western blot and SMG1, ANGP2, and MMSA were identified by immunohistochemistry. CONCLUSIONS In a mouse model of lupus nephritis, expression of SMG1, MMSA, and ATPB were down-regulated, and RRAGB and ANGP2 were upregulated.
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http://dx.doi.org/10.12659/MSM.914365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698093PMC
March 2019

BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment.

Clin Immunol 2019 04 13;201:4-14. Epub 2019 Feb 13.

Tianjin Institute of Urology, Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, PR China.

Bacillus Calmette-Guerin (BCG) is one of the most effective treatments for bladder cancer. Little attention has been paid to the possible role of neutrophils in BCG immunotherapy. In this study, we examined neutrophil extracellular traps (NETs) formation induced by BCG stimulation, and found that BCG-induced NETs exerted cytotoxicity, induced apoptosis and cell-cycle arrest, and inhibited migration in bladder tumor cells. BCG-activated tumor cells but not non-activated ones elicited NETs formation, in which IL-8 and TNF-α from activated tumor cells both took effect. Moreover, NETs activated peripheral blood mononuclear cells (PBMCs) exhibited a higher expression of CD4 and Th1 cytokines. Additionally, the role of NETs in vivo contributed to the recruitment of T cells and monocytes-macrophages and tissue damage, thus preventing tumor growth. NETs proteins mainly caused these effects on tumor and cellular immunity. In conclusion, we demonstrated a novel immunoregulatory role for NETs in the early stages of BCG immunotherapy.
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http://dx.doi.org/10.1016/j.clim.2019.02.005DOI Listing
April 2019

Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B-mediated degradation of BRCA1.

J Cell Mol Med 2019 03 18;23(3):1798-1812. Epub 2018 Dec 18.

Key Lab of Chemical Biology of Ministry of Education, Department of Natural Product Chemistry, School of Pharmaceutical sciences, Shandong University, Jinan, China.

RD-N, an aminomethylated derivative of riccardin D, is a lysosomotropic agent that can trigger lysosomal membrane permeabilization followed by cathepsin B (CTSB)-dependent apoptosis in prostate cancer (PCa) cells, but the underlying mechanisms remain unknown. Here we show that RD-N treatment drives CTSB translocation from the lysosomes to the nucleus where it promotes DNA damage by suppression of the breast cancer 1 protein (BRCA1). Inhibition of CTSB activity with its specific inhibitors, or by CTSB-targeting siRNA or CTSB with enzyme-negative domain attenuated activation of BRCA1 and DNA damage induced by RD-N. Conversely, CTSB overexpression resulted in inhibition of BRCA1 and sensitized PCa cells to RD-N-induced cell death. Furthermore, RD-N-induced cell death was exacerbated in BRCA1-deficient cancer cells. We also demonstrated that CTSB/BRCA1-dependent DNA damage was critical for RD-N, but not for etoposide, reinforcing the importance of CTSB/BRCA1 in RD-N-mediated cell death. In addition, RD-N synergistically increased cell sensitivity to cisplatin, and this effect was more evidenced in BRCA1-deficient cancer cells. This study reveals a novel molecular mechanism that RD-N promotes CTSB-dependent DNA damage by the suppression of BRCA1 in PCa cells, leading to the identification of a potential compound that target lysosomes for cancer treatment.
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http://dx.doi.org/10.1111/jcmm.14077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378192PMC
March 2019

Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment.

Sci Rep 2018 11 21;8(1):17157. Epub 2018 Nov 21.

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan.

Podocytes are highly specialized cells that line the glomerulus of the kidney and play a role in filtration. Podocyte injury plays a critical role in the development of many kidney diseases, but the underlying mechanisms remain unclear. In this study, we identified that neurofilament heavy polypeptide (NEFH), an intermediate filament component, protects podocyte from injury. We observed that NEFH was upregulated after ADRIAMYCIN(ADR)-induced podocyte injury in both mice and cultured murine podocytes. Immunofluorescence and co-immunoprecipitation analyses revealed that NEFH was colocalized with synaptopodin, a podocyte-specific marker. High NEFH expression in podocytes prevented the Adriamycin-induced reduction in synaptopodin expression. The siRNA-mediated knockdown of NEFH in podocytes reduced the number of vinculin-containing focal contacts, thereby reducing adhesion to the extracellular matrix and increasing podocyte detachment. In addition, NEFH expression was significantly increased in renal biopsy specimens from patients with focal segmental glomerulosclerosis and membranous nephropathy, but in those with minimal change disease. These findings indicate that NEFH is expressed in podocytes during the disease course and that it prevents the reduction in synaptopodin expression and detachment of podocytes.
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http://dx.doi.org/10.1038/s41598-018-35465-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249220PMC
November 2018

The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells.

Cell Signal 2019 01 30;53:327-338. Epub 2018 Oct 30.

Department of Nephrology, The First Hospital of China Medical University, No. 155 Nangjing Bei Street, Shenyang, Liaoning, China.

The kidney is one of the fastest-aging organs, and renal senescence has become a major disease affecting human health. Renal cellular senescence is regulated by the joint action of multiple signal transduction pathways. The previous study by our research group found that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was involved in angiotensin II (Ang II)-induced senescence of human glomerular mesangial cells. However, the unique role of STAT3 activation in Ang II-induced senescence of human glomerular mesangial cells and the underlying mechanisms remain unclear. The present study revealed that Ang II induced premature senescence, promoted autophagy and activated oxidative stress responses in human glomerular mesangial cells. Autophagy mediates the senescence-inducing effect of Ang II on human glomerular mesangial cells. Inhibition of oxidative stress with N-acetylcysteine (NAC) or interference with STAT3/mechanistic target of rapamycin (mTOR) activity with S3I-201 or STAT3-siRNA suppressed autophagy to a certain extent, which was conducive to delaying the senescence of glomerular mesangial cells. The antioxidant probucol reduced autophagy in human glomerular mesangial cells and alleviated the aging process of these cells by regulating STAT3/mTOR. These findings identify a role of STAT3/mTOR-regulated autophagy in Ang II-induced senescence of human glomerular mesangial cells and may provide a theoretical basis for anti-senescence treatment in clinical practice.
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http://dx.doi.org/10.1016/j.cellsig.2018.10.021DOI Listing
January 2019

Serine/threonine kinase 32C is overexpressed in bladder cancer and contributes to tumor progression.

Cancer Biol Ther 2019 25;20(3):307-320. Epub 2018 Oct 25.

a Department of Urology, Tianjin institute of urology , The 2nd Hospital of Tianjin Medical University , Tianjin , P.R. China.

Tumor markers of bladder cancer (BC) have been investigated for many years, but the clinical treatment based on these biomarkers is still unsatisfactory. STK32C, a member of the serine/threonine protein kinase of AGC superfamily, was first found to be highly expressed in brain tissues; however, the role of STK32C in malignant disease has not been determined. Data from TCGA database showed that the STK32C gene is overexpressed in BC and a number of other human tumors. In the current study, immunohistochemistry revealed that high expression of STK32C protein in tumor tissues was significantly associated with poor clinico pathologic features and a short relapse-free survival (RFS) in patients with BC. Slicing of STK32C inhibited tumor cell proliferation, migration and invasion in vitro. In vivo animal experiments demonstrated that knocking-down of STK32C restricted the growth of tumor cells in mice. Finally, microarray analysis revealed that silencing of STK32C inhibited the activity of the HMGB1 pathway and regulated the expression of key genes in this pathway. In conclusion, our study showed novel promoting roles for STK32C in human tumors, which may provide a new therapeutic target for the patients with BC.
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http://dx.doi.org/10.1080/15384047.2018.1529098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370379PMC
May 2020