Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.
Humans ; Cellular Senescence/genetics* ; Kidney Diseases/pathology* ; Senescence-Associated Secretory Phenotype/physiology* ; Animals ; Epigenesis, Genetic/physiology*

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Animals ; Rabbits ; Atrial Fibrillation/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Signal Transduction ; NF-E2-Related Factor 2/pharmacology* ; Molecular Docking Simulation ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism* ; Inflammation/metabolism* ; Heme Oxygenase-1

OBJECTIVE: To explore the method of measuring root volume with cone-beam computed tomography (CBCT) three-dimensional reconstruction technology, and to study root length and root volume of upper and lower central incisors in patients with skeletal Class Ⅲ malocclusion treated by surgical orthodontic treatment. METHODS: Twenty patients with skeletal Class Ⅲ malocclusion undergoing surgical orthodontic treatment were selected. CBCT data at three time points, before decompensation treatment (T0), after decompensation treatment (before orthognathic surgery, T1), and the end of post-operative orthodontic treatment (T2) were collected. Three-dimensional reconstruction technology was used to measure the root length and root volume of the upper and lower central incisors (including total root volume, cervical root and apical root), calculate the percentage of reduction volume, and measure the distance of tooth movement after orthodontic treatment. Data were statistically analyzed by SPSS 20.0 software. Least significant difference (LSD) method was used for pair comparison between the groups subject to normal distribution, and non-parametric test was used for comparison between the groups not subject to normal distribution. The differences of root length and root volume of upper and lower incisors were compared, and the characteristics of root absorption were analyzed. RESULTS: Root length and root volume of the upper and lower central incisors were reduced during the surgical orthodontic treatment (P < 0.05) in cases. Both the root volume of cervical root and apical root were significantly reduced (P < 0.05), the reduction of apical root was more significant. The percentage of root volume reduction of the upper central incisor was (30.51±23.23)%, and lower central incisor (23.24±11.96)%. Compared with the upper central incisor, the root volume reduction amount and percentage of the lower central incisor were smaller, and apical root volume reduction of the upper central incisor was greater than that of the lower central incisor, which was statistically significant (P < 0.05). During pre-surgical orthodontic treatment, maxillary central incisor palatal moving was in a controlled tipping manner, and the mandibular central incisor tipped labially. CONCLUSION In patients with skeletal Class Ⅲ malocclusion, root length and total root volume of upper and lower central incisors decreased during surgical orthodontic treatment. Root volume measurement indicated that the cervical root also had root resorption. The difference in root resorption of the upper and lower central incisors might be related to the distance and direction of teeth movement. CBCT three-dimensional reconstruction will compensate for the limitation of root length measurement in evaluating root resorption.
Cone-Beam Computed Tomography/methods* ; Humans ; Incisor/diagnostic imaging* ; Malocclusion, Angle Class III/surgery* ; Maxilla/surgery* ; Root Resorption/etiology*

Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems. The immunopotentiator thymosin alpha-1 (Tα1) has recently been reported to have anti-inflammatory and neuroprotective functions in rodents. However, how Tα1 affects inflammatory pain remains unclear. In the present study, intraperitoneal injection of Tα1 attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivity, and decreased the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in inflamed skin and the spinal cord. We found that CFA-induced peripheral inflammation evoked strong microglial activation, but the effect was reversed by Tα1. Notably, Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter (VGLUT) and down-regulated the vesicular γ-aminobutyric acid transporter (VGAT) in the spinal cord. Taken together, these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microglia-induced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.

BACKGROUND: An increasing number of publications are drawing attention to the associations between six common polymorphisms in HOX transcript anti-sense RNA (HOTAIR) and the risk of cancers, while these results have been controversial and inconsistent. We conducted an up-to-date meta-analysis to pool eligible studies and to further explore the possible relationships between HOTAIR polymorphisms (rs920778, rs7958904, rs12826786, 4,759,314, rs874945, and rs1899663) and cancer risk. METHODS: A systematic retrieval was conducted up to 1 July 2017 in the PubMed, Web of Science, and CNKI databases. Eighteen eligible publications including 45 case-control studies with 58,601subjects were enrolled for assessing the associations between the 6 polymorphisms in HOTAIR and cancer risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed to reveal the polymorphisms and susceptibility to cancer. All the statistical analyses were performed using STATA 11.0 software. RESULTS: The pooled analyses detected significant associations between the rs920778 polymorphism and increased susceptibility to cancer in recessive, dominant, allelic, homozygous, and heterozygous models. For the rs7958904 polymorphism, we obtained the polymorphism significantly decreased susceptibility to overall cancer risk among five genetic models rather than recessive and homozygous models. For the rs12826786 polymorphism, we identified it significantly increased susceptibility to cancer risk in all genetic models rather than heterozygous models. However, no significant association was found between the rs1899663, rs874945, and rs4759314 polymorphisms and susceptibility of cancer. CONCLUSION These findings of the meta-analysis suggest that HOTAIR polymorphism may contribute to cancer susceptibility.
Genetic Predisposition to Disease ; epidemiology ; Genotype ; Humans ; Neoplasms ; epidemiology ; genetics ; Odds Ratio ; Polymorphism, Single Nucleotide ; RNA, Long Noncoding ; genetics ; metabolism ; Risk Factors

OBJECTIVETo study the role of Beclin1 gene in autophagy and apoptosis of SW620 cells.

METHODSRNA interference was used to knockdown the expression of Beclin 1 in SW620 cells, and the cell viability was measured by MTT assays. The autophagic activity in serum-starved SW620 CRC cells was evaluated by assessing endogenous microtubule-associated protein 1 light chain 3 (LC3) protein levels using immunofluorescence assay. Flow cytometry was used to measure the apoptosis rate of SW620 cells treated with serum deprivation, staurosporine or etoposide, and the protein expression of Beclin1 was detected using Western blotting.

RESULTSThe viability of cells in pSUPER-Becl group was significantly reduced after serum deprivation (P<0.05). Serum deprivation for 24 h resulted in a stronger apoptotic resistance in cells in the control and pSUPER-non groups than in pSUPER-Becl group (P<0.05). Treatment with staurosporine the most significantly increased the cell apoptosis in pSUPER-Becl group (P<0.05), and similar effect was observed with etoposide treatment (P<0.05). As the time of serum deprivation extended, the expression of Beclin 1 in control group and pSUPER-non group increased progressively (P<0.05), which was consistent with the changes in LC3 expression; LC3 expression in pSUPER-Becl group decreased significantly with a prolonged serum starvation (P<0.05).

CONCLUSIONBeclin 1 is a crucial regulator of autophagy and apoptosis in colorectal cancer cells to maintain the balance between autophagy and apoptosis. Beclin 1 may serve as a protective mechanism to protect colorectal cancer cells from injury caused by low nutrition and chemotherapy byregulating cell autophagy.

Objective To explore the prediction efficiency of multilayer perception (MLP) model in prediction of diabetes mellitus (DM) complicated with coronary heart disease (CHD) by TCM personality and constitutions; To provide a new method for objective prediction. Methods This research utilized single factor logistic regression to filter out variables, which were significant factors of TCM personality and constitutions as analytic variables for MLP and multivariate logistic regression to establish TCM prediction model of personality and constitutions for DM complicated with CHD. The prediction efficiency of the above models were tested by receiver operating characteristic curve (ROC curve). Results The sensitivity, specificity and AUC of MLP were 0.915 (0.862, 0.968), 0.846 (0.793, 0.912) and 0.913 (0.806, 0.987) respectively, which was better than the logistic regression, while these indexes of logistic regression were 0.834 (0.695, 0.953), 0.762 (0.623, 0.901), and 0.869 (0.730, 0.941) respectively. Conclusion The MLP model is better than logistic regression model in prediction of DM complicated with CHD by TCM personality and constitutions.

Objective: To determine the hemoglobin level and blood pressure and the factors that influence their recovery in relocated workers who were unfit for duties at high altitude. Methods: The physical examination data of 693 relocated workers who previously worked at high altitude were dynamically monitored from January 2006 to June 2015 in order to examine the recovery of hemoglobin level and blood pressure. Results: The rate of hemoglobin recovery was 81.37% among the 161 relocated workers with abnormal hemoglobin levels, and the rate of blood pressure recovery was 69.51% among the 164 relocated workers with abnormal blood pressure. The rates of hemoglobin and blood pressure recovery were decreased in individuals aged 40 years and older. The peak recovery time of hemoglobin was 11-15 months following relocation, and that of blood pressure was 5-7 months and 11-13 months following relocation. The half-year blood pressure recovery rate and 2-year hemoglobin recovery rate following relocation were significantly higher in workers who worked at 2500-3000 m altitude than in those at ≥3000 m (P<0.05) . Total cholesterol and educational level were factors that influence the half-year blood pressure recovery in relocated workers (P<0.05) . Conclusion The rate of hemoglobin and blood pressure recovery are high among relocated workers who previously worked at high altitude. Factors that influence blood pressure, such as total cholesterol, should be closely monitored so that high-altitude workers with abnormal blood pressure and hemoglobin level can be relocated as early as possible.

OBJECTIVETo discriminate and analyze the relative frequencies of alleles in HLA-DRB1*12:01:01G(HLA-DRB1*12:01:01/12:06/12:10/12:17) and HLA-DRB1*14:01:01G (DRB1*14:01:01/14:54) groups and assess their associations with HLA-DRB3 and HLA-DQB1 loci.

METHODSA total of 115 DNA samples previously typed as HLA-DRB1*12:01:01G and 108 samples from HLA-DRB1*14:01:01G were selected. DNA sequences for exons 1 to 3 of the HLA-DRB1 locus were analyzed for HLA-DRB1*12:01:01G, and exons 2 to 3 were analyzed for HLA-DRB1*14:01:01G by polymerase chain reaction sequence-based typing (PCR-SBT). Genotyping of HLA-DRB3 and HLA-DQB1 were achieved by PCR-SBT.

RESULTSAmong 115 samples previously typed as HLA-DRB1*12:01:01G, 101 (87.8%) were confirmed as HLA-DRB1*12:01:01 and 14 (12.2%) were HLA-DRB1*12:10, but HLA-DRB1*12:06 and HLA-DRB1*12:17 alleles were not identified. For 108 samples previously typed as HLA-DRB1*14:01:01G, all were typed as HLA-DRB1*14:54. HLA-DRB1*12:01:01 was linked with HLA-DRB3*01:01:02 and HLA-DQB1*03:01, while HLA-DRB1*12:10 was strongly linked with HLA-DRB3*02:02:01 and HLA-DQB1*03:01. HLA-DRB1*14:54 was strongly linked with HLA-DRB3*02:02:01 and two different HLA-DQB1*05:02, *05:03 alleles.

CONCLUSIONHLA-DRB1*12:01:01 was more prevalent than HLA-DRB1*12:10 in the HLA-DRB1*12:01:01G group, and HLA-DRB1*14:54 was the dominant allele for HLA-DRB1*14:01:01G.

Alleles ; Exons ; Gene Frequency ; Genotype ; HLA-DQ beta-Chains ; genetics ; HLA-DRB1 Chains ; genetics ; HLA-DRB3 Chains ; genetics ; Humans