Function and inhibition of P38 MAP kinase signaling: Targeting multiple inflammation diseases.

Inflammation is a natural host defense mechanism that protects the body from pathogenic microorganisms. A growing body of research suggests that inflammation is a key factor in triggering other diseases (lung injury, rheumatoid arthritis, etc.). However, there is no consensus on the complex mechanism of inflammatory response, which may include enzyme activation, mediator release, and tissue repair. In recent years, p38 MAPK, a member of the MAPKs family, has attracted much attention as a central target for the treatment of inflammatory diseases. However, many p38 MAPK inhibitors attempting to obtain marketing approval have failed at the clinical trial stage due to selectivity and/or toxicity issues. In this paper, we discuss the mechanism of p38 MAPK in regulating inflammatory response and its key role in major inflammatory diseases and summarize the synthetic or natural products targeting p38 MAPK to improve the inflammatory response in the last five years, which will provide ideas for the development of novel clinical anti-inflammatory drugs based on p38 MAPK inhibitors.

Synthesis, anti-aging and mechanism of magnolol derivatives.

Magnolol (M), a hydroquinone containing an allyl side chain, is one of the major active components of Houpoea officinalis for antioxidation and anti-aging. To enhance the antioxidant activity of magnolol, the different sites of magnolol were structurally modified in this experiment, and a total of 12 magnolol derivatives were obtained. Based on the preliminary exploration of the anti-aging effect of magnolol derivatives in a Caenorhabditis elegans (C. elegans) model. Our results indicate that the active groups of magnolol exerting anti-aging effects were allyl groups and hydroxyl on the phenyl. Meanwhile, the anti-aging effect of the novel magnolol derivative M27 was found to be significantly superior to that of magnolol. To investigate the effect of M27 on senescence and the potential mechanism of action, we investigated the effect of M27 on senescence in C. elegans. In this study, we investigated the effect of M27 on C. elegans physiology by examining body length, body curvature and pharyngeal pumping frequency. The effect of M27 on stress resistance in C. elegans was explored by acute stress experiments. The mechanism of M27 anti-aging was investigated by measuring ROS content, DAF-16 nuclear translocation, sod-3 expression, and lifespan of transgenic nematodes. Our results indicate that M27 prolonged the lifespan of C. elegans. Meanwhile, M27 improved the healthy lifespan of C. elegans by improving pharyngeal pumping ability and reducing lipofuscin accumulation in C. elegans. M27 increased resistance to high temperature and oxidative stress in C. elegans by reducing ROS. M27 induced DAF-16 translocation from cytoplasm to nucleus in transgenic TJ356 nematodes and upregulated the expression of sod-3 (a gene downstream of DAF-16) in CF1553 nematodes. Furthermore, M27 did not extend the lifespan of daf-16, age-1, daf-2, and hsp-16.2 mutants. This work suggests that M27 may ameliorate aging and extend lifespan in C. elegans through the IIS pathway.

RAS-targeted cancer therapy: Advances in drugging specific mutations.

Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on different RAS allelic mutations or even different cancers with KRASG12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RAS mutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RAS mutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors.

Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular. Here, we provide a comprehensive review for DYRK1A from the structure and function of DYRK1A, the roles of DYRK1A in various types of diseases, including diabetes mellitus, neurodegenerative diseases, and kinds of cancers, and the studies of its natural and synthetic inhibitors.

Tubular aryl hydratocarbon receptor upregulates EZH2 to promote cellular senescence in cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is one of the serious clinical syndromes with high morbidity and mortality. Despite substantial progress in understanding the mechanism of AKI, no effective drug is available for treatment or prevention. In this study, we identified that a ligand-activated transcription factor aryl hydrocarbon receptor (AhR) was abnormally increased in the kidneys of cisplatin-induced AKI mice or tubular epithelial TCMK-1 cells. The AhR inhibition by BAY2416964 and tubular conditional deletion both alleviated cisplatin-induced kidney dysfunction and tubular injury. Notably, inhibition of AhR could improve cellular senescence of injured kidneys, which was indicated by senescence-associated ß-galactosidase (SA-ß-gal) activity, biomarker p53, p21, p16 expression, and secretory-associated secretory phenotype IL-1ß, IL-6 and TNFα level. Mechanistically, the abnormal AhR expression was positively correlated with the increase of a methyltransferase EZH2, and AhR inhibition suppressed the EZH2 expression in cisplatin-injured kidneys. Furthermore, the result of ChIP assay displayed that EZH2 might indirectly interact with AhR promoter region by affecting H3K27me3. The direct recruitment between H3K27me3 and AhR promoter is higher in the kidneys of control than that of cisplatin-treated mice, suggesting EZH2 reversely influenced AhR expression through weakening H3K27me3 transcriptional inhibition on AhR promoter. The present study implicated that AhR and EZH2 have mutual regulation, which further accelerated tubular senescence in cisplatin-induced AKI. Notably, the crucial role of AhR is potential to become a promising target for AKI.

Middle-size molecule clearance as measured by ß2-microglobulin in high-flux versus low-flux dialysis and hemodiafiltration: A prospective randomized controlled trial.

BACKGROUND: Whereas most studies to date have mainly concentrated on the comparison between high-flux hemodialysis (HFHD) and hemodiafiltration (HDF), or HFHD and low-flux hemodialysis (LFHD) in relation to the clearance of ß2-microglobulin (ß2M) in HD patients, there have been few related to combined HFHD and HDF therapy. To compare the clearance of middle-sized molecules as measured by ß2M in HFHD versus LFHD and HDF. METHODS: A prospective, single-center, open-label, observer-blinded, randomized controlled trial was conducted at the West China Hospital of Sichuan University in China. Patients received either HFHD or LFHD and HDF 3 times a week with follow-ups at one and 3 months. The primary endpoint was the clearance of ß2M at 3 months. The secondary endpoints included hemodialysis-related adverse events, changes in anemia, states of nutrition, and inflammatory indices. RESULTS: After 3 months of treatment, the HFHD+HDF group achieved a higher satisfaction level than the LFHD+HDF group, with decreased serum ß2M concentrations (34.493 ± 7.257 vs. 43.593 ± 9.036 mg/L, p < 0.001) and elevated red blood cell counts (3.959 ± 0.742 vs. 3.602 ± 0.578 × 1012 /L, p = 0.015). Compared with baseline, both kinds of treatment led to increases in serum urea (t = -3.623, p = 0.001 vs. t = -4.240, p < 0.001), cholesterol (t = -2.511, p = 0.016 vs. t = -4.472, p < 0.001), and magnesium (t = -2.648, p = 0.011 vs. t = -3.561, p = 0.001). An elevated level of serum albumin (t = -2.683, p = 0.010) was observed only in the HFHD+HDF group. CONCLUSIONS: Combined therapy with HFHD and HDF has a beneficial effect on improving ß2M clearance, red blood cell management, and nutrition status in HD patients.

Function and inhibition of Haspin kinase: targeting multiple cancer therapies by antimitosis.

OBJECTIVES: Haploid germ cell-specific nuclear protein kinase (Haspin) is a serine/threonine kinase as an atypical kinase, which is structurally distinct from conventional protein kinases. KEY FINDINGS: Functionally, Haspin is involved in important cell cycle progression, particularly in critical mitosis regulating centromeric sister chromatid cohesion during prophase and prometaphase, and subsequently ensuring proper chromosome alignment during metaphase and the normal chromosome segregation during anaphase. However, increasing evidence has demonstrated that Haspin is significantly upregulated in a variety of cancer cells in addition to normal proliferating somatic cells. Its knockdown or small molecule inhibition could prevent cancer cell growth and induce apoptosis by disrupting the regular mitotic progression. Given the specificity of its expressed tissues or cells and the uniqueness of its current known substrate, Haspin can be a promising target against cancer. Consequently, selective synthetic and natural inhibitors of Haspin have been widely developed to determine their inhibitory power for various cancer cells in vivo and in vitro. SUMMARY: Here our perspective includes a comprehensive review of the roles and structure of Haspin, its relatively potent and selective inhibitors and Haspin's preliminary studies in a variety of cancers.

The Emerging Role of Epigenetic Methylation in Kidney Disease.

Kidney disease has complex and multifactorial pathophysiology and pathogenesis. Recent studies have revealed that epigenetic methylation changes, namely DNA methylation, histone methylation and non-histone methylation, are strongly implicated in various forms of kidney diseases. This review provides a perspective on the emerging role of epigenetic methylation in kidney disease, including the effects of DNA methylation in diverse promoter regions, regulation and implication of histone methylation, and recent advances and potential directions related to non-histone methylation. Monitoring or targeting epigenetic methylation has the potential to contribute to development of therapeutic approaches for multiple kidney diseases.

Coherent false seizure prediction in epilepsy, coincidence or providence?

OBJECTIVE: Seizure forecasting using machine learning is possible, but the performance is far from ideal, as indicated by many false predictions and low specificity. Here, we examine false and missing alarms of two algorithms on long-term datasets to show that the limitations are less related to classifiers or features, but rather to intrinsic changes in the data. METHODS: We evaluated two algorithms on three datasets by computing the correlation of false predictions and estimating the information transfer between both classification methods. RESULTS: For 9 out of 12 individuals both methods showed a performance better than chance. For all individuals we observed a positive correlation in predictions. For individuals with strong correlation in false predictions we were able to boost the performance of one method by excluding test samples based on the results of the second method. CONCLUSIONS: Substantially different algorithms exhibit a highly consistent performance and a strong coherency in false and missing alarms. Hence, changing the underlying hypothesis of a preictal state of fixed time length prior to each seizure to a proictal state is more helpful than further optimizing classifiers. SIGNIFICANCE: The outcome is significant for the evaluation of seizure prediction algorithms on continuous data.

Selective EZH2 inhibitor zld1039 alleviates inflammation in cisplatin-induced acute kidney injury partially by enhancing RKIP and suppressing NF-κB p65 pathway.

Enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), is a histone lysine methyltransferase mediating trimethylation of histone H3 at lysine 27 (H3K27me3), which is a repressive marker at the transcriptional level. EZH2 sustains normal renal function and its overexpression has bad properties. Inhibition of EZH2 overexpression exerts protective effect against acute kidney injury (AKI). A small-molecule compound zld1039 has been developed as an efficient and selective EZH2 inhibitor. In this study, we evaluated the efficacy of zld1039 in the treatment of cisplatin-induced AKI in mice. Before injection of cisplatin (20 mg/kg, i.p.), mice were administered zld1039 (100, 200 mg/kg, i.g.) once, then in the following 3 days. We found that cisplatin-treated mice displayed serious AKI symptoms, evidenced by kidney dysfunction and kidney histological injury, accompanied by EZH2 upregulation in the nucleus of renal tubular epithelial cells. Administration of zld1039 dose-dependently alleviated renal dysfunction as well as the histological injury, inflammation and cell apoptosis in cisplatin-treated mice. We revealed that zld1039 administration exerted an anti-inflammatory effect in kidney of cisplatin-treated mice via H3K27me3 inhibition, raf kinase inhibitor protein (RKIP) upregulation and NF-κB p65 repression. In the cisplatin-treated mouse renal tubular epithelial (TCMK-1) cells, silencing of RKIP with siRNA did not abolish the anti-inflammatory effect of EZH2 inhibition, suggesting that RKIP was partially involved in the anti-inflammatory effect of zld1039. Collectively, EZH2 inhibition alleviates inflammation in cisplatin-induced mouse AKI via upregulating RKIP and blocking NF-κB p65 signaling in cisplatin-induced AKI. The potent and selective EZH2 inhibitor zld1039 has the potential as a promising agent for the treatment of AKI.

Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney-specific expression quantitative trait analysis and identified that the expression of beta-mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in MANBA using phenome-wide association analysis of 40,963 subjects with exome sequencing data. MANBA is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of Manba Manba heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.

The roles of NLRP3 inflammasome-mediated signaling pathways in hyperuricemic nephropathy.

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. High-serum uric acid can trigger renal inflammation. The inflammasome family has several members and shows a significant effect on inflammatory responses. NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) senses the stimuli signal of excessive uric acid and then it recruits apoptosis-related specular protein (ASC) as well as aspartic acid-specific cysteine protease (caspase)-1 precursor to form NLRP3 inflammasome. NLRP3 inflammasome is activated in acute kidney injury (AKI), chronic kidney diseases (CKD), diabetic nephropathy (DN), and HN. This review focuses on important role for the involvement of NLRP3 inflammasome and associated signaling pathways in the pathogenesis of hyperuricemia-induced renal injury and the potential therapeutic implications. Additionally, several inhibitors targeting NLRP3 inflammasome are under development, most of them for experiment. Therefore, researches into NLRP3 inflammasome modulators may provide novel therapies for HN.

Management of tunneled-cuffed catheter-related right atrial thrombosis in hemodialysis patients.

OBJECTIVES: Catheter-related right atrial thrombosis (CRAT) is an underreported but potentially life-threatening complication associated with the use of tunneled-cuffed catheters among hemodialysis (HD) patients. Because little is known about the evidence-based guidelines for the optimal management of CRAT among HD patients, this article reports findings based on 20 patients diagnosed with CRAT after catheter replacement and anticoagulation treatment. METHODS: The article retrospectively reviews the hospital records of 20 HD patients treated in the West China Hospital with diagnosis of CRAT from March 2013 to May 2016. Once CRAT was diagnosed, tunneled-cuffed catheters were exchanged over a guidewire in situ and the locations of the new catheter tips were adjusted to be away from the original sites. Immediately after the insertion of a new tunneled-cuffed catheter and at the end of each HD session, both ports of the catheters were locked with unfractionated heparin solution. Patients younger than 70 years of age were treated with warfarin at a target International Normalized Ratio of 1.5 to 1.9, whereas those older than 70 years were treated with dual antiplatelet therapy. All patients were on regular dialysis without thrombolysis or thrombectomy. RESULTS: During the follow-up, two patients died of gastrointestinal massive hemorrhage and one died of acute myocardial infarction. No fatal pulmonary embolism or other CRAT complication-related deaths were observed. A total of eight patients had complete dissolution of CRAT, and 12 patients had reduction in thrombi size. CONCLUSIONS: Maintenance of HD by replacing catheters and providing oral anticoagulation/antiplatelet therapies may be an effective strategy for treating HD patients with CRAT.

In Situ Preservation Fraction of Parathyroid Gland in Thyroidectomy: A Cohort Retrospective Study.

BACKGROUND AND OBJECTIVES: Parathyroid failure is the most common symptom after thyroidectomy. To prevent it, a gland was preserved in situ or an ischemic one was autotransplanted. This study explored the relationship between in situ preservation of the parathyroid gland and gland failure. METHODS: Consecutive patients who underwent initial total thyroidectomy were enrolled retrospectively in a prospectively maintained database. Patients were divided into groups by parathyroid gland remaining in situ fraction (PGRIF) (PGRIF = number of in situ glands/(total number of identified glands - number of glands in specimen). Patients were graded by tertiles and followed at least one year after surgery. RESULTS: 559 patients were included. PGRIF is significantly inversely associated with transient hypoparathyroidism, protracted hypoparathyroidism, and postoperative hypocalcemia. PGRIF was identified as an independent risk factor for transient hypoparathyroidism, protracted hypoparathyroidism, and postoperative hypocalcemia (OR = 0.177, 0.190, and 0.330, resp.). Autotransplantation of parathyroid gland would not affect the calcium level in the long term. CONCLUSION: In situ preservation of parathyroid gland is crucial for parathyroid function. Less preserved is the independent risk factor for postoperative hypoparathyroidism and hypocalcemia, resulting in a worse function of parathyroid gland in the long term.

A Dual-Stimuli-Responsive Sodium-Bromine Battery with Ultrahigh Energy Density.

Stimuli-responsive energy storage devices have emerged for the fast-growing popularity of intelligent electronics. However, all previously reported stimuli-responsive energy storage devices have rather low energy densities (<250 Wh kg-1 ) and single stimuli-response, which seriously limit their application scopes in intelligent electronics. Herein, a dual-stimuli-responsive sodium-bromine (Na//Br2 ) battery featuring ultrahigh energy density, electrochromic effect, and fast thermal response is demonstrated. Remarkably, the fabricated Na//Br2 battery exhibits a large operating voltage of 3.3 V and an energy density up to 760 Wh kg-1 , which outperforms those for the state-of-the-art stimuli-responsive electrochemical energy storage devices. This work offers a promising approach for designing multi-stimuli-responsive and high-energy rechargeable batteries without sacrificing the electrochemical performance.

Subclinical hypothyroidism would not lead to female sexual dysfunction in Chinese women.

BACKGROUND: There is dearth of research about female sexual dysfunction (FSD), especially in China, because of conservative beliefs. Previous studies indicated the relationship between subclinical hypothyroidism and anxiety and depression. However, there is dearth of research regarding the relationship between subclinical hypothyroidism and FSD in Chinses women. METHOD: A hospital-based research was conducted. Female sexual function was measured by CVFSFI which includes 19 items. Participants were identified as FSD if CVFSFI ≤ 23.45. Logistics analysis was used to determine risk factor of FSD. All of them finished CVFSFI, Beck Depression Inventory (BDI) self-reporting questionnaires and had thyroid hormone tests. Based on presence and absence of subclinical hypothyroidism, participants were divided into two groups. Risk factors of FSD were identified. RESULT: One thousand one hundred nineteen participants with CVFSFI score 25.8 ± 3.9 were enrolled in final analysis. Incidence of subclinical hypothyroidism and FSD in Chinese women was 15.0% and 26.5% respectively. There were no significant difference between subclinical hypothyroidism and control group in FSFI score and prevalence of FSD. Age, Depression (medium risk) was identified as risk factors for nearly all types of FSD, and Income (ranges from 40,000 to 100,000 RMB/year) as protective factor. Subclinical hypothyroidism had no significant relationship with FSD. CONCLUSION: Subclinical hypothyroidism is not the risk factor for FSD in urban women of China.

Metabolomics reveal mitochondrial and fatty acid metabolism disorders that contribute to the development of DKD in T2DM patients.

Diabetic kidney disease (DKD) is the leading cause of ESRD; however, early intervention can greatly prevent the progression of DKD; thus, sensitive biomarkers for DKD are still required. This study was aimed at the identification of potential biomarkers and revelation of underlying pathways in DKD patients by non-targeted metabolomics. Gas chromatography-mass spectrometry was used to analyze urine obtained from the control and type 2 diabetes mellitus (T2DM) and DKD patients, and the renal histological changes in DKD patients were assessed. The DKD group showed increased level of uric acid, 1,5-anhydroglucitol, hippuric acid, stearic acid, and palmitic acid and reduced level of uracil, glycine, aconitic acid, isocitric acid, 4-hydroxybutyrate, 2-deoxyerythritol, and glycolic acid as compared to the control and T2DM groups. Further analysis indicated that many of the changed metabolites were involved in mitochondrial and fatty acid (FA) metabolism, and combined mitochondrial and FA metabolites showed better diagnosis values for DKD. Histological results confirmed that renal expression of key proteins was reduced in DKD patients with respect to mitochondrial biogenesis (PGC-1α, p-AMPK) and FA oxidation (PPAR-α, CPT-1) as compared to that in the control and T2DM groups. This study highlighted that both mitochondrial and FA metabolism were disturbed in DKD, and thus, they could serve as combined biomarkers for the prediction of DKD.

Protocol for management after thyroidectomy: a retrospective study based on one-center experience.

BACKGROUND AND AIM: The optimal approach to detect and treat symptomatic hypocalcemia (SxH) after thyroidectomy is still uncertain. In our retrospective study, we sought to set a standardized postoperative management protocol on the basis of relative change of parathyroid hormone (PTH) and absolute value of postoperative day 1 (POD1) PTH. METHODS: Patients who underwent thyroidectomy were identified retrospectively in our prospective database. Blood was collected 1 day before surgery and on POD1. Extra calcium and calcitriol supplement was prescribed when necessary. Meanwhile, postoperative signs of SxH were treated and recorded in detail. Patients were followed up for 1 month after surgery and then 3 months thereafter. RESULTS: A total of 744 patients were included in the final analysis. Transient SxH occurred in 86 (11.6%) patients, and persistent SxH occurred in 4 (0.54%) patients in more than half year after surgery. Relative decrease of PTH reached its maximal discriminative effect at 70% (area under the curve [AUC] =0.754), with a sensitivity of 72.1% and a specificity of 75%. In Group 1 (≤70%), 24 (4.67%) patients were interpreted as having SxH, whereas in Group 2, 62 (27.0%) patients had SxH (>70%), P<0.001. Days of symptom relief in Group 1-1 (1, 2) were significantly shorter than those in Group 2-2 (1, 10), P=0.023. In Group 2, 112 (80%) patients with POD1 PTH <1 pmol/L were treated with calcitriol, whereas only 8 (8.89%) patients with POD1 PTH ≥1 pmol/L were treated with calcitriol (P<0.001). According to relief of SxH and recovery of parathyroid function, treating with and without calcitriol showed no difference in patients with POD1 PTH <1 and ≥1 pmol/L. CONCLUSION: Relative decrease of PTH >70% is a significant risk factor for SxH in post-thyroidectomy. The decreasing percent of PTH ≤70% ensures discharge on POD1, but longer hospitalization was advocated for patients with decreasing percent of PTH >70%, who needed extra calcitriol supplement when POD1 PTH <1 pmol/L.