The role of a novel mineralocorticoid receptor antagonist, finerenone, in chronic kidney disease: mechanisms and clinical advances.

BACKGROUND: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. CONCLUSION: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy.

Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007-2016.

BACKGROUND: The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it has been reported that α-Klotho is downregulated in patients with insulin resistance (IR), the association between Klotho and IR is complex and controversial. The triglyceride-glucose (TyG) index has provided a practical method for assessing IR. With this in mind, our study aimed to investigate the relationship between the TyG index and soluble α-Klotho protein levels in US populations, both with and without diabetes mellitus. METHODS: This cross-sectional study analyzed data from middle-aged and older participants in the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. The participants were divided into two groups based on their diabetes mellitus status: those with diabetes and those without diabetes. To evaluate the relationship between the TyG index and the concentration of the α-Klotho protein in each group, a series of survey-weighted multivariable linear regression models were employed. Furthermore, to examine the association between these two variables, multivariable-adjusted restricted cubic spline curves and subgroup analysis were generated. RESULTS: The study involved 6,439 adults aged 40 years or older, with a mean age of 57.8 ± 10.9 years. Among them, 1577 (24.5%) had diabetes mellitus. A subgroup analysis indicated that the presence of diabetes significantly affected the relationship between the TyG index and the α-Klotho level. After considering all covariables, regression analysis of the participants without diabetes revealed that the α-Klotho concentration decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) with each one unit increase in TyG (p < 0.001). The decline in α-Klotho levels with elevated TyG was more pronounced in the female population. In patients with diabetes mellitus, a non-linear association between the TyG index and α-Klotho was observed. There was no significant correlation observed between the two when TyG index were below 9.7. However, there was an increase in klotho levels of 106.44 pg/ml for each unit increase in TyG index above 9.7 (95% CI: 28.13, 184.74) (p = 0.008). CONCLUSION: Our findings suggested that the presence of diabetes may influence the relationship between the TyG index and soluble α-Klotho. Furthermore, there seem to be sex differences in individuals without diabetes. Further studies are necessary to validate these findings.

Different outcomes following parathyroidectomy in patients with uremic tumoral calcinosis: two case reports.

BACKGROUND: Uremic tumoral calcinosis (UTC) is a rare complication in hemodialysis patients, whose mechanism remains incompletely understood. We report two cases with UTC who experienced completely different patterns of regression following parathyroidectomy, although there were no significant differences in serum calcium levels, parathyroid hormone, or phosphorus production between the two patients. CASE PRESENTATION: Case 1 had a substantial improvement in soft tissue calcification. However, in Case 2, one calcified mass was partially absorbed, while the others were aggravated with severe microvascular calcification and subcutaneous extravascular calcification. Whole-exome sequencing data revealed five mutation sites associated with atherosclerosis. CONCLUSION: The different outcomes in UTC patients after PTX are rare. Further studies are required to elucidate the mechanism of paradoxical changes occurring in patients with UTC after parathyroidectomy.

Follow-up Results and Clinical Significance of Magnetic Resonance Spectroscopy Combined with Fluorescence Microscopy in Resection of High Grade Supra-tentoria Gliomas.

Objective To investigate the clinical effectiveness of magnetic resonance spectroscopy (MRS) combined with sodium fluorescein(FL) in the treatment of high grade gliomas(HGG). Methods From August 2013 to 2015 November,the clinical data of 72 supratentorial HGG(WHO grade Ⅲ-Ⅳ) patients who had received surgical treatment in our hospital were retrospectively studied,among whom 43 cases received MRS combined with intra-perative FL navigation(observation group),and 29 cases only received conventional surgery(control group). Post-operative radiotherapy and chemotherapy were applied for more than 3 months. Routine enhanced MRI were performed 24-48 hours after the operation to investigate the extent of tumor resection. Six months after the operation,the quality of life of patients was evaluated by using the Karnofsky score,and 1-year postoperative survival rate and progression-free survival(PFS) were observed. Results Postoperative MRI showed that the rate of gross total resection(GTR) in observation group was significantly higher than that in control group(72.09%vs.51.72%;χ2=23.88,P=0.001),and the GTR rate of WHO grade Ⅳ tumors was significantly higher than that of WHO grade Ⅲ tumors in observation group(92.86% vs.62.07%;χ2=6.06,P=0.042). The postoperative Karnofsky score in the observation group was significantly higher than that in control group(µ=2.34,P=0.021). The mean time of follow-up was(16.4±2.4) months(8-21 months) and there was no statistical significant difference between observation group and control group in 1-year survival rate(74.07% vs.77.50%;χ2=4.90,P=0.165) and PFS [(13.2±1.2) months vs.(12.7±2.0) months;χ2=7.26,P=0.067]. In observation group,the PFS of WHO grade Ⅳ patients was significantly higher than that in control group [(14.2±0.3) months vs.(10.0±1.1) months;χ2=11.03,P=0.031]. There was also no statistical significant difference between WHO grade Ⅳ tumors in two groups in terms of 1-year survival rate(71.43% vs.72.54%;χ2=5.33,P=0.089),and there was no statistical significant difference between WHO grade Ⅲ tumors in two groups in 1-year survival rate(75.86% vs. 72.22%;χ2=3.78,P=0.250) and in PFS [(13.7±1.4) months vs.(12.4±0.8) months;χ2=4.85,P=0.083]. Conclusions MRS combined with intraoperative FL navigation technology can improve the resection rate and improve survival quality of patients,and there is no evidence that MRS combined with intraoperative FL navigation prolong the overall survival of patients with high-grade gliomas. Different outcome may be found with longer follow-up and increased simple size.

Major Metabolite Levels of Preoperative Proton Magnetic Resonance Sectroscopy and Intraoperative Fluorescence Intensity in Glioblastoma.

Objective To compare the intraoperative major metabolite level of preoperative proton magnetic resonance spectroscopy(1H-MRS)and fluorescence intensity marked with fluorescein sodium(FLs)in glioblastoma(GBM)and thus provide an objective basis for fluorescence surgical treatment of GBM. Methods All newly diagnosed patients by plain and enhanced magnetic resonance imaging from the April 1,2014 to December 31,2015 were enrolled in this study.All of them received 1H-MRS and marked with FLs.The expression of Ki67 in tumor boundary were confirmed by postoperative pathology and determined by immunostaining assay.The relationship between 1H-MRS metabolite levels and tumor fluorescence intensity was analyzed. Results Totally 33 patients were included in the study.Preoperative 1H-MRS revealed high-grade gliomas in 25 cases.The N-acetylaspartate(NAA)decreased significantly and choline(Cho)increased significantly in high-grade gliomas.The ratios of Cho/NAA,NAA/creatine(Cr),and Cho/Cr significantly differed in different tumor regions(P=0.02,P=0.01,and P=0.00,respectively).Surgical results were marked with FLs intraoperatively.Tissue fluorescence were clearly seen.There were 29 patients undergoing total resection and 4 cases undergoing subtotal resection.No acute encephalocele occured after operation,while 2 patients suffered from epilepsy.Postoperative pathology results included:28 cases were diagnosed as GBM(22 cases consistent with 1H-MRS diagnosis).The results of GBM fluorescence imaging included:the level of fluorescence intensity in tumor parenchyma was significantly higher than that in tumor boundary and peritumoral edema(P=0.01).The result of 1H-MRS metabolite analysis included:The kurtosis of NAA and of Cho and the ratio of Cho/NAA were significantly different according the fluorescence intensity in tumor parenchyma(P=0.01,P=0.02,and P=0.01).While there was no difference in the kurtosis of NAA,the kurtosis of Cho and the ratio of Cho/NAA were significantly different according the fluorescence intensity in tumor boundary(P=0.02, P=0.00).In peritumoral edema,there was no significant different in kurtosis of NAA and of Cho and in the ratio of Cho/NAA(P=0.23,P=0.09,P=0.14).Immunohistochemistry in GBM tumor boundary showed different Ki67 expressions according to different fluorescence imaging(P=0.03). Conclusions The fluorescence intensity in GBM parenchyma is higher than that in other tumor regions,and there are different metabolic levels in different fluorescence intensity.The metabolic information marked by FLs and provided by 1H-MRS before operationis are important,and the correlation between them should be further investigated.

Anti-hypertensive and renoprotective effects of berberine in spontaneously hypertensive rats.

OBJECTIVES: We aimed to investigate the effects of berberine on renin-angiotensin system (RAS) and pro-inflammatory cytokines, as well as its effects on blood pressure and renal damage in spontaneously hypertensive rats. METHODS: Berberine was administrated to spontaneously hypertensive rats (SHR rats) between 3 and 20 weeks of age. Blood pressure was monitored in 3-, 6-, 9-, 12-, 16- and 20-week-old SHR rats and age-matched Wistar Kyoto rats (WKY rats). Besides, we measured levels of angiotensin II, aldosterone and pre-inflammatory cytokines (IL-6, IL-17, IL-23) in serum and kidney, as well as levels of collagen III and collagen IV in kidney and urinary markers of renal injury (osteopontin, kidney-injury-molecule (KIM-1) and albumin) in 3-, 6-, 9-, 12-, 16- and 20-week-old SHR rats and WKY rats. Glomerulosclerosis was also assessed with hematoxylin and eosin staining. RESULTS: SHR rats developed hypertension at the age of 6 weeks and had increased levels of angiotensin II, aldosterone, IL-6, IL-17, IL-23, collagen III, collagen IV, osteopontin, KIM-1 and albumin, as well as more severe glomerulosclerosis, compared to the aged-matched WKY rats. Berberine delayed the onset and attenuated the severity of hypertension, as well as partially inhibited the increases of the above substances in SHR rats. CONCLUSION: Berberine could delay the onset and attenuate the severity of hypertension, as well as ameliorate hypertension-induced renal damage in SHR rats. Furthermore, berberine could inhibit the activities of RAS and pre-inflammatory cytokines IL-6, IL-17 and IL-23, which are involved in the pathophysiology of hypertension.

Use of laser microdissection in the analysis of renal-infiltrating T cells in murine lupus.

OBJECTIVE: To clarify the role of T cells in kidney pathology of three widely used murine lupus models. MATERIAL AND METHODS: Cells infiltrating the glomeruli and perivascular areas in MRL/lpr (n = 10 female), NZB× NZW F1 (B/W F1) (n = 9 female), and BXSB (n = 10 male) mice were captured by laser microdissection (LMD). Samples were subjected to nested reverse transcription polymerase chain reaction (RT-PCR) with primers specific to ß-actin, T-cell receptor ß chain (TCR-Cß), interleukin (IL)-10, IL-13, IL-17, and interferon-g (IFN-γ). Frozen sections of lesions were also stained immunohistochemically for tissue and cellular characterization. RESULTS: T cells infiltrating the glomeruli and perivascular areas predominantly produced IFN-γ, IL-13, and IL-17 in MRL/lpr, B/W F1, and BXSB mice, with IL-17 expression in glomeruli of BXSB mice being significantly lower than that of MRL/lpr and B/W F1 mice. IL-10 was detected only in the perivascular areas of MRL/lpr and B/W F1 mice and not in glomeruli isolates. Immunohistochemical staining revealed positive for the expression of Thy-1, CD4, CD8, and B220 in glomeruli and perivascular areas from all three strains of mice. CONCLUSIONS: Cytokine balance in murine SLE is complex and cannot be attributed simply to the balance between Th1 and Th2 cells. Th17 cells may play a critical role in disease pathology, possibly with greater contribution toward disease progression in MRL/lpr and B/W F1 mice than in BXSB mice. Furthermore, these findings lend support to the concept that different molecular mechanisms underlie glomerulonephritis as compared to vasculitis.

Renal anemia: from relative insufficiency of EPO to imbalance of erythropoiesis and eryptosis.

Chronic kidney disease has emerged as a major health issue both in China and worldwide. Renal anemia frequently occurs in patients with chronic kidney disease, and its severity and incidence rate increase as the disease progresses. Over the last 30 years, the administration of exogenous EPO and EPO stimulants has been employed to alleviate renal anemia, suggesting that a relative deficiency in EPO may be a primary cause. However, this approach has overshadowed other contributing factors, particularly eryptosis, which results from the reduced lifespan of red blood cells. Numerous studies reveal that there are nephrogenic and extrarenal EPO secretion indicating that an absolute deficiency of EPO is not always present in patients. Therefore, this paper speculates that renal anemia may arise when EPO-driven erythropoiesis fails to adequately compensate for aggravating eryptosis. Other factors including iron metabolism disorder, uremic toxin accumulation, inflammatory state, oxidative stress, and secondary hyperparathyroidism affect EPO reactivity bone marrow hematopoiesis and eryptosis, leading to an imbalance between red blood cell production and destruction, and cause anemia ultimately. More further studies on the pathogenesis and treatment of renal anemia would be expected to provide evidence to support our opinion.

Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

Mechanisms and efficacy of traditional Chinese herb monomers in diabetic kidney disease.

Diabetic kidney disease (DKD) is a serious complication of diabetes and is the primary cause of end-stage renal disease. Current treatment strategies primarily focus on the inhibition of the renin-angiotensin-aldosterone system and the attainment of blood glucose control. Although current medical therapies for DKD have been shown to delay disease progression and improve long-term outcomes, their efficacy is limited and they may be restricted in certain cases, particularly when hyperkalemia is present. Traditional Chinese medicine (TCM) treatment has emerged as a significant complementary approach for DKD. TCM monomers, derived from various Chinese herbs, have been found to modulate multiple therapeutic targets and exhibit a broad range of therapeutic effects in patients with DKD. This review aims to summarize the mechanisms of action of TCM monomers in the treatment of DKD, based on findings from clinical trials, as well as cell and animal studies. The results of these investigations demonstrate the potential effective use of TCM monomers in treating or preventing DKD, offering a promising new direction for future research in the field. By providing a comprehensive overview of the mechanisms and efficacy of TCM monomers in DKD, this review highlights the potential of these natural compounds as alternative therapeutic options for improving outcomes in patients with DKD.

The pH-sensitive chondroitin sulphate-based nanoparticles for co-delivery of doxorubicin and berberine enhance the treatment of breast cancer.

In the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) facilitate drug resistance and tumor metastasis. Therefore, more and more attention has been focused on the regulation of TME by preventing the cross-talk between tumor cells and CAFs in the treatment of breast cancer. In this study, we have combined the benefits of deep drug penetration, pH sensitivity, and tumor-targeting delivery to prepare chondroitin sulphate (CS)-based nanomicelles (BBR/CS-DOX) for the co-delivery of doxorubicin (DOX) and berberine (BBR). A unique MCF-7 + MRC-5 co-cultured cell model and 4 T1 + NIH3T3 co-implanted mice model, were established to simulate the TME of breast cancer (BC). As expected, BBR/CS-DOX could accumulate in tumor egion, be taken up by both tumor cells and CAFs, and improve drug absorption and retention. Compared with free drugs, BBR/CS-DOX demonstrated stonger pro-apoptotic and anti-metastatic effect in vitro and in vivo, respectively the histological studies showed that BBR/CS-DOX efficiently prevented the activation of fibroblasts, inhibited extracellular matrix (ECM) deposition, and decreased tumor angiogenesis, showing superior anti-tumor efficacy. In summary, BBR/CS-DOX has the potential to significantly enhance the therapeutic effect of breast cancer through inhibiting the "CAFs-tumor cells" crosstalk, and has promising clinical application prospects.

Sestrin2 knockout exacerbates high-fat diet induced metabolic disorders and complications in female mice.

BACKGROUND: Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice. METHODS: Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues. RESULTS: In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice. CONCLUSION: Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2's novel role as a regulator of obesity in female mice.

Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study.

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 µM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 µM and 0.39 ± 0.05 µM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 µM, 2.04 ± 0.28 µM, and 11.79 ± 0.83 µM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.

Epidemiology of 369 diseases and injuries attributable to 84 risk factors: 1990-2019 with 2040 projection.

The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990-2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

Global, Regional, and National Epidemiology of Diabetes in Children From 1990 to 2019.

Importance: Diabetes in children is a global epidemic that causes various medical conditions associated with an increased incidence of premature death. Objective: To investigate the trends in diabetes incidence, mortality, and disability-adjusted life-years (DALYs) in children, with risk factors for diabetes-associated death, from 1990 to 2019. Design, Setting, and Participants: This was a cross-sectional study that used data from the Global Burden of Diseases (GBD) 2019 in 204 countries and territories. Children with diabetes who were aged 0 to 14 years were included in the analysis. Data were analyzed from December 28, 2022, to January 10, 2023. Exposure: Childhood diabetes from 1990 to 2019. Main Outcome Measures: Incidence, all-cause and cause-specific deaths, DALYs, and corresponding estimated annual percentage changes (EAPCs). These trends were stratified according to region, country, age, sex, and Sociodemographic Index (SDI). Results: A total of 1 449 897 children (738 923 male [50.96%]) were included in the analysis. In 2019, there were 227 580 incident cases of childhood diabetes worldwide. Cases of childhood diabetes increased by 39.37% (95% uncertainty interval [UI], 30.99%-45.45%) from 1990 to 2019. Over 3 decades, diabetes-associated deaths decreased from 6719 (95% UI, 4823-8074) to 5390 (95% UI, 4450-6507). The global incidence rate increased from 9.31 (95% UI, 6.56-12.57) to 11.61 (95% UI, 7.98-15.98) per 100 000 population; however, the diabetes-associated death rate decreased from 0.38 (95% UI, 0.27-0.46) to 0.28 (95% UI, 0.23-0.33) per 100 000 population. Among the 5 SDI regions, the low SDI region had the highest childhood diabetes-associated mortality rate in 2019. Regionally, North Africa and the Middle East had the largest increase in incidence (EAPC, 2.06; 95% CI, 1.94-2.17). Among 204 countries, Finland had the highest national incidence of childhood diabetes in 2019 (31.60 per 100 000 population; 95% UI, 22.65-40.36), Bangladesh had the highest diabetes-associated mortality rate (1.16 per 100 000 population; 95% UI, 0.51-1.70), and the United Republic of Tanzania had the highest DALYs rate (100.16 per 100 000 population; 95% UI, 63.01-155.88). Globally, environmental/occupational risk, nonoptimal temperature, high temperature, and low temperature were key risk factors for childhood diabetes-associated mortality in 2019. Conclusions and Relevance: Childhood diabetes is an increasing global health challenge with rising incidence. Results of this cross-sectional study suggest that despite the global decline in deaths and DALYs, the number of deaths and DALYs remains high among children with diabetes, especially in low SDI regions. Improved understanding of the epidemiology of diabetes in children may facilitate prevention and control.

Shear Wave Elastography in the Diagnosis of Peripheral Neuropathy in Patients With Chronic Kidney Disease Stage 5.

Objective: To observe the feasibility of shear wave elastography (SWE) in the diagnosis of peripheral neuropathy in patients undergoing hemodialysis [chronic kidney disease stage 5 dialysis (CKD5D)]. Methods: Forty patients with CKD5D were divided into a uremic peripheral neuropathy (UPN) group (n = 25) and a non-UPN group (n = 15) according to the results of a neuro-electrophysiological examination. Sixteen healthy control subjects were also enrolled in this study. Two-dimensional ultrasound examination was conducted, and SWE was then performed to measure Young's modulus of the tibial nerve. The left and right diameters (D1), anterior and posterior diameters (D2), perimeter (C), cross-sectional area (CSA), and Young's modulus (E) were measured three times at the same non-entrapment site. The average values were recorded and calculated. The following evaluation indices were also analyzed: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). Results: D1, D2, C, and CSA were not significantly different among the three groups (P > 0.05). However, the difference in the E value among the three groups was statistically significant (P < 0.05). The AUC was 0.889 based on the E value. Using a tibial nerve E value of 48.35 kPa as the cutoff value, the sensitivity, specificity, PPV, and NPV were 86.0%, 84.0%, 81.1%, and 88.1%, respectively. Conclusions: SWE is useful for the diagnosis of peripheral neuropathy in patients with CKD5D. Young's modulus of 48.35 kPa for the tibial nerve is the optimal cutoff value and has the best diagnostic efficiency for peripheral neuropathy in CKD5D patients.

LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2.

In our previous study, we have found that leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) can improve the chemosensitivity in U251 cells whereas the role of LRIG1 in multidrug resistance (MDR) remains unknown. Here, we reported that LRIG1 can reverse MDR by inhibiting epidermal growth factor (EGF) receptor (EGFR) and secondary inhibiting ATP-binding cassette, sub-family B member 1(ABCB1) and ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2). Our data showed that the expression of LRIG1 was significantly higher in O6-methylguanine DNA methyltransferase (MGMT) Promoter Methylation positive glioblastoma tissues compared to MGMT Promoter Methylation negative glioblastoma tissues. In addition, we found that LRIG1 expression was significantly decreased in MDR cells U251/TMZ compared to U251cells. Our results demonstrated that over-expression of LRIG1 can reverse the MDR. The expression of ABCB1 and ABCG2 were markedly suppressed when LRIG1 was over-expressed, supporting the negative relationship between LRIG1 level and ABCB1 and ABCG2 level in human specimen. Furthermore, we found that LRIG1 downregulated ABCB1 and ABCG2 through suppressing EGFR expression. In case of EGFR knockdown, the effect of LRIG1 on regulating MDR, ABCB1 and ABCG2 was partially compromised. Our results, for the first time, showed that LRIG1 can reverse MDR in glioblastoma, by negatively regulating EGFR and secondary suppressing the levels of ABCB1 and ABCG2.

LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway.

The radiotherapy as a local and regional modality is widely applied in treatment of glioma, but most glioblastomas are commonly resistant to irradiation treatment. It remains challengeable to seek out efficient strategies to conquer the resistance of human glioblastoma cells to radiotherapy. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a newly discovered tumor suppressor which involved in regulation of chemosensitivity in various human cancer cells. In the present study, we established a radioresistant U251 cell line (U251R) to investigate the role of LRIG1 in regulation of radiosensitivity in human glioblastoma cells. Significantly decreased expression level of LRIG1 and enhanced expression of EGFR and phosphorylated Akt were detected in U251R cells compared with the parental U251 cells. U251R cells exhibited an advantage in colony formation ability, which accompanied by remarkably reduced X-ray-induced γ-H2AX foci formation and cell apoptosis. LRIG1 overexpression significantly inhibited the colony formation ability of U251R cells and obviously enhanced X-ray-inducedγ-H2AX foci formation and cell apoptosis. In addition, up-regulated expression of LRIG1 suppressed the expression level of EGFR and phosphorylated Akt protein. Our results demonstrated that LRIG1 expression was related to the radiosensitivity of human glioblastoma cells and may play an important role in the regulation of cellular radiosensitivity of human glioblastoma cells through the EGFR/Akt signaling pathway.

Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity.

Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis.

LRIG1 enhances chemosensitivity by modulating BCL-2 expression and receptor tyrosine kinase signaling in glioma cells.

PURPOSE: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) are an inhibitor of receptor tyrosine kinases (RTKs) that was discovered in recent years, and many studies showed that LRIG1 is a tumor suppressor gene and may be related to tumor drug resistance. In this study, we explored whether LRIG1 protein expression can improve the chemosensitivity of glioma cells and what was its mechanism. MATERIALS AND METHODS: We collected 93 cases of glioma tissues and detected the expression of LRIG1 and BCL-2. We constructed a multidrug resistance cell line U251/multidrug resistance (MDR) and examined the change of LRIG1 and BCL-2 at mRNA and protein expression levels. LRIG1 expression was upregulated in U251/MDR cells and we detected the change of multidrug resistance. Meanwhile, we changed the expression of LRIG1 and BCL-2 and explored the relationship between LRIG1 and BCL-2. Finally, we also explored the relationship between LRIG1 and RTKs. RESULTS: LRIG1 was negatively correlated with BCL-2 expression in glioma tissue and U251/MDR cells, and upregulation of LRIG1 can enhance chemosensitivity and inhibit BCL-2 expression. Furthermore, LRIG1 was negatively correlated with RTKs in U251/MDR cells. CONCLUSION: These results demonstrated that LRIG1 can improve chemosensitivity by modulating BCL-2 expression and RTK signaling in glioma cells.