The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Erratum: [Corrigendum] Mesenchymal stem cells expressing interleukin­18 inhibit breast cancer in a mouse model.

[This corrects the article DOI: 10.3892/ol.2018.8166.].

Erratum: [Corrigendum] Mesenchymal stem cells expressing interleukin­18 suppress breast cancer cells in vitro.

[This corrects the article DOI: 10.3892/etm.2015.2286.].

hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair.

BACKGROUND: Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved. METHODS: hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4). RESULTS: The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria. CONCLUSION: Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.

The role of mitochondrial fission factor in podocyte injury in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus (DM) and has become the second cause of end-stage renal disease (ESRD). This study intends to investigate the molecular mechanism of increased mitochondrial fission in podocytes under the effect of high glucose (HG), and to preliminarily study the role of mitochondrial fission factor (MFF)-mediated mitochondrial fission in podocyte injury of DN. In vitro studies, we found that HG induced increased mitochondrial fission and podocyte damage. At the same time MFF mRNA and protein levels was increased, suggesting that MFF was transcriptional upregulated under HG conditions. Consistent with this, in vivo studies found that mitochondrial fission was also significantly increased in podocytes of diabetic nephropathy mice, and MFF expression was up-regulated. Therefore, our study proves that mitochondrial fission increases in podocytes under DM both in vitro and in vivo, and the up-regulation of MFF expression may be one of the reasons for the increase of mitochondrial fission. After inhibiting the expression of MFF, the survival rate of podocytes was significantly decreased under HG conditions, suggesting that MFF may play a protective role in podocyte injury in DN.

Human umbilical cord mesenchymal stem cells alleviate the imbalance of CD4+ T cells via protein tyrosine phosphatase non-receptor type 2/signal transducer and activator of transcription 3 signaling in ameliorating experimental autoimmune thyroiditis in rats.

This study aimed to investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on experimental autoimmune thyroiditis (EAT) and the underlying mechanisms by utilizing a porcine thyroglobulin-induced EAT rat model. The rats received four tail vein injections of vehicle or hUCMSCs at an interval of 7 days and were sacrificed on day 28 after the first injection. Hematoxylin and eosin staining and enzyme-linked immunosorbent assays (ELISAs) were used to assess the therapeutic effects of hUCMSCs on EAT. Splenic lymphocytes were isolated from rats, and the proportions of CD4+ T cell subsets were analyzed by flow cytometry. Splenic CD4+ T cells from EAT rats were cocultured with hUCMSCs. A loss-of-function assay for protein tyrosine phosphatase non-receptor type 2 (PTPN2) was performed to explore the involvement of PTPN2/signal transducer and activator of transcription 3 (STAT3) signaling on the therapeutic benefit of hUCMSCs in EAT. hUCMSC treatment significantly alleviated inflammation, reduced serum thyroid antibody levels, and decreased the ratios of IL-17α+/CD25+FOXP3+ cells and serum IFN-γ/IL-4 in EAT rats. Furthermore, hUCMSC treatment upregulated PTPN2 protein expression in splenic lymphocytes of EAT rats as well as enhanced the PTPN2 protein level and attenuated phosphorylation of STAT3 in CD4+ T cells in vitro. Importantly, knockdown of Ptpn2 significantly reversed hUCMSC-mediated suppression of cell proliferation and hUCMSC-induced alterations in the expression of inflammatory cytokines in CD4+ T cells. Thus, hUCMSC treatment alleviates thyroid inflammation and the CD4+ T cell imbalance in EAT via PTPN2/STAT3 signaling, serving as a promising therapeutic approach for autoimmune thyroiditis.

Resveratrol Enhances Wound Healing in Type 1 Diabetes Mellitus by Promoting the Expression of Extracellular Vesicle-Carried MicroRNA-129 Derived from Mesenchymal Stem Cells.

Recent studies have shown the promotive effect of resveratrol on wound healing. This study aims to explore the underlying molecular mechanism of resveratrol in type 1 diabetes mellitus (T1DM) through microRNA (miR)-129-containing extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) based on in silico analysis. The rat model of T1DM was established by intraperitoneal injection of sodium citrate containing streptozotocin, and the wound was made around the deep fascia. Rat MSCs were isolated and treated with resveratrol (SRT501), and the corresponding EVs (SRT501-EVs) were isolated, where the expression of miR-129 was determined. By performing function experiments, the effect of SRT501-EVs and miR-129 on the biological functions of human umbilical vein endothelial cells (HUVECs) was determined. Finally, the binding relationship between miR-129 and tumor necrosis factor receptor-associated factor 6 (TRAF6) was also determined by the dual-luciferase reporter gene assay. miR-129 was shown as a candidate related to both resveratrol and wound healing in T1DM. SRT501-EVs promoted the skin wound healing of T1DM rats and also further improved the proliferative, migratory, and tube formation potentials of HUVECs. Resveratrol inhibited the expression of TRAF6 in HUVECs stimulated by MSC-conditioned medium and promoted the transfer of miR-129 via EVs, while TRAF6 was confirmed as a target gene of miR-129. Furthermore, inhibition of miR-129 attenuated the proangiogenic effect of resveratrol on HUVECs. Resveratrol exerts promotive role in wound healing in T1DM through downregulation of TRAF6 via MSC-EV-carried miR-129, suggesting a regulatory network involved in the wound healing process in T1DM.

Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients.

Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patients. It is well known to contribute to CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3 ± 8.0 months, patients with higher TMAO levels (≥50 µM) had a higher risk of new-onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, C-reactive protein, BMI and ß2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, TNF-α, IL-6, and IL-1ß. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α and CCL2 expression in endothelial cells. In conclusion, our data demonstrate that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis in PD patients.

High-Salt Diet Accelerated the Decline of Residual Renal Function in Patients With Peritoneal Dialysis.

Objective: This study aims to investigate the relationship between dietary salt intake and residual renal function in peritoneal dialysis (PD) patients. Methods: The daily salt intake of the patients was calculated based on a 3 day dietary record. Sixty-two patients were divided into three groups: 33 patients in the low salt intake group (salt intake <6.0 g/day), 17 in the medium salt intake group (salt intake 6.0 to <8.0 g/day), and 12 in the high salt intake group (salt intake ≥8.0 g/day). Regular follow-up was conducted every 3 months. Urine volume, peritoneal ultrafiltration volume, and other clinical indicators were recorded. Biochemical indexes were detected to evaluate the changes in residual renal function and peritoneal function during follow-up. Results: A positive correlation between dietary sodium intake and sodium excretion was found. During 12-month follow-up, a decrease of residual renal function showed a significant difference among the three groups (p = 0.041) (15.3 ± 27.5 vs. 12.5 ± 11.5 vs. 32.9 ± 18.4 L/W/1.73 m2 in the low-, medium-, and high salt intake groups, respectively). Consistently, a higher decline of residual renal function (adjusted ß, 20.37; 95% CI, 2.83, 37.91) was found in participants with high salt intake (salt intake ≥8 g/day) compared with those in non-high salt intake. Conclusion: Our study showed that the sodium excretion by peritoneal dialysis was positively correlated with dietary sodium intake in PD patients. The high salt intake diet (salt intake ≥8 g/day) may lead to a faster decline of residual renal function in PD patients.

A comparative study of acarbose, vildagliptin and saxagliptin intended for better efficacy and safety on type 2 diabetes mellitus treatment.

As a complicated metabolic disorder, type 2 diabetes mellitus (T2DM) is becoming a major health concern worldwide. Drugs including acarbose, saxagliptin and vildagliptin are applied, but their efficacy is still required to be compared. Therefore, the study aimed to evaluate the efficacy and safety of acarbose, saxagliptin and vildagliptin in the treatment of T2DM. Ninety patients diagnosed with T2DM were treated with acarbose, saxagliptin and vildagliptin, respectively (30 patients for each drug). All patients were examined at 0, 4 and 12 weeks after treatment with vital signs recorded. Fasting blood glucose and blood biochemical indices were analyzed. In addition, fecal samples were taken for microbial macrogenome sequencing and safety evaluation within 12 weeks after treatment. Blood glucose level decreased at 4 and 12 weeks after treatment, and the total cholesterol (TC) and high-density lipoprotein (HDL) levels at 12 weeks were different. Genus abundance of intestinal flora was altered at different time points. Acarbose increased Butyricimonas level first and then decreased it during drug treatment. Saxagliptin increased Megamonas and decreased Turicibacter genus level gradually. Pseudomonas, Klebsiella, Blautia, Faecalibacterium and Roseburia levels fluctuated after Vildagliptin treatment, which increased fasting C-peptide level greater than the other two drugs. Saxagliptin showed higher adverse reactions than acarbose and vildagliptin. Collectively, acarbose, vildagliptin, and saxagliptin can effectively reduce the HbA1c level and affect the intestinal flora distribution in T2DM patients, and the adverse reactions of acarbose and vildagliptin are less than saxagliptin, providing alternative strategies for the treatment of T2DM.

Normal parathyroid hormone and non-proliferative diabetic retinopathy in patients with type 2 diabetes.

AIMS/INTRODUCTION: To investigate the associations between parathyroid hormone (PTH) and non-proliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Data were collected from 2,322 patients with type 2 diabetes mellitus in hospital between 2017 and 2019. The odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of PTH were obtained by logistic regression analysis after adjusting the potential confounding variation. RESULTS: The patients were stratified into quartiles (Q1-Q4) based on the PTH levels, with the cut-off limits of ≤23.74, 23.74-29.47, 29.47-37.30 and >37.30 pg/mL in men, and ≤24.47, 24.47-31.22, 31.22-39.49 and >39.49 pg/mL in women. The first quartile (Q1) represents the lowest quartile and the fourth quartile (Q4) is the highest. According to the quartiles (Q1-Q4), the prevalence rate of NPDR in patients showed a significantly decreasing trend (37.9%, 36.3%, 34.0% vs 24.0% in men; 43.2%, 40.5%, 31.1% vs 26.2% in women, both P < 0.05). Independent of age, diabetes duration and other metabolic factors, multivariate logistic regression showed that participants in Q4 had a lower OR of NPDR than those in Q1 (OR 0.443, 95% confidence interval 0.300-0.654, P < 0.001 for men; OR 0.428, 95% confidence interval 0.283-0.646, P < 0.001 for women). CONCLUSIONS: Low serum PTH levels were significantly associated with complications of NPDR in inpatients. Its causality remains to be further studied.

Serum progesterone and retinopathy in male patients with type 2 diabetes: A cross-sectional study.

AIMS/INTRODUCTION: The aim of this study was to investigate the relationship between serum progesterone (P) and retinopathy in male patients with type 2 diabetes mellitus, and to investigate whether P is associated with its progression. MATERIALS AND METHODS: A total of 1,376 male participants with type 2 diabetes mellitus were recruited from Affiliated Hospital of Medical College Qingdao University (Qingdao, China). Through logistic regression analysis after adjusting the potential confounding variation, the odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of progesterone were obtained. RESULTS: According to the quartiles of P levels, the prevalence rate of diabetic retinopathy (DR) in the last quartile is obviously greater to other quartiles (52.5-34.9%, 31.9%, 37.5%, P < 0.001). Compared with those in the first quartile, the prevalence of DR for the last quartile had an OR of 1.85 in the non-proliferative diabetic retinopathy group, while the OR was 8.35 in the proliferative diabetic retinopathy group (P < 0.001, unadjusted model). When adjusted for age, body mass index, duration of type 2 diabetes mellitus, glycated hemoglobin, blood pressure and other variables, the ORs for DR in the fourth quartile were 2.13 (95% confidence interval 1.49-3.06) in the non-proliferative diabetic retinopathy group and 8.44 (95% confidence interval 2.69-26.43) in the proliferative diabetic retinopathy group (P < 0.001). The positive association between P and DR risk was independent in adjusted logistic regression. CONCLUSIONS: High levels of serum progesterone are significantly associated with DR in male hospitalized patients. This could mean that a higher P level in men is a potential clinical factor to identify DR, and the causality remains to be further explored.

The effects of adipose-derived mesenchymal stem cells combined with sodium selenite on Hashimoto's thyroiditis.

Recent research found that sodium selenite (Na2SeO3) could ameliorate oxidative damage in patients with Hashimoto's thyroiditis (HT). Additionally, the effects of adipose-derived mesenchymal stem cells (AMSCs) in an animal model of HT were also reported. However, the effects of AMSCs combined with Na2SeO3 on HT are unknown. We investigated the combined effects of AMSCs and Na2SeO3 in a rat model of HT and the in vitro effect of Na2SeO3 on AMSCs using gene microarray analyses. In the HT rat model, the combination of AMSCs and Na2SeO3 restored thyroid tissue structure to that of normal controls and increased the levels of most antioxidant and inflammatory cytokines examined, but decreased the levels of interleukin 10 (IL-10) in HT thyroid tissues. At 0.5-20 µM, Na2SeO3 promoted AMSC growth and increased the levels of reduced glutathione and total antioxidant capacity in AMSCs (P<0.05). Na2SeO3 increased the levels of hepatocyte growth factor (HGF), transforming growth factor beta (TGF-ß), and stem cell factor (SCF) in AMSC culture supernatants. The results of the gene microarray analyses showed that the expression levels of certain genes involved in mitosis, DNA replication and repair, ubiquitination, synthesis and metabolism, and mitochondrial transport changed in response to Na2SeO3 treatment. In conclusion, the combination of AMSCs and Na2SeO3 restored the function and structure of the thyroid in an HT model, and Na2SeO3 promoted the growth, improved the secretion, and the antioxidant capacity of AMSCs in vitro. This combination treatment may provide a new therapy for patients with HT.

Lpl-C310R mutation is associated with impaired glucose tolerance and endoplasmic reticulum stress in skeletal muscle.

Primary Hypertriglyceridemia refers to a loss-of-function genetic defect which prevents the triglyceride (TG) in chylomicrons (CM) from lipolysis, leading to the accumulation of TG. The mutation of lipoprotein lipase (LPL) gene has been recognized as the main cause of primary hypertriglyceridemia. Recently, a new LPL gene mutation p.C310R(c. T928C) was identified in a family with hypertriglyceridemia. The proband was manifested by severe hypertriglyceridemia and diabetes. Skeletal muscle is the major LPL-synthesizing tissue and insulin response target tissue. However, little is known about the effects of LPL gene mutation on skeletal muscle. This study is intended to observe the effects of LPL-C310R mutation on glycolipid metabolism and skeletal muscle. We found that a significantly decreased LPL plasma concentration, activity and the expression levels in skeletal muscle were observed in LplC310R/+ mice comparing to wild type mice. Those mutant mice also exhibited increased fasting plasma TG, free fat acids (FFA) and insulin, as well as FFA in muscle, and decreased glucose tolerance. Enhanced expression of BIP and elevated phosphorylation of IRE1α were observed in skeletal muscle, suggesting increased endoplasmic reticulum stress (ERS). Consistent with this, increased phosphorylation of JNK was also observed. Meanwhile, remarkably enhanced phosphorylation of IRS-1 (Ser307) and decreased phosphorylation of AKT were observed in skeletal muscle of mutant mice, suggesting impaired insulin signaling. Significant lipid deposition and morphological changes in endoplasmic reticulum and mitochondria were observed in the skeletal muscle of mutant mice but not in wild type control. Results demonstrate Lpl C310R mutation caused impaired glucose tolerance, ER stress and impaired insulin signaling in skeletal muscle.

Hypermethylation of the RSK4 promoter associated with BRAF V600E promotes papillary thyroid carcinoma.

Ribosomal S6 kinase 4 (RSK4) is a putative tumor suppressor gene which is inactivated by epigenetic events in a number human malignancies; however, its role in papillary thyroid carcinoma (PTC) remains largely unknown. The aim of this study was to explore the methylation status of the RSK4 promoter in PTC, and to determine its potential role in thyroid carcinogenesis. Reverse transcription­quantitative PCR (RT­qPCR) and western blot analyses were performed to examine the RSK4 mRNA and protein levels, respectively. Methylation­specific PCR (MSP) and bisulfite genomic sequencing (BGS) were used to analyze methylation status of the RSK4 gene. Sanger sequencing was further carried out to detect the BRAF V600E mutation. Cell proliferation assay was finally performed to evaluate the role of hypermethylation in the growth of PTC cells. The association between RSK4 methylation and the clinicopathological characteristics of patients with PTC was assessed. The methylation frequency of the RSK4 promoter in PTC tissues was higher than that in paired paracancerous tissues. Coincidentally, the RSK4 mRNA levels were also downregulated in PTC tissues when compared with the paracancerous counterparts. The hypermethylation of RSK4 was associated with tumor size and lymph node metastasis. Furthermore, the BRAF V600E mutation may influence RSK4 expression and methylation. Moreover, RSK4 hypermethylation was observed in thyroid cancer cell lines, which was consistent with a lack of RSK4 expression. Upon the 5­Aza­deoxycytidine treatment of thyroid cancer cells, RSK4 expression was significantly upregulated, while cell proliferation was inhibited. On the whole, the findings of the present study demonstrate that the hypermethylation of the RSK4 promoter may be one of the mechanisms responsible for the poor RSK4 expression in PTC. Thus, these data suggest that RSK4 may serve as a molecular target for the early diagnosis and treatment of PTC.

Resveratrol prevents diabetic nephropathy by reducing chronic inflammation and improving the blood glucose memory effect in non-obese diabetic mice.

Chronic inflammation plays an important role in the development of diabetic nephropathy. Advanced glycation end product receptor (RAGE), nuclear factor kappa B (NF-κB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) are involved in the development of inflammation. Resveratrol is a plant antitoxin; it is believed to have anti-inflammatory effects and can improve blood glucose. We speculate that resveratrol treatment can protect renal function by reducing blood glucose, decreasing the expression of inflammatory factors. Non-obese diabetic (NOD) mice were randomly divided into three groups: T1DM, insulin (INS) and resveratrol (Res) groups. Mice without diabetes were classified as the non-diabetic control group (NOD-C group). The blood glucose (BG) level, blood urea nitrogen (BUN) level, serum creatinine (SCr) level and 24-h urinary microalbumin quantitative (UMA) were measured. The glomerulosclerosis index and basement membrane thickness were calculated under light and electron microscopes. The expression levels of RAGE, NF-кB (P65) and NOX4 in renal tissues were detected by Western blot analysis. We found that resveratrol treatment significantly reduced blood glucose within 28 days of the experiment, but the hypoglycemic effect was not lasting. At the same time, resveratrol reduced BUN, SCr, 24 h UMA and the expression of the inflammatory factors RAGE, NF-кB (P65) and NOX4 and improved the renal pathological structure. We believe that resveratrol improves renal function not only by its anti-inflammatory effect but also by improving the metabolic memory of hyperglycemia.

Orientin Protects Podocytes from High Glucose Induced Apoptosis through Mitophagy.

Diabetic nephropathy (DN) is one of the serious complications of diabetes mellitus. Orientin, a major bioactive constituent of Fenugreek, has been reported to possess antihyperglycemic properties. However, its effects on DN remain unclear. Therefore, we explored the protective effect of orientin on podocytes. Here, we assessed cell viability and toxicity, level of autophagy, mitochondrial morphological changes, and podocyte apoptosis. The results indicated that high glucose (HG) induced podocyte apoptosis as well as mitochondrial injury can be partially blocked by orientin. The results showed that orientin could repair autophagy disorder induced by HG, while 3-methyladenine (3-MA) reversed the protection of orientin. Our study demonstrated the possibility of treating DN with orientin.

[Effect of dietary sodium intake on residual renal function in patients undergoing peritoneal dialysis: a prospective study of 33 cases].

OBJECTIVE: To explore the impact of dietary sodium-intake on residual renal function in patients undergoing peritoneal dialysis (PD). METHODS: Thirty-three patients on PD with stable dialysis were regularly followed up for 12 months. The daily sodium intake of the patients was calculated based on the 3-day dietary record. Based on the mean daily sodium intake, the patients enrolled were divided into low-salt group (sodium intake≤3.0 g/day, 19 patients) and high-salt group (sodium intake>3.0 g/day, 14 patients). The baseline data of the patients were recorded, and the indicators of residual renal function and peritoneal function were regularly tested. The patients were followed-up at 3-month intervals, and their urine volume, peritoneal ultrafiltration volume and other clinical indicators were recorded and the biochemical indexes were detected to evaluate the changes in the residual renal function and peritoneal function. RESULTS: There was a positive correlation between the total sodium excretion and dietary sodium intake in these patients (r=0.536, P=0.0013), and sodium excretion by dialysis was positively correlated with their sodium intake (r=0.901, P=0.000). Regression analysis suggested that the total sodium excretion was correlated with dietary sodium intake (ß=0.416, 95% CI: 0.170-0.666; P < 0.0018); sodium excretion by dialysis was associated with dietary sodium intake (ß=0.489, 95% CI: 0.395-0.582; P < 0.001). The residual renal function was reduced by 17.48±11.22 L /(w·1.73 m2) in the low-salt group, as compared to 30.20±18.30 L /(w·1.73 m2) in the high-salt group (P=0.032). The reduction in the residual renal function was correlated with sodium intake in the PD patients (r=0.409, P=0.018). Multivariate regression analysis showed that sodium intake was an independent factor contributing to the reduction of residual renal function (ß=14.646, 95% CI 7.426-21.866, P < 0.001). CONCLUSIONS: Sodium excretion by PD in patients with continuous ambulatory PD is positively correlated with their dietary sodium intake, which contribute to the decrease of residual renal function. A high dietary sodium intake may accelerate the reduction of residual renal function in these patients.

Novel Mutations in the ß2 Integrin Gene (ITGB2) in a Moderate Leukocyte Adhesion Defect type 1 Patient.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder caused by reduced expression or function of CD18. It was well accepted that LAD1 resulted from mutations in the gene for the integrin ß2 subunit. METHODS: We reported a moderate LAD1 patient with 2 novel ITGB2 mutations, and further investigated the role of the 2 mutations on the expression and function of CD18 by gene transfection. RESULTS: The 2 novel mutations included a frameshift deletion viz c.954G del, which was considered as a major pathogenic gene for the patient, and a missense mutation viz c.1802C>A (Cys601Phe), which caused a damaging effect on the ITGB2 protein. There was no significant difference in protein expression between 293 T cells with mutant ITGB2 p.601C>F and 293 T cells with wild type ITGB2. When investigating the cellular location of the mutant ITGB2 in HeLa cells, we found that the mutant ITGB2 (p.601C>F) protein could not locate to the cell membrane. This indicated that the mutant ITGB2 protein could not perform its function at cell membrane level. CONCLUSION: The 2 novel ITGB2 mutations affected the expression and function of CD18 and might be pathogenic genes for LAD1.

Mesenchymal stem cells expressing interleukin-18 inhibit breast cancer in a mouse model.

Development of an improved breast cancer therapy has been an elusive goal of cancer gene therapy for a long period of time. Human mesenchymal stem cells derived from umbilical cord (hUMSCs) genetically modified with the interleukin (IL)-18 gene (hUMSCs/IL-18) were previously demonstrated to be able to suppress the proliferation, migration and invasion of breast cancer cells in vitro. In the present study, the effect of hUMSCs/IL-18 on breast cancer in a mouse model was investigated. A total of 128 mice were divided into 2 studies (the early-effect study and the late-effect study), with 4 groups in each, including the PBS-, hUMSC-, hUMSC/vector- and hUMSC/IL-18-treated groups. All treatments were injected along with 200 µl PBS. Following therapy, the tumor size, histological examination, and expression of lymphocytes, Ki-67, cluster of differentiation 31 and cytokines [interleukin (IL)-18, IL-12, interferon (IFN)-γ and TNF-α] in each group were analyzed. Proliferation of cells (assessed by measuring tumor size and Ki-67 expression) and metastasis, (by determining pulmonary and hepatic metastasis) of breast cancer cells in the hUMSC/IL-18 group were significantly decreased compared with all other groups. hUMSCs/IL-18 suppressed tumor cell proliferation by activating immunocytes and immune cytokines, decreasing the proliferation index of proliferation marker protein Ki-67 of tumor cells and inhibiting tumor angiogenesis. Furthermore, hUMSCs/IL-18 were able to induce a more marked and improved therapeutic effect in the tumor sites, particularly in early tumors. The results of the present study indicate that hUMSCs/IL-18 were able to inhibit the proliferation and metastasis of breast cancer cells in vivo, possibly leading to an approach for a novel antitumor therapy in breast cancer.