Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis.

BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS: Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.

Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 µM) and THBru (20, 40 µM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

Update of dialysis initiation timing in end stage kidney disease patients: is it a resolved question? A systematic literature review.

BACKGROUND: The exact optimal timing of dialysis for ESKD patients remains unknown. This study systematically reviewed the available evidence with regard to the optimal initiation of maintenance dialysis in ESKD patients. METHODS: An electronic search was performed in Embase, PubMed and the Cochrane Library in order to find studies investigating associations between variables reference to "start of dialysis" and outcomes. Quality assessment and bias assessment were performed by the Newcastle-Ottawa scale and the ROBINSI tool. Due to the heterogeneity of studies, a meta-analysis could not be performed. RESULTS: Thirteen studies were included; four studies included only haemodialysis patients, three peritoneal dialysis, six both; study outcomes included mortality, cardiovascular events, technique failure, quality of life and others. Nine studies mainly focused on the optimal GFR of maintenance dialysis initiation; five studies showed none association between GFR and mortality or other adverse outcomes, two studies showed dialysis initiation at higher GFR levels were with poor prognosis, and 2 studies showed higher GFR levels with better prognosis. Three studies paid attention to comprehensive assessment of uremic signs and/or symptoms for optimal dialysis initiation; uremic burden based on 7 uremic indicators (hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate) were not associated with mortality; another equation (combination of sex, age, serum creatinine, blood urea nitrogen, serum albumin, haemoglobin, serum phosphorus, diabetes mellitus, and heart failure) based on fuzzy mathematics to assess the timing of haemodialysis initiation was accuracy to prognose 3-year survival; the third study found that volume overload or hypertension was associated with the highest risk for subsequent mortality. Two studies compared urgent or optimal start in dialysis, a study reported increased survival in optimal start patients, another reported no differences between Urgent-Start-PD and Early-Start-PD regarding 6-month outcomes. LIMITATIONS: Heterogeneity among the studies was quite high, with differences in sample size, variable and group characteristics; no RCT studies were included, which weakened the strength of evidences. CONCLUSIONS: The criteria for dialysis initiation were varied. Most studies proved that GFR at dialysis initiation was not associated with mortality, timing of dialysis initiation should not be based on GFR, assessments of volume load and patient's tolerance to volume overload are prospective approaches.

Containing anti-PLA2R IgG antibody induces podocyte injury in idiopathic membranous nephropathy.

Background: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear.Method: A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established in vitro podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed.Results: Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced (p = 0.016 and p = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group (p = 0.008).Conclusion: The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.

Semiconductor SERS on Colourful Substrates with Fabry-Pérot Cavities.

Non-metallic materials have emerged as a new family of active substrates for surface-enhanced Raman scattering (SERS), with unique advantages over their metal counterparts. However, owing to their inefficient interaction with the incident wavelength, the Raman enhancement achieved with non-metallic materials is considerably lower with respect to the metallic ones. Herein, we propose colourful semiconductor-based SERS substrates for the first time by utilizing a Fabry-Pérot cavity, which realize a large freedom in manipulating light. Owing to the delicate adjustment of the absorption in terms of both frequency and intensity, resonant absorption can be achieved with a variety of non-metal SERS substrates, with the sensitivity further enhanced by ≈100 times. As a typical example, by introducing a Fabry-Pérot-type substrate fabricated with SiO2 /Si, a rather low detection limit of 10-16  M for the SARS-CoV-2S protein is achieved on SnS2 . This study provides a realistic strategy for increasing SERS sensitivity when semiconductors are employed as SERS substrates.

Posttranslational modifications in GPCR internalization.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors that serve as the most important drug targets. Classically, GPCR internalization has been considered to lead to receptor desensitization. However, many studies over the past decade have reported that internalized membrane receptors can trigger distinct signal activation. The "internalized activation" provides a completely new understanding for the receptor internalization, the mechanism of physiology/pathology and novel drug targets for precision medicine. GPCR internalization undergoes a series of strict regulations, especially by posttranslational modifications (PTMs). Here, this review summarizes different PTMs in GPCR internalization and analyzes their significance in GPCR internalization dynamics, internalization routes, postinternalization fates, and related diseases, which will offer new insights into the regulatory mechanism of GPCR signaling and novel drug targets for precision medicine.

Elucidating the cation hydration ratio in water-in-salt electrolytes for carbon-based supercapacitors.

The solvation of cations is one of the important factors that determine the properties of electrolytes. Rational solvation structures can effectively improve the performance of various electrochemical energy storage devices. Water-in-Salt (WIS) electrolytes with a wide electrochemically stable potential window (ESW) have been proposed to realize high cell potential aqueous electrochemical energy storage devices relying on the special solvation structures of cations. The ratio of H2O molecules participating in the primary solvation structure of a cation (a cation hydration ratio) is the key factor for the kinetics and thermodynamics of the WIS electrolytes under an electric field. Here, acetates with different cations were used to prepare WIS electrolytes. And, the effect of different cation hydration ratios on the properties of WIS electrolytes was investigated. Various WIS electrolytes exhibited different physicochemical properties, including the saturated concentration, conductivity, viscosity, pH values and ESW. The WIS electrolytes with a low cation hydration ratio (<100%, an NH4-based WIS electrolyte) or a high cation hydration ratio (>100%, a K-based WIS electrolyte and a Cs-based WIS electrolyte) exhibit more outstanding conductivity or a wide ESW, respectively. SCs constructed from active carbon (AC) and these WIS electrolytes exhibited distinctive electrochemical properties. A SC with an NH4-based WIS electrolyte was characterized by higher capacity and better rate capability. SCs with a K-based WIS electrolyte and a Cs-based WIS electrolyte were characterized by a wider operating cell potential, higher energy density and better ability to suppress self-discharge and gas production. These results show that a WIS electrolyte with a low cation hydration ratio or a high cation hydration ratio is suitable for the construction of power-type or energy-type aqueous SCs, respectively. This understanding provides the foundation for the development of novel WIS electrolytes for the application of SCs.

Kanglexin delays heart aging by promoting mitophagy.

Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.

Optimal targets of chronic kidney disease-mineral and bone disorder markers for Chinese patients with maintenance peritoneal dialysis: a single-center retrospective cohort study.

BACKGROUND: The chronic kidney disease-mineral and bone disorder（CKD-MBD) is known to be associated with increased mortality in dialysis patients, but whether current global guidelines for CKD-MBD, which were primarily developed from hemodialysis, are suitable for peritoneal dialysis (PD) patients practice require further investigation. METHODS: This is a single-center retrospective cohort study. In total 491 prevalent PD patients (median follow-ups: 34 months) from Peking Union Medical College Hospital (PUMCH) from January 2004 to December 2017 were included and followed until 30 June 2018. In the first dialysis year, the average levels of serum calcium, albumin-corrected calcium (CorCa), phosphorus, and parathyroid hormone (PTH) levels were the interested predictors in Cox proportional regression model. RESULTS: Of these PD patients (age 58 ± 17 years), 52% were male and 36% had diabetic nephropathy. In Cox regression over first-year mean parameters, PTH <100 pg/mL (HR = 1.97, 95% CI 1.32 to 2.94, p < 0.001) and ≥300 pg/mL (HR = 2.24, 95% CI 1.32 to 3.81, p = 0.003) were associated with increased all-cause mortality than that of PTH 100-200 pg/mL. Patients with albumin-corrected serum calcium level < 2.13 mmol/L also had higher risk of death than patients with level of 2.13 to 2.38 mmol/L (HR = 2.06, 95% CI 1.06 to 4.01, p = 0.02). Serum phosphorus ≥1.45 mmol/L were associated with increased all-cause mortality. However, lacking of data on 25-hydroxy vitamin D, alkaline phosphatase, and activated vitamin-D are limitations of our analysis. CONCLUSIONS: As one of the largest PD cohort study focusing on CKD-MBD, we demonstrated that the level of CKD-MBD markers in the first PD year are independent predictors of all-cause mortality. PTH 100-300 pg/mL might be the best target for Chinese PD patients.

Clinicopathological characteristics and prognosis of patients with IgA nephropathy and renal vasculitic lesions.

BACKGROUND: We studied patients with IgA nephropathy (IgAN) and compared those with and without renal vasculitic lesions (RVLs). METHODS: From January 2006 to December 2011, patients with biopsy-proven primary IgAN at our institution were retrospectively examined and assigned to an RVL group or a no-RVL group. RVLs were defined as thromboses in arteries and/or arterioles, necrosis of capillary loops, crescent formation, and fibrinoid necrosis of small blood vessels. The association of RVLs with clinical outcomes was analyzed using multivariate models. The primary composite endpoint was end-stage renal disease or doubling of serum creatinine. RESULTS: There were 1570 patients, 50.2% (788) with RVLs and 49.8% (782) without RVLs. The RVL group was younger; had shorter disease course, more severe proteinuria and hematuria, worse renal function; and were prescribed more steroids and/or immunosuppressants. The RVL group had a greater prevalence of global glomerular sclerosis, more crescents, and a higher Oxford classification grade. A total of 501 patients in the RVL group (50.7%) and 487 in the no-RVL group (49.3%) completed follow-up. The RVL group was more likely to reach the composite endpoint after 1, 3, and 5 years (all P < 0.001). Proteinuria, anemia, low eGFR, and global and segmental sclerosis were independent predictors of progression to the composite endpoint in patients with RVLs. CONCLUSIONS: Almost half of our IgAN patients had RVLs, and these patients were younger and had worse renal function, with more severe proteinuria, hematuria, and severe pathologic lesions. IgAN patients with RVLs had worse renal outcomes than those without RVLs.

Effect of Glomerular Mannose-Binding Lectin Deposition on the Prognosis of Idiopathic Membranous Nephropathy.

OBJECTIVE: Co-deposition of mannose-binding lectin (MBL) and IgG4 anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies under subepithelial cells has been observed in patients with idiopathic membranous nephropathy (iMN), but the relationships of MBL deposition to iMN severity and progression remain unclear. METHODS: Patients diagnosed with iMN who underwent renal puncture were enrolled and followed up for a median of 17 months (interquartile range [IQR], 9-25 months). Serum anti-PLA2R and anti-thrombospondin type-1 domain-containing 7A antibodies and MBL were detected by ELISA. Glomerular MBL and anti-PLA2R antibodies were detected by immunofluorescence. Proteinuria remission, including complete remission (CR), was defined as a clinical event. Clinicopathological characteristics and kidney outcomes were compared between patients with and without MBL deposition. RESULTS: In 67 prevalent patients with biopsy-proven iMN, serum anti-PLA2R antibodies and anti-THSD7A antibodies were present in 37 (55.3%) and 1 (1.4%) patient with iMN. The positivity of glomerular MBL deposition and tissue anti-PLA2R antibody was 53 (79.1%) and 49 (73.1%), respectively. No significant difference was found between the MBL-positive and negative groups in the albumin level (26.5 ± 6.6 and 28.6 ± 6.1 g/L), eGFR (104.8 ± 17.4 and 114.6 ± 16.1 mL/min/1.73 m2), 24-h proteinuria (5.35 and 4.25 g/day), or serum MBL level corrected by serum Cr 4.92 (IQR, 0.86, 8.90) and 2.28 (IQR, 0.4, 5.62). In a Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure, eGFR, immunosuppressive agent use, 24-h proteinuria, and anti-PLA2R antibody concentration, glomerular MBL deposition was independently associated with ICR of proteinuria (HR, 6.31; 95% CI, 1.1-36.1; p = 0.039). CONCLUSIONS: The MBL pathway of complement activation is commonly initiated in patients with iMN, and patients with MBL deposition reach ICR faster than patients without MBL deposition.

Clinical, pathological characteristics and outcomes of immunoglobulin A nephropathy patients with different ages.

AIM: To determine the clinical and pathological differences in immunoglobulin A (IgA) nephropathy (IgAN) with different ages, and to determine whether age is a risk factor for progression of IgAN. METHODS: This was a single centre retrospective cohort study. Patients with biopsy-diagnosed primary IgAN were stratified into three groups: young-aged (14-29 years), middle-aged (30-49 years) and older-age (≥50 years). The primary outcome was end-stage renal disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2 , dialysis or renal transplantation) or doubling of the baseline serum creatinine. RESULTS: A total of 981 patients were enrolled, including 65 (6.6%) patients in older-age group, 517 (52.7%) in middle-aged group and 399 (40.7%) in young-aged group. The older-age group had significantly higher levels of serum IgA, cholesterol, triglycerides and creatinine, and a reduced eGFR. In contrast to the young adults who had a higher percentage of crescent formation in glomeruli, the older-aged patients had more severe chronic pathological changes including global glomerulosclerosis and vascular lesions (p < .01). The cumulative renal survival in the older-age group was slightly shorter than that in the young adult or middle-aged group, but not achieving significant (p > .05). The 3- and 5-year renal survival rates were similar among the three groups. A multivariate Cox regression analysis showed that age was not an independent predictor of an unfavourable prognosis. CONCLUSION: The IgAN patients with aged 50 years or older had different clinical pathological changes as compared with younger patients. However, aging was not found as an independently predictor of renal progression of IgAN. Prolonged follow up is necessary to confirm this trend.

Association Analysis of the MHC in Lupus Nephritis.

Lupus nephritis (LN) is one of the most prevalent and serious complications of SLE, with significant effects on patient and renal survival. Although a large number of genetic variants associated with SLE have been identified, biomarkers that correlate with LN are extremely limited. In this study, we performed a comprehensive sequencing analysis of the whole MHC region in 1331 patients with LN and 1296 healthy controls and validated the independent associations in another 950 patients with LN and 1000 controls. We discovered five independent risk variants for LN within the MHC region, including HLA-DRß1 amino acid 11 (Pomnibus<0.001), HLA-DQß1 amino acid 45 (P<0.001; odds ratio, 0.58; 95% confidence interval, 0.52 to 0.65), HLA-A amino acid 156 (Pomnibus<0.001), HLA-DPß1 amino acid 76 (Pomnibus<0.001), and a missense variant in PRRC2A (rs114580964; P<0.001; odds ratio, 0.38; 95% confidence interval, 0.30 to 0.49) at genome-wide significance. These data implicate aberrant peptide presentation by MHC classes 1 and 2 molecules and sex hormone modulation in the development of LN.

Association between G6PD deficiency and hyperbilirubinemia in neonates: a meta-analysis.

Hyperbilirubinemia is prevalent in newborns and multiple factors are responsible for the occurrence of neonatal hyperbilirubinemia. G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency is recognized as one of the risk factors. However, many pediatricians did not take into account the probable effect of G6PD-deficiency when severe neonatal hyperbilirubinemia occurred. The aim of the present study was to perform a meta-analysis to investigate whether G6PD-deficiency increases the risk of hyperbilirubinemia and phototherapy in newborn. We searched PubMed and Embase databases for eligible articles according to explicit study inclusion and exclusion criteria. Risk ratios (RRs) and 95% confidence interval (CI) were selected as the evaluation indexes. Cochrane Q and I(2) test were utilized to assess the heterogeneity among studies. A total of five cohort studies were included in this meta-analysis. There were 21,585 participants enrolled in these studies including 877 newborns with hyperbilirubinemia and 261 newborns receiving phototherapy. Comparison of the incidence of hyperbilirubinemia in newborns with G6PD-deficiency to the ones with normal G6PD in each study yielded a pooled RR of 3.92 (95% CI, 2.13-7.20; P <.0001). The pooled RR of receiving phototherapy in G6PD-deficiency neonates is 3.01 (95% CI, 2.20-4.12; P <.0001) when compared to G6PD normal neonates. This study revealed a significant correlation between G6PD-deficiency and neonatal hyperbilirubinemia, as well as G6PD-deficiency and phototherapy. G6PD-deficient newborns have higher risk of hyperbilirubinemia and phototherapy than the ones with normal G6PD. Monitoring the level of G6PD in newborns is important for predicting the occurrence of hyperbilirubinemia.

Therapeutic effects of probiotics on neonatal jaundice.

OBJECTIVE: To evaluate the therapeutic effects of probiotics on neonatal jaundice and the safety. METHODS: Sixty-eight neonates with jaundice were divided into a control group and a treatment group (n=34) randomly, and treated by blue light phototherapy and that in combination with probiotics. The serum bilirubin levels were detected before and 1, 4, 7 days after treatment. The time when therapy showed effects and jaundice faded, clinical outcomes as well as adverse reactions were recorded. The categorical data were expressed as (±s) and compared by t test. The numerical data were expressed as (case, %) and compared by χ² test. P<0.05 was considered statistically significant. RESULTS: Serum bilirubin levels of the two groups were similar before treatment (P>0.05). The levels significantly decreased 1, 4 and 7 days after treatment (P<0.05), but there was no significant inter-group difference on the post-treatment 1st day (P>0.05). The treatment group underwent more significant decreases on the 4th and 7th days than the control group did (P=0.002, 0.001). In the treatment group, the therapy exerted effects on (1.0±0.5) d and jaundice faded on (3.8±1.7) d, which were (2.6±0.6) d and (5.3±2.1) d respectively in the control group (P=0.001, 0.002). The effective rate of the treatment group significantly exceeded that of the control group (P=0.002). There were no obvious adverse reactions in either group. CONCLUSIONS: Probiotics lowered the serum bilirubin levels of neonates with jaundice rapidly, safely and significantly, and accelerated jaundice fading as well. This method is worthy of application in clinical practice.

Genetic and clinical characterization of familial renal glucosuria.

Background: Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in SLC5A2 encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize proximal tubule solute transport, glucagon secretion and the genotype-phenotype relationship in FRG patients. Methods: We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients. We built an open-source online calculator of RTG, evaluated the proximal tubule transport of amino acid, uric acid and phosphate, and explored glucagon secretion after glucose ingestion in FRG patients. Results: We identified 12 novel SLC5A2 variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, Y339*, V39F, G491E, A464E and G360D) in our cohort and yielded 111 SLC5A2 variants from literature review. RTG in our cohort ranged from 1.0 to 9.2 mmol/L. Patients with two SLC5A2 variants had lower RTG (3.9 vs 6.2 mmol/L) and higher 24-h urinary glucose excretion (24hUG) than single-variant carriers (291.0 vs 40.0 mmol/1.73 m2). Patients with homozygous missense or in-frame indels had mean 24hUG of 457.2 mmol/1.73 m2, comparable to those with homozygous truncating variants (445.0 mmol/1.73 m2) and significantly more than those with homozygous splicing variants (196.6 mmol/1.73 m2). Patients with homozygous missense variants involving conservative residues (582.0 mmol/1.73 m2) had more 24hUG than those with variants at non-conservative residues (257.6 mmol/1.73 m2). Four out of 14 tested patients had mild aminoaciduria. The RTG of FRG patients had no significant correlation to phosphate reabsorption but a potential negative correlation to the fractional excretion of uric acid. Postprandial suppression of glucagon secretion was absent in most FRG patients. Conclusions: We built a comprehensive map showing the impact of SLC5A2 variant type and variant location on glucosuria severity. Our results highlighted the role of key residues in maintaining the transport function of SGLT2 and the functional link between glucosuria and reabsorption of amino acid and uric acid in FRG patients.

Tetrahydroberberrubine exhibits preventive effect on obesity by activating PGC1α-mediated thermogenesis in white and brown adipose tissue.

The escalating prevalence of obesity presents formidable challenges, necessitating the development of effective therapeutic strategies. In this study, we aimed to elucidate the preventive effects on obesity of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and to unravel its underlying mechanism. Using an obese mouse model induced by a high-fat diet (HFD), THBru was found to markedly ameliorate obesity, as evidenced by reduced body weight, decreased Lee's index, diminished fat mass in epididymal white adipose tissue (WAT) and brown adipose tissue (BAT), alongside improved dyslipidemia. Notably, at the same dose, THBru exhibited superior efficacy compared to BBR. RNA-sequencing and gene set enrichment analysis indicated THBru activated thermogenesis, which was further confirmed in WAT, BAT, and 3 T3-L1 cells. Bioinformatics analysis of RNA-sequencing data revealed the candidate gene Pgc1α, a key regulator involved in thermogenesis. Moreover, THBru was demonstrated to elevate the expression of PGC1α by stabilizing its mRNA in WAT, BAT and 3 T3-L1 cells. Furthermore, PGC1α knockdown blocked the pro-thermogenic and anti-obesity action of THBru both in vivo and in vitro. This study unravels the preventive effects of THBru on obesity through the activation of PGC1α-mediated thermogenesis, thereby delineating its potential therapeutic implications for obesity and associated disorders.

Proteomic analysis in peritoneal dialysis patients with different peritoneal transport characteristics.

Peritoneal membranes can be categorized as high, high average, low average, and low transporters, based on the removal or transport rate of solutes. In this study, we used proteomic analysis to determine the differences in proteins removed by different types of peritoneal membranes. Peritoneal transport characteristics in patients who received peritoneal dialysis therapy were assessed by a peritoneal equilibration test. Two-dimensional differential gel electrophoresis technology followed by quantitative analysis was performed to study the variation in protein expression from peritoneal dialysis effluents (PDE) among different groups. Proteins were identified by MALDI-TOF-MS/MS analyses. Further validation in PDE or serum was performed utilizing ELISA analysis. Proteomics analysis revealed ten protein spots with significant differences in intensity levels among different groups, including vitamin D-binding protein, complement C3, apolipoprotein-A1, complement factor C4A, haptoglobin, alpha-1 antitrypsin, immunoglobulin kappa light chain, alpha-2-microglobulin, retinol-binding protein 4 and transthyretin. The levels of vitamin D-binding protein, complement C3, and apolipoprotein-A1 in PDE derived from different groups were greatly varied (P<0.05). However, no significant difference was found in the serum levels of these proteins among different groups (P>0.05 for all groups). This study provides a novel overview of the differences in PDE proteomes of four types of peritoneal membranes. Vitamin D-binding protein, complement C3, and apolipoprotein-A1 showed enhanced expression in PDE of patients with high transporter.