Cold atmospheric plasma for chronic kidney disease-related skin disorders.

BACKGROUND AND HYPOTHESIS: An estimated 80% of individuals with chronic kidney disease (CKD) experience concomitant skin disorders, yet experimental research that elucidates the pathological changes in CKD-affected skin is limited. Cold atmospheric plasma (CAP) has shown promise in regulating keratinocyte proliferation, skin barrier function, and anti-inflammatory activity. We hypothesize that CAP emerges as a promising therapeutic avenue for CKD-related skin diseases. METHODS: Male and female C57/BL6 mice were administered a 0.2% adenine diet to generate a CKD mouse model. Skin samples from dialysis patients were also collected. These models were used to investigate the pathological alterations in the renal glomeruli, tubules, and epidermis. Subsequently, the potential impact of CAP on the stratum corneum, keratinocytes, skin hydration, and inflammation in mice with CKD were examined. RESULTS: Renal biopsies revealed glomerular and tubular atrophy, epithelial degeneration and necrosis in uriniferous tubules, and significant renal interstitial fibrosis. Skin biopsies from patients with CKD and mice showed stratum corneum thickening, epidermis atrophy, skin hydration dysfunction, and excessive inflammation. CAP attenuated skin atrophy, hydration dysfunction, and inflammation in mice with CKD, as evidenced by the activated level of YAP1/ß-catenin and Nrf-2/OH-1, enhanced expression of K5 and Ki67, increased levels of AQP3, collagen I, and GLUT1, reduced infiltration of CD3+ T cells, and diminished levels of IL-6 and TNF-α. CONCLUSION: This study provides valuable insights into the pathological changes in skin associated with CKD in both patients and animal models. It also establishes that CAP has the potential to effectively mitigate skin atrophy, hydration dysfunction, and inflammation, suggesting a novel therapeutic avenue for the treatment of CKD-related skin disorders.

Circular RNA circVmn2r1 acts as a miR-223-3p sponge to promote kidney aging by regulating NLRP3 expression in mice.

Kidney aging accelerates the progression of various acute and chronic kidney diseases and can also induce pathological changes in other organs throughout the body. Circular RNAs (circRNAs), have been demonstrated to play a vital role in aging and age-related diseases. However, biological functions and the underlying molecular mechanism of circRNAs in kidney aging remain largely unclear. Uncovering the functions of circRNAs in kidney aging and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human aging. Here we report the important role of circVmn2r1 in the progression of kidney aging. We found that circVmn2r1 was one of the top expressed circRNAs in mouse kidney by RNA sequencing and was significantly upregulated in 24-month-old mouse kidney compared to 3-month-old. More importantly, we demonstrated that overexpression of circVmn2r1 promoted kidney aging in senescence-accelerated mouse prone 8 (SAMP8) mice. Cellular assays with mouse kidney tubular epithelium (TCMK-1) cells under both gain-of-function and loss-of-function conditions demonstrated that circVmn2r1 inhibited proliferation and promoted senescence, whereas miR-223-3p counteracted these effects. Mechanistic analysis demonstrated that circVmn2r1 acted as a miR-223-3p sponge to relieve the repressive effect of miR-223-3p on its target NLRP3, which we proved could inhibit proliferation and promote senescence of TCMK-1 cells. Our results indicate that circVmn2r1 promotes kidney aging through acting as a miR-223-3p sponge, consequently upregulating NLRP3 expression, and can be a valuable diagnostic marker and an important therapeutic target for kidney aging.

SGLT2i improves kidney senescence by down-regulating the expression of LTBP2 in SAMP8 mice.

Senescent kidney can lead to the maladaptive repairment and predispose age-related kidney diseases. Here, we explore the renal anti-senescence effect of a known kind of drug, sodium-dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence-accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence-related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK-2) cells induced by H2 O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti-senescence role. Dapagliflozin down-regulate the LTBP2 expression in kidney tissues and HK-2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein-docking analysis implies there is salt-bridge formation between them; these all indicate the possibility of weak-interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2 O2 , dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non-diabetes environment; the mechanism may be through regulating the role of LTBP2.

Altered gut mycobiome in patients with end-stage renal disease and its correlations with serum and fecal metabolomes.

BACKGROUND: The relationship between the gut mycobiome and end-stage renal disease (ESRD) remains largely unexplored. METHODS: In this study, we compared the gut fungal populations of 223 ESRD patients and 69 healthy controls (HCs) based on shotgun metagenomic sequencing data, and analyzed their associations with host serum and fecal metabolites. RESULTS: Our findings revealed that ESRD patients had a higher diversity in the gut mycobiome compared to HCs. Dysbiosis of the gut mycobiome in ESRD patients was characterized by a decrease of Saccharomyces cerevisiae and an increase in various opportunistic pathogens, such as Aspergillus fumigatus, Cladophialophora immunda, Exophiala spinifera, Hortaea werneckii, Trichophyton rubrum, and others. Through multi-omics analysis, we observed a substantial contribution of the gut mycobiome to host serum and fecal metabolomes. The opportunistic pathogens enriched in ESRD patients were frequently and positively correlated with the levels of creatinine, homocysteine, and phenylacetylglycine in the serum. The populations of Saccharomyces, including the HC-enriched Saccharomyces cerevisiae, were frequently and negatively correlated with the levels of various toxic metabolites in the feces. CONCLUSIONS: Our results provided a comprehensive understanding of the associations between the gut mycobiome and the development of ESRD, which had important implications for guiding future therapeutic studies in this field.

Safety and efficacy of sequential treatments for postmenopausal osteoporosis: a network meta-analysis of randomised controlled trials.

Background: The sequential anti-osteoporotic treatment for women with postmenopausal osteoporosis (PMO) is important, but the order in which different types of drugs are used is confusing and controversial. Therefore, we performed a network meta-analysis to compare the efficacy and safety of available sequential treatments to explore the most efficacious strategy for long-term management of osteoporosis. Methods: In this network meta-analysis, we searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to September 19, 2023 to identify randomised controlled trials comparing sequential treatments for women with PMO. The identified trials were screened by reading the title and abstract, and only randomised clinical trials involving sequential anti-osteoporotic treatments and reported relevant outcomes for PMO were included. The main outcomes included vertebral fracture risk, the percentage change in bone mineral density (BMD) in different body parts, and all safety indicators in the stage after switching treatment. A frequentist network meta-analysis was performed using the multivariate random effects method and evaluated using the surface under the cumulative ranking curve (SUCRA). Certainty of evidence was assessed using the Confidence in the Network Meta-Analysis (CINeMA) framework. This study is registered with PROSPERO: CRD42022360236. Findings: A total of 19 trials comprising 18,416 participants were included in the study. Five different sequential treatments were investigated as the main interventions and compared to the corresponding control groups. The intervention groups in this study comprised the following treatment switch protocols: switching from an anabolic agent (AB) to an anti-resorptive agent (AR) (ABtAR), transitioning from one AR to another AR (ARtAAR), shifting from an AR to an AB (ARtAB), switching from an AB to a combined treatment of AB and AR (ABtC), and transitioning from an AR to a combined treatment (ARtC). A significant reduction in the incidence of vertebral fractures was observed in ARtC, ABtAR and ARtAB in the second stage, and ARtC had the lowest incidence with 81.5% SUCRA. ARtAAR and ABtAR were two effective strategies for preventing fractures and improving BMD in other body parts. Especially, ARtAAR could improve total hip BMD with the highest 96.1% SUCRA, and ABtAR could decrease the risk of total fractures with the highest 94.3% SUCRA. Almost no difference was observed in safety outcomes in other comparisons. Interpretation: Our findings suggested that the ARtAAR and ABtAR strategy are the effective and safe sequential treatment for preventing fracture and improving BMD for PMO. ARtC is more effective in preventing vertebral fractures. Funding: The National Natural Science Foundation of China (82170900, 81970762), the Hunan Administration of Traditional Chinese Medicine, and the Hunan Province High-level Health Talents "225" Project.

Risk of incident chronic kidney disease in metabolically healthy obesity and metabolically unhealthy normal weight: A systematic review and meta-analysis.

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD.

Serum Phosphorus Might Be a Predictor of Kidney Disease Progression in IgA Nephropathy.

INTRODUCTION: High serum phosphorus level has been reported to be a risk factor for disease progression in patients with chronic kidney disease, whereas, its role in IgA nephropathy (IgAN) still remains uncertain. This study aimed to investigate the association between serum phosphorus and progression of IgAN. METHODS: A total of 247 patients diagnosed with IgAN from 2016.11 to 2019.12 at the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively enrolled in this study. The association between serum phosphorus and kidney disease progression events, defined as 30% estimated glomerular filtration rate (eGFR) decline or kidney failure, was evaluated using Cox models. RESULTS: Serum phosphorus was an independent risk factor for poor renal outcome after adjusting for age, gender, urine protein, MAP, eGFR, hemoglobin, Oxford S and T scores (HR, 2.586; 95% CI, 1.238-5.400, p = 0.011). The addition of serum phosphorus to the reference model containing clinical and pathological variables significantly improved the risk prediction of IgAN progression (C statistic, 0.836; 95% CI, 0.783-0.889) as compared with the reference model (C statistic, 0.821; 95% CI, 0.756-0.886). The ability of serum phosphorus level to predict progression was much stronger in IgAN patients without use of immunosuppression (HR 5.173; 95% CI, 1.791-14.944; p = 0.002). CONCLUSION: Higher serum phosphorus levels were independently associated with kidney disease progression in patients with IgAN, especially in those without immunosuppression. The addition of serum phosphorus to clinical and pathological data at the time of biopsy significantly improved risk prediction of IgAN progression.

Gut microbiota and risk of lower respiratory tract infections: a bidirectional two-sample Mendelian randomization study.

Introduction: Observational studies have reported the association between gut microbiota and the risk of lower respiratory tract infections (LRTIs). However, whether the association reflects a causal relationship remains obscure. Methods: A bidirectional twosample Mendelian randomization (MR) analysis was conducted by assessing genome-wide association study (GWAS) summary statistics for gut microbiota taxa and five common LRTIs. MR methods including inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode were used to analyze the causality. Gene pleiotropy was tested using MR-Egger regression and MR-PRESSO methods. Cochran's Q test was used to check for heterogeneity. Leave-one-out analysis was used to assess the stability of effect sizes. Detected significant associations were validated by using an independent LRTI GWAS summary statistics dataset. An optional MR method of causal analysis using summary effect estimates (CAUSE) was further performed as a validation to avoid potential false-positive results. Results: According to the MR-Egger estimates in forward MR analysis, a causal effect of gut Blautia on increased odds of bronchiectasis and pneumonia was suggested. MR-Egger regression pleiotropy intercept methods detected no significant horizontal pleiotropy between the instrumental variables of these associations. MR-PRESSO global test examined no potential horizontal pleiotropy. Cochran's Q test showed that no heterogeneity biased the results. The leave-one-out sensitivity analyses suggested robust causality results. These associations with consistent effect direction were successfully replicated in IVW analysis by using the validation GWAS dataset. However, these evidence of causality did not survive after applying strict Bonferroni correction or CAUSE analysis. The reverse MR analysis failed to achieve consistent results in the effect of LRTIs on gut microbiota through comprehensive discovery and validation processes. Discussion: This study established no strong causality between genetically predicted gut microbiome and the risk of lower respiratory tract infections. However, specific subtypes of microbial genera, such as Blautia, were identified as potential influencers and require further investigation, particularly at the species or strain levels.

Progress of newborn screening in China. / 中国新生儿筛查进展.

Newborn screening (NBS) plays a significant role in reducing the risk of birth defects. NBS in China began in the early 1980s. Under the protection of laws and regulations and the leadership of the national health administration, approved screening centers in public hospitals took the responsibility for publicity, screening, diagnosis, treatment, follow-up and management of birth defects. As of 2022, 31 provinces (autonomous regions and municipalities directly under the central government) have carried out NBS for phenylketonuria, congenital hypothyroidism, and hearing loss, 23 provinces have carried out screening for glucose-6-phosphate dehydrogenase (with a screening rate of 89.24%), and 24 provinces have carried out screening for congenital adrenal cortical hyperplasia (91.45% screening rate). Over the past four decades, screening techniques have evolved from bacterial inhibition, fluorescence analysis, and tandem mass spectrometry for the detection of biochemical markers to genetic testing, which has greatly contributed to the expansion of the types of diseases screened for. The combined use of metabolomics and genomics is currently being explored. Effective management and rigorous quality control of NBS are prerequisites for improving the quality and ensuring the accuracy of screening. The Quality Management System for Newborn Screening System Network (QMS-NBS), established by the National Center for Clinical Laboratories, covers all screening centers and related blood collection agencies. The operation of the QMS-NBS allows the quality and performance of screening to be transparent and measurable, ensuring the quality and efficiency of screening. This article provides an overview of the history of NBS, especially the evolution of policies for the NBS in China, the construction of screening institutions, the number of newborns screened, the incidence rates of screened diseases, the changes in screening technology, the expansion of new diseases screened for, and the quality control of NBS. Overall, the progress in NBS in China has not only benefited from the development and standardization at the technological level, but also benefited from the construction of policies, regulations and ethics.

Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial.

Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18-70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ -1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and -0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11-0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

HDAC4 regulates the proliferation, migration, and invasion of trophoblasts in pre-eclampsia through the miR-134-5p/FOXM1 axis.

Epigenetics, including histone modifications and noncoding RNAs, affects abnormal placental function in pre-eclampsia (PE). This study was conducted to explore the role of histone deacetylase 4 (HDAC4) in trophoblast invasion and migration. The expression levels of HDAC4, microRNA (miR)-134-5p, and forkhead box protein M1 (FOXM1) in placentas from PE patients and healthy controls and their correlations were examined. HTR8/SVneo cells were cultured and underwent gene intervention. Then, trophoblast proliferation, invasion, and migration were evaluated by 5-ethynyl-2'deoxyuridine, Transwell, and scratch assays. The enrichments of HDAC4 and acetylated histone H3 at lysine 9 (H3K9Ac) on the miR-134-5p promoter were quantified by chromatin immunoprecipitation. The binding of miR-134-5p to FOXM1 was analyzed by dual-luciferase assay. HDAC4 and FOXM1 were downregulated while miR-134-5p was upregulated in PE placentas. HDAC4 downregulation impaired trophoblast proliferation, invasion, and migration while HDAC4 overexpression played the opposite role. Mechanically, HDAC4 deacetylated H3K9Ac to repress miR-134-5p expression by erasing H3K9Ac, reduced the binding of miR-134-5p to FOXM1, and then promoted FOXM1 transcription. miR-134-5p overexpression or FOXM1 downregulation abrogated the promotive role of HDAC overexpression in trophoblast invasion and migration. Our study unraveled a novel mechanism of trophoblast proliferation, invasion, and migration and proposed that HDAC4 may be a promising target for the treatment of PE.

LncRNA XIST promotes insulin resistance in gestational diabetes mellitus via the microRNA-181b-5p/NDRG2 axis.

Many studies have explored the role of lncRNA X inactivation-specific transcript (XIST) in diabetes. This study was designed to unravel the regulatory mechanism of XIST on animal models of gestational diabetes mellitus (GDM) progression via the microRNA (miR)-181b-5p/N-myc downstream-regulated gene 2 (NDRG2) axis. XIST, miR-181b-5p, and NDRG2 expression levels in GDM mice were detected. The GDM mice were subjected to gain- and loss-of-function assays to examine the change of glucose metabolism indices (fasting blood glucose (FBG), fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR)), serum oxidative stress factors (glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA)), serum inflammatory factors (interleukin-1 ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α)), pathological changes of pancreatic tissues, and apoptotic cells in pancreatic islets in GDM mice. XIST and NDRG2 expression were elevated while miR-181b-5p expression was depleted in GDM mice. Down-regulated XIST or NDRG2 or up-regulated miR-181b-5p reduced the FBG level, HOMA-IR, and serum IL-1ß, IL-6, and TNF-α, and MDA contents, elevated the FINS, GSH, and SOD level, mitigated pathological changes in pancreatic tissues, and decelerated apoptotic cells in pancreatic islets in GDM mice. Silenced XIST dampens insulin resistance in GDM mice via the modulation of the miR-181b-5p/NDRG2 axis.

The Comparation of Renal Anti-Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non-Diabetes Environment.

Delaying kidney senescence process will benefit renal physiologic conditions, and prompt the kidney recovering from different pathological states. The renal anti-senescence effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and metformin have been proven in diabetic settings, but the roles of each one and combination of two drugs in natural kidney aging process remain undefined and deserve further research. Senescence-accelerated mouse prone 8 (SAMP8) were orally administered dapagliflozin, metformin, and a combination of them for 16 weeks. Dapagliflozin exhibits better effects than metformin in lowering senescence related markers, and the combination therapy shows the best results. In vitro experiments demonstrate the same results that the combination of dapagliflozin and metformin can exert a better anti-senescence effect. Blood metabolites detection in vivo shows dapagliflozin mainly leads to the change of blood metabolites enriched in choline metabolism, and metformin tends to induce change of blood metabolites enriched in purine metabolism. In conclusion, the results suggest dapagliflozin may have a better renal anti-senescence effect than metformin in non-diabetes environment, and the combination of the two drugs can strengthen the effect. The two drugs can lead to different blood metabolites alteration, which may lead to different systemic effects.

Tai Chi as a complementary exercise for pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVES: With the characteristics of mindfulness and breathing techniques, Tai Chi has been recommended with therapeutic values in chronic obstructive pulmonary disease (COPD). However, its strengths as a complementary exercise for conventional pulmonary rehabilitation (PR) remain unclear. DESIGN AND SETTING: This single-blinded randomised controlled trial recruited patients with mild to severe stable COPD. Eligible participants were randomly assigned to the group with usual care (control), total body recumbent stepper (TBRS) exercise, Tai Chi (TC), or combined TBRS exercise and Tai Chi (TBRS-TC). Patients received a two-month hospital-based supervised exercise, followed by a ten-month community- or home-based rehabilitation program. RESULTS: A total of 120 participants were recruited, and 102 were included in the per-protocol analysis. The mean changes in St George's Respiratory Questionnaire (SGRQ) total score from baseline to the post-hospital exercise in the control group, TBRS group, TC group, and TBRS-TC group was 2.62 (95 % CI -8.99 to 8.99), -9.28 (95 % CI -13.96 to -4.60), -10.19 (95 % CI -13.72 to -6.67), and -16.75 (95 % CI -20.25 to -13.24), respectively, with a statistically significant difference between groups in favor of the TBRS-TC exercise (P < 0.001). The remarkable effect of TBRS-TC exercise in improving the quality of life maintained until the end of the community- or home-based rehabilitation training (P < 0.001). Besides, a statistically better effect with the TBRS-TC exercise was also observed in the outcomes regarding exercise capacity, pulmonary function, symptom burden, and systemic inflammation after the whole process of 12-month integrative PR exercise programme. CONCLUSIONS: Based on the results, a novel integrated exercise modality combining Tai Chi and conventional pulmonary rehabilitation was developed. It might contribute to more positive effects in patients with stable COPD. REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-15006874) prior to commencing recruitment.

Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management.

Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.

Fat distribution measurements by chemical shift-encoded transition region extraction predict the risk of hyperglycaemia, dyslipidaemia and metabolic syndrome in mice.

Metabolically healthy or unhealthy obesity is closely related to metabolic syndrome (MetS). To validate a more accurate diagnostic method for obesity that reflects the risk of metabolic disorders in a pre-clinical mouse model, C57BL/6J mice were fed high-sucrose-high-fat and chow diets for 12 weeks to induce obesity. MRI was performed and analysed by chemical shift-encoded fat-water separation based on the transition region extraction method. Abdominal fat was divided into upper and lower abdominal regions at the horizontal lower border of the liver. Blood samples were collected, and the glucose level, lipid profile, liver function, HbA1c and insulin were tested. k-means clustering and stepwise logistic regression were applied to validate the diagnosis of hyperglycaemia, dyslipidaemia and MetS, and to ascertain the predictive effect of MRI-derived parameters to the metabolic disorders. Pearson or Spearman correlation was used to assess the relationship between MRI-derived parameters and metabolic traits. The receiver-operating characteristic curve was used to evaluate the diagnostic effect of each logistic regression model. A two-sided p value less than 0.05 was considered to indicate statistical significance for all tests. We made the precise diagnosis of obesity, dyslipidaemia, hyperglycaemia and MetS in mice. In all, 14 mice could be diagnosed as having MetS, and the levels of body weight, HbA1c, triglyceride, total cholesterol and low-density lipoprotein cholesterol were significantly higher than in the normal group. Upper abdominal fat better predicted dyslipidaemia (odds ratio, OR = 2.673; area under the receiver-operating characteristic curve, AUCROC = 0.9153) and hyperglycaemia (OR = 2.456; AUCROC = 0.9454), and the abdominal visceral adipose tissue (VAT) was better for predicting MetS risk (OR = 1.187; AUCROC = 0.9619). We identified the predictive effect of fat volume and distribution in dyslipidaemia, hyperglycaemia and MetS. The upper abdominal fat played a better predictive role for the risk of dyslipidaemia and hyperglycaemia, and the abdominal VAT played a better predictive role for the risk of MetS.

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation.

BACKGROUND: Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited. METHODS: Drug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins. RESULTS: After the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR. CONCLUSIONS: RES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.

[Effects of Mulching and Application of Organic and Chemical Fertilizer on Greenhouse Gas Emission and Water and Nitrogen Use in Summer Maize Farmland].

To explore the effects of mulching and the application of organic and chemical fertilizer on N2O, CO2, and CH4 emission; maize yield; water use efficiency (WUE); and nitrogen fertilizer use efficiency under the conditions of the same nitrogen fertilizer input in summer maize farmland, an experiment was conducted in the Guanzhong Plain of China. In this experiment, the two main experimental factors were mulching (M) and no-mulching, and the secondary experimental factors included no fertilizer application (CK), organic fertilizer substituting chemical fertilizer at 0% (T0, 0.00 kg·hm-2 organic fertilizer and 225.00 kg·hm-2 chemical fertilizer), 25% (T25, 56.25 kg·hm-2 organic fertilizer and 168.75 kg·hm-2 chemical fertilizer), 50% (T50, 112.50 kg·hm-2 organic fertilizer and 112.50 kg·hm-2 chemical fertilizer), 75% (T75, 168.75 kg·hm-2 organic fertilizer and 56.25 kg·hm-2 chemical fertilizer), and 100% (T100, 225.00 kg·hm-2 organic fertilizer and 0.00 kg·hm-2 chemical fertilizer), for a total of 12 treatments. The results showed as follows:1 both mulching and fertilizer application (with or without mulching) factors significantly increased soil N2O and CO2 emissions and reduced soil uptake of CH4(P<0.05). Compared to chemical fertilizer treatments, the organic fertilizer treatments reduced soil N2O emission by 11.8% to 52.6% and 14.1% to 68.0% and increased soil CO2 emission by 5.1% to 24.1% and 15.1% to 48.7% under mulching and no-mulching conditions, respectively (P<0.05). Compared to that under no-mulching, the global warming potential (GWP) under mulching increased by 140.7% to 206.6%. Compared to that in the CK treatment, the GWP of fertilized treatments increased by 36.6% to 67.6% and 31.2% to 89.1% under mulching and no-mulching conditions (P<0.05), respectively. Combined with the yield factor, the greenhouse gas intensity (GHGI) under the mulching condition increased by 103.4% to 166.2% compared to that under the no-mulching condition. Therefore, GHG emissions could be reduced by increasing yields. 2 The mulching treatments increased maize yield by 8.4% to 22.4% and WUE by 4.8% to 24.9% (P<0.05). Fertilizer application significantly increased maize yield and WUE. The organic fertilizer treatments increased yield by 2.6% to 8.5% and WUE 13.5% to 23.2% under the mulching condition compared to that in the MT0 treatment and increased yield by 3.9% to 14.3% and WUE 4.5% to 18.2% under the no-mulching condition compared to that in the T0 treatment. 3 In the 0-40 cm soil layer, the total nitrogen content of mulching treatments was increased by 2.4% to 24.7% compared with that of the no-mulching treatments. Fertilizer application treatments increased the total nitrogen content by 18.1% to 48.9% and 15.4% to 49.7% under the mulching and no-mulching conditions, respectively. Mulching and fertilizer application promoted nitrogen accumulation and nitrogen fertilizer use efficiency in maize plants (P<0.05). Compared to that in chemical fertilizer treatments, the organic fertilizer treatments increased nitrogen fertilizer use efficiency by 2.6% to 8.5% and 3.9% to 14.3% under mulching and no-mulching conditions, respectively. Combining ecological and economic benefits, the MT50 under mulching conditions and T75 under no-mulching conditions can be recommended as planting models to guarantee stable yield and achieve green and sustainable agricultural production.