Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Factors Associated with Infection Severity of Diabetic Foot Ulcers: A Cross-Sectional Study.

Background: Infection in the ulcerated foot is a foremost cause of morbidity, constituting the biggest proportion of hospitalization and amputation among patients with diabetic foot ulcers. Assessment of infection severity lays a foundation for making treatment decisions, for which the IDSA/IWGDF classification is recommended. Different factors may cause various severity of infection. However, few investigations have been conducted concerning factors associated with infection severity of diabetic foot ulcers. Objective: To investigate factors associated with infection severity of diabetic foot ulcers. Methods: This cross-sectional study involved 150 subjects hospitalized in the Department of Endocrinology of Sun Yat-sen Memorial Hospital in Guangdong Province between July 2020 and September 2021. The IDSA/IWGDF classification was adopted to assess ulcer infection severity. Demographic and disease information, laboratory reports, and ulcer assessment results were evaluated for an association with the infection severity. The generalized linear model was performed to conduct multivariate analyses of the factors associated with the severity of foot infection. Results: The prevalence of mild, moderate, and severe infected diabetic foot was 23.3%, 64.7% and 10.2%, respectively. The results of generalized linear models showed a correlation between Alb (OR = -1.74, 95%CI1.12-6.58, p = .023), CRP (OR = 2.13, 95%CI1.38-7.21, p = .014), PCT (OR = 2.01, 95%CI1.29-7.64, p = .013), microbial type (OR = 2.04, 95%CI1.43-7.83, p = .004) and ulcer infection severity. Conclusion: Alb, CRP, PCT and microbial type were among the factors influencing infection severity of diabetic foot ulcers.

Corrigendum to "Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway".

[This corrects the article DOI: 10.1155/2018/4371396.].

Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway.

After activation, G protein-coupled receptors (GPCRs) are desensitized by ß-arrestins (ARRBs). Moreover, ARRBs can initiate a second wave of signaling independent of G proteins. Thyroid-stimulating hormone receptor (TSHR) is one of the GPCR members. In our previous study, TSHR was identified in the liver; the major role of TSHR in cholesterol metabolism was illustrated, as TSH could regulate hepatic cholesterol metabolism via cAMP/PKA/CREB/HMGCR and SREBP2/HNF4α/CYP7A1 pathways. It has been reported that ARRB2 predominates over ARRB1 in TSHR internalization. However, the significance of ARRBs in TSH-initiated cholesterol metabolism has not been illustrated. In our study, the effects of ARRBs on TSH-regulated cholesterol metabolism are investigated. ARRB1/2 was genetically inactivated in C57BL/6 mice and HepG2 cell line, respectively. Cholesterol levels in arrestin-knockout mice and arrestin-knockdown cells were measured. Molecules participating in cholesterol metabolism were analyzed. It turned out that deficiencies in ARRB1 led to decreased cholesterol levels and decreased TSH-stimulated AKT phosphorylation. Subsequently, the inhibitory effect on CYP7A1 by SREBP2 was reduced due to lowered mature SREBP2 level. Other than the failures of TSH in ARRB-knockdown cells, the AKT activator SC79 could enhance AKT phosphorylation and mature SREBP2 level. Our results demonstrate that ARRBs, especially ARRB1, are involved in TSH-regulated cholesterol metabolism through the AKT pathway.

Bacterial Profile and Antibiotic Resistance in Patients with Diabetic Foot Ulcer in Guangzhou, Southern China: Focus on the Differences among Different Wagner's Grades, IDSA/IWGDF Grades, and Ulcer Types.

OBJECTIVE: To understand the bacterial profile and antibiotic resistance patterns in diabetic foot infection (DFI) in different Wagner's grades, IDSA/IWGDF grades, and different ulcer types in Guangzhou, in order to provide more detailed suggestion to the clinician about the empirical antibiotic choice. METHODS: 207 bacteria were collected from 117 DFIs in Sun Yat-sen Memorial Hospital from Jan.1, 2010, to Dec.31, 2015. The clinical data and microbial information were analyzed. RESULTS: The proportion of Gram-negative bacteria (GNB) was higher than Gram-positive bacteria (GPB) (54.1% versus 45.9%), in which Enterobacteriaceae (73.2%) and Staphylococcus (65.2%) were predominant, respectively. With an increasing of Wagner's grades and IDSA/IWGDF grades, the proportion of GNB bacterial infection, especially Pseudomonas, was increased. Neuro-ischemic ulcer (N-IFU) was more susceptible to GNB infection. Furthermore, with the aggravation of the wound and infection, the antibiotic resistance rates were obviously increased. GPB isolated in ischemic foot ulcer (IFU) showed more resistance than the N-IFU, while GNB isolates were on the opposite. CONCLUSIONS: Different bacterial profiles and antibiotic sensitivity were found in different DFU grades and types. Clinician should try to stay updated in antibiotic resistance pattern of common pathogens in their area. This paper provided them the detailed information in this region.

Relative variations of gut microbiota in disordered cholesterol metabolism caused by high-cholesterol diet and host genetics.

Recent studies performed provide mechanistic insight into effects of the microbiota on cholesterol metabolism, but less focus was given to how cholesterol impacts the gut microbiota. In this study, ApoE-/- Sprague Dawley (SD) rats and their wild-type counterparts (n = 12) were, respectively, allocated for two dietary condition groups (normal chow and high-cholesterol diet). Total 16S rDNA of fecal samples were extracted and sequenced by high-throughput sequencing to determine differences in microbiome composition. Data were collected and performed diversity analysis and phylogenetic analysis. The influence of cholesterol on gut microbiota was discussed by using cholesterol dietary treatment as exogenous cholesterol disorder factor and genetic modification as endogenous metabolic disorder factor. Relative microbial variations were compared to illustrate the causality and correlation of cholesterol and gut microbiota. It turned out comparing to genetically modified rats, exogenous cholesterol intake may play more effective role in changing gut microbiota profile, although the serum cholesterol level of genetically modified rats was even higher. Relative abundance of some representative species showed that the discrepancies due to dietary variation were more obvious, whereas some low abundance species changed because of genetic disorders. Our results partially demonstrated that gut microbiota are relatively more sensitive to dietary variation. Nevertheless, considering the important effect of bacteria in cholesterol metabolism, the influence to gut flora by "genetically caused cholesterol disorder" cannot be overlooked. Manipulation of gut microbiota might be an effective target for preventing cholesterol-related metabolic disorders.

Bortezomib and lenalidomide as front-line therapy for multiple myeloma.

The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.

Lenalidomide versus thalidomide based regimens as first-line therapy for patients with multiple myeloma.

Thalidomide (T) and lenalidomide (R) have been used as first-line therapy for previously untreated myeloma. However, direct head-to-head comparison between them is lacking. We performed an indirect meta-analysis to assess the treatment effects of lenalidomide- versus thalidomide-based regimens using common comparators. A comprehensive literature search was undertaken. The initial search yielded 1345 citations, of which 11 randomized controlled trials (RCTs) enrolling 4162 patients met the inclusion criteria. Indirect comparison of lenalidomide versus thalidomide maintenance after autologous stem cell transplant (ASCT) showed a progression-free survival (PFS) benefit (hazard ratio [HR] 0.75, 95% confidence interval [CI] [0.67, 0.85], p < 0.001) but no survival difference (HR 0.83, [0.63, 1.09], p = 0.19) when using observation/placebo as the common comparator. Similarly, the indirect comparison of melphalan-prednisone plus lenalidomide followed by lenalidomide maintenance (MPR-R) versus melphalan-prednisone-thalidomide induction followed by thalidomide maintenance (MPT-T) showed a statistically significant PFS advantage for MPR-R (HR 0.53, 95% CI [0.46, 0.60], p < 0.001), but no difference for overall survival (OS) (HR 0.97, [0.81, 1.17], p = 0.74). Additionally, the significant heterogeneity among pooled studies for the outcome of discontinuation rate due to treatment-related adverse events between MPT-T and MPR-R subgroups (p = 0.007) indicated that the discontinuation rate from thalidomide trials seems to be higher than that from lenalidomide trials. In conclusion, lenalidomide seems to be a more potent and less toxic agent than thalidomide in the treatment of patients with multiple myeloma. Further, a direct head-to-head trial comparing lenalidomide versus thalidomide is clearly warranted.

Rapid and complete reconstitution of autologous haemopoiesis after cord blood infusion in treatment-naive patients with severe aplastic anemia receiving high-dose cyclophosphamide/ATG therapy.

UNLABELLED: Although high-dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. So, we designed a clinical study to investigate the effects of high-dose cyclophosphamide/ATG combined with cord blood infusion as first-line therapy for patients with severe aplastic anemia. PATIENTS AND METHOD: Between January 2003 and September 2007, we treated 16 treatment-naive patients with severe aplastic anemia with cord blood infusion after high-dose cyclophosphamide (50 mg/kg/d × 2) and rabbit antithymocyte globulin (3 mg/kg/d × 5) therapy. RESULTS: Although only one patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37 d after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment-free remission: nine patients met the criteria for a complete remission; six patients achieved a partial remission. CONCLUSION: Infusion of cord blood after high-dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment-naive patients with severe aplastic anemia. These promising results merit further investigation and confirmation on a larger number of patients.

Expression changes of hypothalamic Ahi1 in mice brain: implication in sensing insulin signaling.

Growing evidence suggests that the brain, in particular the hypothalamus, directly senses hormones and nutrients to initiate feeding behavior and metabolic responses in the control of energy homeostasis. However, the molecular mechanisms underlying this important process have remained largely unknown. Our study provides the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a sensor of insulin signaling in the hypothalamus. We found that fasting increased the expression of hypothalamic Ahi1 which was accompanied by lower levels of circulating insulin compared with satiated mice, while re-feeding decreased the expression of hypothalamic Ahi1 which was accompanied by higher levels of circulating insulin. We also found the up-regulated expression of hypothalamic Ahi1 in high-fat induced obese mice, db/db mice, and streptozotocin induced diabetic mice. In addition, we demonstrated that insulin could decrease the expression of Ahi1 in neuroblastoma cell line N18TG2. Taken together, our results indicate that hypothalamic Ahi1 functions as a sensor of insulin signaling.

Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor.

It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT(2C)R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT(2C)R. Ahi1 promoted the degradation of 5-HT(2C)R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT(2C)R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT(2C)R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT(2C)R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT(2C)R to modulate the serotonin signaling pathway.

Brainstem Hap1-Ahi1 is involved in insulin-mediated feeding control.

The function of the brainstem Hap1-Ahi1 complex in the regulation of feeding behavior was investigated. When mice were fasted or treated with 2-deoxy-D-glucose (2-DG), Hap1-Ahi1 was significantly upregulated. By using streptozotocin (STZ) to decrease the circulating insulin in mice, Hap1-Ahi1 was significantly increased. Furthermore, intra-brain injection of insulin decreased the expression of Hap1-Ahi1 in the brainstem. Moreover, when we knocked down the expression of brainstem Hap1 by RNAi, the mice showed decreased food intake and lower body weights. Collectively, our results indicate that the Hap1-Ahi1 complex in the brainstem works as a sensor for insulin signals in feeding control.