Minimizing Contact Resistance and Flicker Noise in Micro Graphene Hall Sensors Using Persistent Carbene Modified Gold Electrodes.

Scalable micro graphene Hall sensors (µGHSs) hold tremendous potential for highly sensitive and label-free biomagnetic sensing in physiological solutions. To enhance the performance of these devices, it is crucial to optimize frequency-dependent flicker noise to reduce the limit of detection (LOD), but it remains a great challenge due to the large contact resistance at the graphene-metal contact. Here we present a surface modification strategy employing persistent carbene on gold electrodes to reduce the contact resistivity by a factor of 25, greatly diminishing µGHS flicker noise by a factor of 1000 to 3.13 × 10-14 V2/Hz while simultaneously lowering the magnetic LOD SB1/2 to 1440 nT/Hz1/2 at 1 kHz under a 100 µA bias current. To the best of our knowledge, this represents the lowest SB1/2 reported for scalable µGHSs fabricated through wafer-scale photolithography. The reduction in contact noise is attributed to the π-π stacking interaction between the graphene and the benzene rings of persistent carbene, as well as the decrease in the work function of gold as confirmed by Kelvin Probe Force Microscopy. By incorporating a microcoil into the µGHS, we have demonstrated the real-time detection of superparamagnetic nanoparticles (SNPs), achieving a remarkable LOD of ∼528 µg/L. This advancement holds great potential for the label-free detection of magnetic biomarkers, e.g., ferritin, for the early diagnosis of diseases associated with iron overload, such as hereditary hemochromatosis (HHC).

Accessing the relationship between six surrogate insulin resistance indexes and the incidence of rapid kidney function decline and the progression to chronic kidney disease among middle-aged and older adults in China: Results from the China health and retirement longitudinal study.

AIMS: Insulin resistance is closely related to kidney function decline, but which insulin resistance index could better predict rapid kidney function decline (RKFD) remains unclear. We aimed to evaluate the prospective association between six insulin resistance indexes: Chinese Visceral Adiposity Index (CVAI), Lipid Accumulation Product (LAP), Atherogenic Index of Plasma (AIP), triglyceride-glucose (TyG) index, triglyceride-glucose × Body Mass Index (TyGBMI) and triglyceride-glucose × waist circumference (TyGWC) with RKFD and further the progression to chronic kidney disease (CKD). METHODS AND MEASUREMENTS: Data were obtained from the China Health and Retirement Longitudinal Study. Participants with normal kidney function (eGFRcr-cys ≥60 ml/min per 1.73 m2) and ≥45 years old were included at the baseline (year 2011). The eGFR was estimated by a combination of serum creatinine and cystatin C. The primary outcome was RKFD, defined as an annualized decline in eGFRcr-cys of 5 ml/min per 1.73 m2 or more. Secondary outcome was progression to CKD under the condition of RKFD, defined as an annualized decline in eGFRcr-cys of 5 ml/min per 1.73 m2 or more combined with eGFRcr-cys <60 ml/min per 1.73 m2 at the exit visit. Logistic analysis was applied for analysis of the association between six insulin resistance indexes and RKFD or progression to CKD. We use receiver operating characteristic curves to study the predictive performance of six insulin resistance indexes. Subgroup analysis were conducted by diabetes or hypertension status of the participants. RESULTS: A total of 3899 participants with normal kidney function were included in this study. After a 3.99 years follow-up, 191 of them ended up with RKFD. Among them, 66 participants progressed to CKD. Logistic analysis showed that per SD increase of all the six insulin resistance indexes were significantly associated with the incidence of RKFD (all P < 0.01), among which, TyGWC had the best predictive value for RKFD. There were significant association between per SD increase of CVAI, LAP, TyGBMI and TyGWC with progression to CKD (all P < 0.01), and CVAI had better predictive role than other indexes. In subgroup analysis, we found that the association between insulin resistance indexes and progression to CKD was more significant in subjects with hypertension or without diabetes. However, no significant differences were observed in the RKFD group. CONCLUSIONS: In this study we proved six insulin resistance indexes were predictively associated with RKFD in Chinese with normal renal function over age 45. TyGWC is the best insulin resistance index for predicting RKFD. CVAI is the best index for predicting further progression to CKD.

Assessment of six surrogate insulin resistance indexes for predicting cardiometabolic multimorbidity incidence in Chinese middle-aged and older populations: Insights from the China health and retirement longitudinal study.

AIMS: Insulin resistance (IR) is associated with cardiometabolic multimorbidity (CMM). We aimed to explore the predictive value of six surrogate IR indexes-Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose (TyG), atherogenic index of plasma (AIP), TyG-body mass index (TyGBMI), and TyG-waist circumference (TyGwaist)-to establish the CMM incidence in Chinese middle-aged and older populations. MATERIAL AND METHODS: To estimate the odds ratio (OR) with a 95% confidence interval (95% CI) for incident CMM using six surrogates, we analysed data from the China Health and Retirement Longitudinal Study using multivariate logistic regression models. The nonlinear dose-response correlation was evaluated using restricted cubic spline analysis; predictive performance was assessed using receiver operator characteristic curves. RESULTS: Among 6451 eligible participants, 268 (4.2%) developed CMM during the 4-year follow-up period. The ORs (95% CI) for incident CMM increased with increasing CVAI quartiles (Q) [Q2: 1.71, 1.03-2.90; Q3: 2.72, 1.70-4.52; Q4: 5.16, 3.29-8.45; all p < 0.05] after full adjustment, with Q1 as the reference. Other indexes yielded similar results. These associations remained significant in individuals with a normal body mass index. Notably, CVAI, AIP, and TyG exhibited a linear dose-response relationship with CMM (Pnonlinear ≥0.05), whereas LAP, TyGBMI, and TyGwaist displayed significant nonlinear correlations (Pnonlinear <0.05). The area under the curve for the CVAI (0.691) was significantly superior to that of other indexes (all p < 0.05). CONCLUSIONS: The six IR surrogates were independently associated with CMM incidence. CVAI may be the most appropriate indicator for predicting CMM in middle-aged and older Chinese populations.

Maternal pre-pregnancy obesity modifies the association between first-trimester thyroid hormone sensitivity and gestational Diabetes Mellitus: a retrospective study from Northern China.

BACKGROUND: Contradictory relationships have been observed between thyroid function and gestational diabetes mellitus (GDM). Previous studies have indicated that pre-pregnancy BMI (pBMI) could modify their relationships. Few studies have illustrated the role of thyroid hormone sensitivity on GDM. We aimed to explore the effect of pre-pregnancy obesity on the association between early pregnancy thyroid hormone sensitivity and GDM in euthyroid pregnant women. METHODS: This study included 1310 women with singleton gestation. Subjects were classified into pre-pregnancy obese and non-obese subgroups by pBMI levels with a cutoff of 25 kg/m2. Sensitivity to thyroid hormone was evaluated by Thyroid Feedback Quartile-Based Index (TFQI), Chinese-referenced parametric TFQI (PTFQI), TSH Index (TSHI) and Thyrotrophic T4 Resistance Index (TT4RI). The associations between these composite indices and GDM were analyzed using multivariate regression models in the two subgroups, respectively. RESULTS: In pre-pregnancy non-obese group, early pregnancy TFQI, PTFQI, TSHI and TT4RI levels were higher in subjects with incident GDM compared to those without GDM (all P < 0.05). By contrast, obese women with GDM exhibited lower levels of those indices (all P < 0.05). The occurrence of GDM were increased with rising TFQI, PTFQI, TSHI and TT4RI quartiles in non-obese women ( all P for trend < 0.05), while exhibited decreased trend across quartiles of those indices in obese women (all P for trend < 0.05). Further logistic analysis indicated contrary relationships between thyroid hormone sensitivity and the occurrence of GDM in the two groups, respectively. The OR of the fourth versus the first quartile of TFQI for GDM was 1.981 (95% CI 1.224, 3.207) in pre-pregnancy non-obese group, while was 0.131 (95% CI 0.036, 0.472) in pre-pregnancy obese group. PTFQI and TSHI yielded similar results. CONCLUSIONS: The association between maternal sensitivity to thyroid hormones during early gestation and the occurrence of GDM was modified by pre-pregnancy obesity.

Apolipoprotein C3 is negatively associated with estrogen and mediates the protective effect of estrogen on hypertriglyceridemia in obese adults.

BACKGROUND: Both estrogen and apolipoprotein C3 (ApoC3) play crucial roles in lipid metabolism. But the link between them remains unclear, and it is unknown whether estrogen regulates triglyceride (TG) levels via ApoC3. Researchers hypothesized that estrogen exerts a regulatory effect on ApoC3 metabolism, and that this regulation could play a significant role in lipid metabolism. To explore this potential link, the present investigation aimed to examine the associations between estradiol (E2), ApoC3, and TG levels in both males and females. METHODS: A total of 519 obese people (133 males and 386 premenopausal females) were recruited. Based on their TG levels, the participants were split into two groups [hypertriglyceridemia (HTG) group: TG ≥ 1.7 mmol/L; control group: TG < 1.7 mmol/L]. Serum ApoC3, E2, and TG levels were measured and compared in those two groups for both sexes separately. To ascertain the connection among E2, ApoC3, and TG, linear regression and mediation analysis were used. RESULTS: Participants in the HTG group presented higher levels of ApoC3 (P < 0.001). In contrast, they tend to have lower E2 levels than the control. Linear regression analysis proposed that in both sexes, E2 was negatively associated with ApoC3 levels. The relationship remained significant after adjustment for confounding factors (male: standardized ß = -0.144, t = -2.392, P < 0.05; female: standardized ß = -0.077, t = -2.360, P < 0.001). Furthermore, mediation analysis revealed the relationship between reduced E2 levels and elevated TG levels is directly mediated by ApoC3. CONCLUSIONS: In obese men and premenopausal women, ApoC3 was negatively and linearly correlated with serum E2 levels. The findings showed that estrogen may suppress ApoC3 expression and thus lower TG levels.

Metabolic crosstalk between thermogenic adipocyte and cancer cell: Dysfunction and therapeutics.

As one of the largest endocrine organs with a wide distribution in organisms, adipose tissue secretes multiple adipokines, cytokines, metabolites, and exosomes to promote tumour development. Elaborating the crosstalk between cancer cells and adipocytes provides a tissue-level perspective of cancer progression, which reflects the heterogeneity and complexity of human tumours. Three main types of adipose tissues, white, brown, and beige adipose tissue, have been described. Thermogenic capacity is a prominent characteristic of brown and beige adipocytes. Most studies so far mainly focus on the contribution of white adipocytes to the tumour microenvironment. However, the role of thermogenic adipose tissue in malignant cancer behaviour has been largely overlooked. Recently, emerging evidence suggests that beige/brown adipocytes play a key role in the development and progression of various cancers. This review focuses on the bidirectional communication between tumour cells and thermogenic adipocytes and the therapeutic strategies to disrupt this interaction.

Glucose metabolism status modifies the relationship between lipoprotein(a) and carotid plaques in individuals with fatty liver disease.

Background and aims: Glucose and lipoprotein(a) [Lp(a)] have been recognized risk factors for atherosclerosis. The impact of both factors on fatty liver patients has not been studied. The aim of this study is to explore the role of high-level Lp(a) and different glucose metabolism statuses on carotid plaques in fatty liver patients. Methods: We selected 4,335 fatty liver patients in this cross-sectional study. The diagnosis of fatty liver disease and carotid plaques was made by ultrasound. Participants were divided into four groups based on glucose metabolism status (normal glucose regulation [NGR], lower bound of impaired fasting glucose [IFG-L], higher bound of impaired fasting glucose [IFG-H], diabetes mellitus [DM]) and then categorized into 12 subgroups according to Lp(a) concentrations. The association between variables was estimated by odds ratio (OR). Results: Carotid plaques were present in 1,613 (37.2%) fatty liver patients. Lp(a)≥30 mg/dL was associated with high risk of carotid plaques in those patients with IFG-L, IFG-H and DM (OR 1.934 [95% CI 1.033-3.618], 2.667 [1.378-5.162], 4.000 [2.219-7.210], respectively; p<0.05). Fatty liver patients with DM plus Lp(a)<10 mg/dL and 10≤Lp(a)<30 mg/dL were more vulnerable to carotid plaques (OR 1.563 [95% CI 1.090-2.241], 1.930 [1.279-2.914]), respectively, p<0.05). Conclusions: Our study first suggested that high-level Lp(a) may raise the risk of carotid plaques in fatty liver patients with not only diabetes but also IFG, manifesting that Lp(a) may be helpful for the early discovery of subclinical atherosclerosis in fatty liver patients with impaired glucose metabolism.

Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.

Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms that dictate the association between copper deficiency and metabolic diseases remain obscure. Here, we reveal that copper restoration caused by hepatic ceruloplasmin (Cp) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1-LKB1-AMPK complex. Overnutrition-mediated Cp elevation results in hepatic copper loss, whereas Cp ablation restores copper content to the normal level without eliciting detectable hepatotoxicity and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation. Therefore, this study reveals a mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and it indicates that targeting copper-SCO1-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.

Reduced Sensitivity to Thyroid Hormones Is Associated With High Remnant Cholesterol Levels in Chinese Euthyroid Adults.

CONTEXT: It remains unclear whether the thyroid system could regulate the atherogenic remnant cholesterol (RC) levels in euthyroid status. OBJECTIVE: We aimed to investigate the relationship between sensitivity to thyroid hormones and RC levels in Chinese euthyroid population. METHODS: This study included 18 766 euthyroid adults. High RC levels were defined as the upper quartile of RC levels. The thyroid hormone sensitivity indices, including thyroid feedback quantile-based index (TFQI), thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI), and free triiodothyronine to free thyroxine (FT3/FT4) ratio were calculated. Linear and binary logistic regression analysis were applied to determine the associations between those composite indices with RC levels by genders. RESULTS: Both females and males with high RC levels exhibited co-existing higher TSH and FT4 levels. Linear regression analysis revealed that TFQI, TSHI, and TT4RI were positively, while FT3/FT4 ratio levels were negatively associated with serum RC levels. The odds ratios (ORs) (95% CI) for high RC levels were increased with rising TFQI quartiles (Q) [females: Q3 1.41 (1.22-1.63), Q4 1.61 (1.39-1.86); males: Q3 1.25 (1.09-1.45), Q4 1.38 (1.19-1.59), all P for trend < 0.001] after full adjustment, with Q1 as the reference. TSHI and TT4RI yielded similar results. By contrast, the ORs (95% CI) for high RC levels were decreased with increasing FT3/FT4 ratio quartiles in both genders (P for trend < 0.001). CONCLUSION: In euthyroid adults, reduced sensitivity to thyroid hormones was associated with high RC levels. Our results suggested an additive cardiometabolic risk of euthyroid population with thyroid hormones insensitivity.

Graphene-Based Ion-Selective Field-Effect Transistor for Sodium Sensing.

Field-effect transistors have attracted significant attention in chemical sensing and clinical diagnosis, due to their high sensitivity and label-free operation. Through a scalable photolithographic process in this study, we fabricated graphene-based ion-sensitive field-effect transistor (ISFET) arrays that can continuously monitor sodium ions in real-time. As the sodium ion concentration increased, the current-gate voltage characteristic curves shifted towards the negative direction, showing that sodium ions were captured and could be detected over a wide concentration range, from 10-8 to 10-1 M, with a sensitivity of 152.4 mV/dec. Time-dependent measurements and interfering experiments were conducted to validate the real-time measurements and the highly specific detection capability of our sensor. Our graphene ISFETs (G-ISFET) not only showed a fast response, but also exhibited remarkable selectivity against interference ions, including Ca2+, K+, Mg2+ and NH4+. The scalability, high sensitivity and selectivity synergistically make our G-ISFET a promising platform for sodium sensing in health monitoring.

Utilizing Gradient Porous Graphene Substrate as the Solid-Contact Layer To Enhance Wearable Electrochemical Sweat Sensor Sensitivity.

Wearable sweat monitoring represents an attractive opportunity for personalized healthcare and for evaluating sports performance. One of the limitations with such monitoring, however, is water layer formation upon cycling of ion-selective sensors, leading to degraded sensitivity and long-term instability. Our report is the first to use chemical vapor deposition-grown, three-dimensional, graphene-based, gradient porous electrodes to minimize such water layer formation. The proposed design reduces the ion diffusion path within the polymeric ion-selective membrane and enhances the electroactive surface for highly sensitive, real-time detection of Na+ ions in human sweat with high selectivity. We obtained a 7-fold enhancement in electroactive surface against 2D electrodes (e.g., carbon, gold), yielding a sensitivity of 65.1 ± 0.25 mV decade-1 (n = 3, RSD = 0.39%), the highest to date for wearable Na+ sweat sensors. The on-body sweat sensing performance is comparable to that of ICP-MS, suggesting its feasibility for health evaluation through sweat.

Adipose Tissue Insulin Resistance Is Positively Associated With Serum Uric Acid Levels and Hyperuricemia in Northern Chinese Adults.

Objective: Adipose tissue plays a crucial role in serum uric acid (UA) metabolism, but the relative contribution of adipose tissue insulin resistance (IR) to serum UA levels and hyperuricemia have not explicitly been illustrated. Herein, we aimed to investigate the association between the adipose tissue insulin resistance index (Adipo-IR) and hyperuricemia in this cross-sectional study. The homeostasis model assessment of insulin resistance (HOMA-IR) index, another widely applied marker to determine systemic IR, was also explored. Methods: A total of 5821 adults were included in this study. The relationship between Adipo-IR or HOMA-IR and serum UA levels was assessed by multivariate linear regression. Binary logistic regression analyses were applied to determine the sex-specific association of the Adipo-IR tertiles and HOMA-IR tertiles with hyperuricemia. Participants were then divided into normal BMI (18.5 ≤ BMI < 24) and elevated BMI (BMI ≥ 24) groups for further analysis. Results: Both Adipo-IR and HOMA-IR were positively correlated with serum UA (P < 0.001). Compared with the lowest tertile, the risks of hyperuricemia increased across Adipo-IR tertiles (middle tertile: OR 1.52, 95%CI 1.24-1.88; highest tertile: OR 2.10, 95%CI 1.67-2.63) in men after full adjustment (P for trend < 0.001). In women, only the highest tertile (OR 2.09, 95%CI 1.52-2.87) was significantly associated with hyperuricemia. Those associations remained significant in participants with normal BMI status. As for HOMA-IR, only the highest tertile showed positive relationships with hyperuricemia in both genders after full adjustment (P for trend < 0.001). The association between HOMA-IR and hyperuricemia disappeared in men with normal BMI status. Conclusions: Adipo-IR was strongly associated with serum UA and hyperuricemia regardless of BMI classification. In men with normal BMI, Adipo-IR, rather than HOMA-IR, was closely associated with hyperuricemia. Altogether, our finding highlights a critical role of adipose tissue IR on serum UA metabolism and hyperuricemia.

The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy.

Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.

The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.

Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning.

BACKGROUND: Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity. METHODS: In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. RESULTS: Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways. CONCLUSIONS: Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

Inhibition of XBP1s ubiquitination enhances its protein stability and improves glucose homeostasis.

BACKGROUND: Hepatic ER stress is a risk factor of insulin resistance and type 2 diabetes. X-box binding protein 1 spliced (XBP1s), a transcription factor, plays a key role in ameliorating insulin resistance and maintaining glucose homeostasis. Unfortunately, the short half-life of the protein dampens its clinical application, and the specific site of lysine residue that could be ubiquitinated and involved in the degradation of XBP1s remains elusive. METHODS AND RESULTS: Here, we identified K60 and K77 on XBP1s as two pivotal ubiquitin sites required for its proteasome-dependent degradation. We also constructed a double mutant form of XBP1s (K60/77R) and found that it showed higher capacity in resisting against ubiquitin-mediated protein degradation, increasing nuclear translocation, enhancing transcriptional activity, suppressing ER stress and promoting Foxo1 degradation, compared to that of wild type XBP1s (WT). Consistently, overexpression of the K60/77R XBP1s mutant in DIO mice increased the ability to reduce ER stress and decrease Foxo1 levels, thus contributed to maintaining glucose homeostasis. CONCLUSION: Our results suggest that delaying the degradation of XBP1s by preventing ubiquitination might provide a strategic approach for reducing ER stress as an anti-diabetes therapy.

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFß1.

Transforming growth factor-ß1 (TGFß1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFß1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFß1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

Single-tunnel anatomic double-bundle anterior cruciate ligament reconstruction has the same effectiveness as double femoral, double tibial tunnel: A prospective randomized study.

PURPOSE: To investigate whether single femoral, single tibial tunnel anatomic double-bundle anterior cruciate ligament (ACL) reconstruction is equal to or superior to double femoral, double tibial tunnel ACL double-bundle anatomic reconstruction in terms of restoring the stability and functions of the knee joint. METHODS: A prospective clinical study was performed to compare 30 cases of single-tunnel ACL double-bundle anatomic reconstruction to 28 cases of double-tunnel ACL double-bundle anatomic reconstruction, with average follow-up of 36 months. All graft tendons were hamstring tendon autografts. Tunnel placements in all the cases were made anatomically. Clinical results were collected after reconstruction. Graft appearance, meniscus status and cartilage state under arthroscopy were compared and analyzed. RESULTS: Tunnel placements were in the anatomic positions in both groups. On the lateral pivot-shift test performed at 36 months postoperatively, there was no significant difference between groups. Clinical results such as International Knee Documentation Committee score, Tegner activity scale, and range of motion showed no significant differences between the groups. The mean thickness of anteromedial graft was reduced by 10.3% and that of the posterolateral graft was reduced by 11.1% from the original graft thickness evaluated by magnetic resonance imaging. No new meniscal tears were found either group; however, cartilage damage occurred in the double-tunnel group at 39.3%, and this rate was significantly higher than that in the single-tunnel group (10.0%). CONCLUSION: Single femoral, single tibial tunnel anatomic double-bundle ACL reconstruction has the same effectiveness as the double femoral, double tibial tunnel in restoring the knee's stability and functions.

The effects of simvastatin preconditioning on the expression of caspase-3 after myocardial ischemia reperfusion injury in rats.

Effect of simvastatin on the expression of caspase-3 in myocardial ischemia reperfusion injury in rats was observed to explore the protective effect of caspase-3 through anti-apoptosis mechanism. A total of 48 healthy male SD rats weighing 160-240 g were selected and divided into 4 groups randomly, namely, the blank group, the sham operation group, the ischemia-reperfusion group and the simvastatin group, with 12 rats in each group. The model of SD rats was made by ligation. The loosen ligature made the reperfusion animal model, the occurrence of arrhythmia in the electrocardiogram of lead II in the experimental animal model was observed, and the area of myocardial infarction in the experimental animal models was detected. The number of apoptotic cells was detected by immunohistochemistry, and the expression of caspase-3 was detected by western blotting. The infarct area in the simvastatin group was significantly lower than the ischemia reperfusion group (P<0.05). The positive rate of the expression of caspase-3 and the positive rate of the expression of apoptotic cells in the ischemic reperfusion and simvastatin groups were significantly higher than that of the blank and sham operation groups, and the positive rate of the expression of caspase-3 and apoptotic cells in the simvastatin group was significantly lower than that of the ischemia-reperfusion group (P<0.05). The arrhythmia score of the simvastatin group was significantly lower than that of the ischemia-reperfusion group (P<0.05). Compared with the blank and sham operation groups, the expression of caspase-3 protein in the ischemia-reperfusion and simvastatin groups was significantly increased, and the expression of caspase-3 protein in the simvastatin group was significantly lower than that of the ischemia reperfusion group (P<0.05). Simvastatin has a protective effect on myocardial ischemia-reperfusion injury, which may be related to the reduction of caspase-3 expression and inhibition of apoptosis.

Ivabradine abrogates TNF-α-induced degradation of articular cartilage matrix.

Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of ß-blockers or in whom treatment with ß-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (If) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.