AMPK induces PIAS3 mediated SUMOylation of E3 ubiquitin ligase Smurf1 impairing osteogenic differentiation and traumatic heterotopic ossification.

AMP-activated protein kinase (AMPK) is a typical sensor of intracellular energy metabolism. Our previous study revealed the role of activated AMPK in the suppression of osteogenic differentiation and traumatic heterotopic ossification, but the underlying mechanism remains poorly understood. The E3 ubiquitin ligase Smurf1 is a crucial regulator of osteogenic differentiation and bone formation. We report here that Smurf1 is primarily SUMOylated at a C-terminal lysine residue (K324), which enhances its activity, facilitating ALK2 proteolysis and subsequent bone morphogenetic protein (BMP) signaling pathway inhibition. Furthermore, SUMOylation of the SUMO E3 ligase PIAS3 and Smurf1 SUMOylation was suppressed during the osteogenic differentiation and traumatic heterotopic ossification. More importantly, we found that AMPK activation enhances the SUMOylation of Smurf1, which is mediated by PIAS3 and increases the association between PIAS3 and AMPK. Overall, our study revealed that Smurf1 can be SUMOylated by PIAS3, Furthermore, Smurf1 SUMOylation mediates osteogenic differentiation and traumatic heterotopic ossification through suppression of the BMP signaling pathway. This study revealed that promotion of Smurf1 SUMOylation by AMPK activation may be implicated in traumatic heterotopic ossification treatment.

Angiogenesis in heterotopic ossification: From mechanisms to clinical significance.

Heterotopic ossification (HO) refers to the formation of pathologic bone in nonskeletal tissues (including muscles, tendons or other soft tissues). HO typically occurs after a severe injury and can occur in any part of the body. HO lesions are highly vascularized. Angiogenesis, which is the formation of new blood vessels, plays an important role in the pathophysiology of HO. Surgical resection is considered an effective treatment for HO. However, it is difficult to completely remove new vessels, which can lead to the recurrence of HO and is often accompanied by significant problems such as intraoperative hemorrhage, demonstrating the important role of angiogenesis in HO. Here, we broadly summarize the current understanding of how angiogenesis contributes to HO; in particular, we focus on new insights into the cellular and signaling mechanisms underlying HO angiogenesis. We also review the development and current challenges associated with antiangiogenic therapy for HO.

Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Association between serum complements and kidney function in patients with diabetic kidney disease.

Objective: We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients. Methods: This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). Results: After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching. Conclusions: Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.

Coagulation Function and Type 2 Diabetic Kidney Disease: A Real-World Observational Study.

Objectives: Type 2 diabetic kidney disease (DKD), a chronic microvascular complication of diabetes, may exhibit a complex interrelation with coagulation function. This study is aimed at elucidating the association between coagulation function and DKD. Methods: This was a real-world observational study conducted in Beijing, involving 2,703 participants. All patients with diabetes were classified into two groups, viz., DKD and non-DKD groups. Effect magnitudes are denoted as odds ratios (OR) with a 95% confidence interval (CI). To mitigate potential bias in group comparisons, we employed propensity score matching (PSM). Results: After adjusting for variables such as age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), triglyceride (TG), c-reactive protein (CRP), platelet (PLT), and serum albumin (sALB), it was discerned that fibrinogen (FIB) (OR, 95% CI, P: 1.565, 1.289-1.901, <0.001) and fibrinogen degradation products (FDP) (1.203, 1.077-1.344, 0.001) were significantly correlated with an increased risk of DKD. To facilitate clinical applications, a nomogram prediction model was established, demonstrating commendable accuracy for DKD prediction. Conclusions: Our findings suggest that elevated levels of FIB and FDP serve as potential risk indicators for DKD, and coagulation function may play an important role in the occurrence and development of DKD.

Berberine and aspirin prevent traumatic heterotopic ossification by inhibition of BMP signalling pathway and osteogenic differentiation.

Heterotopic ossification (HO) is a pathological process that often occurs in soft tissues following severe trauma. There is no effective therapy for HO. The BMP signalling pathway plays an essential role in the pathogenesis of HO. Our previous study showed that AMPK negatively regulates the BMP signalling pathway and osteogenic differentiation. The present study aims to study the effect of two AMPK activators berberine and aspirin on osteogenic differentiation and HO induced by traumatic injury. The effects of two AMPK activators, berberine and aspirin, on BMP signalling and osteogenic differentiation were measured by western blot, ALP and Alizarin red S staining in C3H10T1/2 cells. A mouse model with Achilles tenotomy was employed to assess the effects of berberine and aspirin on HO using µCT and histological analysis. First, our study showed that berberine and aspirin inhibited phosphorylation of Smad1/5 induced by BMP6 and the inhibition was attributed to the down-regulation of ALK2 expression. Second, the combination of berberine and aspirin yielded more potent effects on BMP signalling. Third, we further found that there was an additive effect of berberine and aspirin combination on osteogenic differentiation. Finally, we found that berberine and aspirin blocked trauma-induced ectopic bone formation in mice, which may be through suppression of phosphorylation of Smad1/5 in injured tissues. Collectively, these findings indicate that berberine and aspirin inhibit osteogenic differentiation in C3H10T1/2 cells and traumatic HO in mice, possibly through the down-regulation of the BMP signalling pathway. Our study sheds a light on prevention and treatment of traumatic HO using AMPK pharmacological activators berberine and aspirin.

Association between anemia-related biomarkers and the adequacy of peritoneal dialysis in Chinese patients with chronic kidney disease.

Objectives: The study aimed to examine the association of three anemia-related biomarkers with the adequacy of peritoneal dialysis (PD) in patients with chronic kidney disease (CKD). Methods: This study included 127 PD patients. The total Kt/V urea (Kt/V) was calculated according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. All patients were classified into two groups based on Kt/V, viz., adequate (Kt/V ≥1.7) and inadequate (Kt/V <1.7) groups. Effect sizes are expressed as odds ratios (ORs) and 95% confidence interval (CI). Results: After adjusting for age, gender, hypertension, diabetes, and PD duration, 20 g/L increment in hemoglobin (Hgb) was observed to significantly reduce the risk of inadequate PD by 19% (OR; 95% CI; P: 0.81; 0.70 to 0.95; 0.009), 5 g/L increment in the mean corpuscular hemoglobin concentration (MCHC) by 7% (0.93; 0.88 to 0.98; 0.009), and 5% increment in transferrin saturation (TS) by 23% (0.77; 0.64 to 0.94; 0.012). The gender-specific nomogram model was constructed by incorporating three significant anemia-related biomarkers and convenient influencing factors, and the prediction accuracy was good (concordance index (C-index): 0.686 for men and 0.825 for women). Conclusion: Our findings indicate that the deterioration of three anemia-related biomarkers (Hgb, MCHC, and TS) can precipitate the development of inadequate PD in Chinese patients with CKD.

Association between thyroid hormones and diabetic kidney disease in Chinese adults.

OBJECTIVE: We aimed to explore the association between thyroid hormones and different stages of diabetic kidney disease (DKD) in Chinese adults. METHODS: This is a retrospective study involving 2,832 participants. DKD was diagnosed and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: After propensity score matching (PSM) on age, gender, hypertension, hemoglobin A1c(HbA1c), total cholesterol (TC), serum triglyceride (TG) and duration of diabetes, per 0.2 pg/mL increment in serum free triiodothyronine (FT3) was significantly associated with 13%, 22% and 37% reduced risk of moderate-risk (OR, 95% CI, P: 0.87, 0.70-0.87, < 0.001), high-risk (0.78, 0.70-0.87, < 0.001) and very-high-risk (0.63, 0.55-0.72, < 0.001) DKD stages relative to the low-risk DKD stage, respectively. After PSM analyses, serum FT4 and TSH showed no statistical significance in risk estimates for all DKD stages. To facilitate clinical application, a nomogram prediction model was established for the moderate-risk, high-risk and very-high-risk DKD stages, with decent accuracy. CONCLUSION: Our results indicate that high concentrations of serum FT3 were associated with the significantly reduced risk of having moderate-risk to very-high-risk DKD stages.

BaoShenTongLuo formula protects against podocyte injury by regulating AMPK-mediated mitochondrial biogenesis in diabetic kidney disease.

BACKGROUND: Mitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: High-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC-ESI-MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions. RESULTS: In vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes. CONCLUSION: BSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.

Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.

A predicting model of child-bearing-aged women' spontaneous abortion by co-infections of TORCH and reproductive tract.

To develop a predicting model of child-bearing-aged women' spontaneous abortion (SA) by co-infections of TORCH and reproductive tract, in order to provide a reference tool for accurately predicting the risk of SA and guide the early prevention, diagnosis and treatment of SA. A prospective cohort study was designed based on 218 958 child-bearing-aged women following up in Hebei province in China from 2010 to 2017. Multivariable logistic regression analysis was used to select candidate predictive variables. Fisher's discriminant analysis was performed to build a predictive model, and the validity of the model was evaluated. The incidence rate of SA was 2.4%. Multivariable logistic regression analysis showed that age (OR = 3.507), adverse pregnancy history (OR = 1.509), co-infections status of Candida and HBsAg (ORCandida positive×HBsAg negative  = 4.091, ORCandida negative×HBsAg positive  = 3.327, and ORCandida positive×HBsAg positive  = 13.762), and co-infections status of HBsAg, Rubella (IgG) and CMV (IgG) (ORHBs-Ag negative×Rubella (IgG) negative×CMV (IgG) positive  = 1.789, ORHBs-Ag positive×Rubella (IgG) positive×CMV (IgG) negative  = 3.809, and ORHBsAg positive×Rubella (IgG) positive×CMV (IgG) positive  = 11.919) were the independent predictors of SA. The total discriminant rate reached 91%, with 82% of the sensitivity and 91% of the specificity. The predicting model of child-bearing-aged women' SA by co-infections status has a good performance. The co-infection status of TORCH and reproductive tract are suggested to be considered in pre-pregnancy physical examination.

A Deletion Upstream of SOX10 Causes Light Yellow Plumage Colour in Chicken.

Chicken plumage colour is a complex trait controlled by many genes. Herein, through Rhode Island Red (RIR) and White Leghorn (WL) F1 cross populations, the segregation of plumage color was observed in females, showing white in males, and dark red (DR) and light yellow (LY) in females. The white has been found to be caused by dominant white alleles (I) and the DR phenotype is attributed to a sex-linked recessive silver allele (S∗S). LY is a derived feather colour phenotype and the genetic mechanism of this is unclear. In order to explore the genetic basis for LY, we randomly selected 40 DR and 39 LY chickens for paired-end sequencing. Through the use of association analysis, we found the LY phenotype is caused by a 7.6 kb non-coding deletion near the SOX10 gene. This mutation has been reported to be responsible for dark brown plumage in chicken, and subsequent diagnostic PCR tests showed that the length of the long-range non-coding deletion is 7.6 kb instead of 8.3 kb as previously reported.

Estimation of nitrogen supply for winter wheat production through a long-term field trial in China.

Excessive synthetic nitrogen (N) applications, high mineral N accumulation and low N use efficiency (NUE) are current issues in intensively cultivated winter wheat production system impeding the sustainable development of agriculture in China. To solve these problems, soil accumulated N in the top 1 m of the soil profile before sowing (Nsoil), returned straw-N from the previous maize crop (Nstraw) and fertilizer N application (Nfertilizer) should be comprehensively considered N supply sources in N management. As such, the objective of this research was to determine the optimal total N supply (TNsupply) level needed to meet crop requirements while minimizing environmental impacts. A 9-year on-farm experiment was conducted in accordance with a split-plot design involving two different fertilizer management systems (main treatments) and three N application strategies (sub treatments). Extensive TNsupply levels (ranging from 61 kg ha-1 to 813 kg ha-1) were detected, and relative yield (RY), N input and N output in response to the TNsupply were measured. The relationships between TNsupply and RY, N input, and N output strongly fit linear-plateau, linear, and linear-plateau models, respectively. The minimum TNsupply levels needed to achieve the maximum RY and N output were 325 and 392 kg ha-1, respectively. On the basis of N supply capacity, the TNsupply was removed from the growing system by 61% (N input). As the N input increased past 209 kg ha-1, the NUE declined, at which point the TNsupply reached 433 kg ha-1. Therefore, the suitable TNsupply should range from 325 kg ha-1 (ensuring a total N supply for high yield and N uptake) to 433 kg ha-1 (obtaining a relatively higher NUE and less N loss to the environment). The TNsupply was highlighted to be an indicator for use in N management recommendations. Considering the average high N accumulation in winter wheat production systems, N management should essentially take into account the consumption of Nsoil, the levels of Nstraw and the minimum application of Nfertilizer to obtain high yields while minimizing environmental impacts under suitable TNsupply levels.

Author Correction: Record thermopower found in an IrMn-based spintronic stack.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Record thermopower found in an IrMn-based spintronic stack.

The Seebeck effect converts thermal gradients into electricity. As an approach to power technologies in the current Internet-of-Things era, on-chip energy harvesting is highly attractive, and to be effective, demands thin film materials with large Seebeck coefficients. In spintronics, the antiferromagnetic metal IrMn has been used as the pinning layer in magnetic tunnel junctions that form building blocks for magnetic random access memories and magnetic sensors. Spin pumping experiments revealed that IrMn Néel temperature is thickness-dependent and approaches room temperature when the layer is thin. Here, we report that the Seebeck coefficient is maximum at the Néel temperature of IrMn of 0.6 to 4.0 nm in thickness in IrMn-based half magnetic tunnel junctions. We obtain a record Seebeck coefficient 390 (±10) µV K-1 at room temperature. Our results demonstrate that IrMn-based magnetic devices could harvest the heat dissipation for magnetic sensors, thus contributing to the Power-of-Things paradigm.

Long-distance propagation of short-wavelength spin waves.

Recent years have witnessed a rapidly growing interest in exploring the use of spin waves for information transmission and computation toward establishing a spin-wave-based technology that is not only significantly more energy efficient than the CMOS technology, but may also cause a major departure from the von-Neumann architecture by enabling memory-in-logic and logic-in-memory architectures. A major bottleneck of advancing this technology is the excitation of spin waves with short wavelengths, which is a must because the wavelength dictates device scalability. Here, we report the discovery of an approach for the excitation of nm-wavelength spin waves. The demonstration uses ferromagnetic nanowires grown on a 20-nm-thick Y3Fe5O12 film strip. The propagation of spin waves with a wavelength down to 50 nm over a distance of 60,000 nm is measured. The measurements yield a spin-wave group velocity as high as 2600 m s-1, which is faster than both domain wall and skyrmion motions.

Origin of the emergence of higher T c than bulk in iron chalcogenide thin films.

Fabrication of epitaxial FeSexTe1-x thin films using pulsed laser deposition (PLD) enables improving their superconducting transition temperature (T c) by more than ~40% than their bulk T c. Intriguingly, T c enhancement in FeSexTe1-x thin films has been observed on various substrates and with different Se content, x. To date, various mechanisms for T c enhancement have been reported, but they remain controversial in universally explaining the T c improvement in the FeSexTe1-x films. In this report, we demonstrate that the controversies over the mechanism of T c enhancement are due to the abnormal changes in the chalcogen ratio (Se:Te) during the film growth and that the previously reported T c enhancement in FeSe0.5Te0.5 thin films is caused by a remarkable increase of Se content. Although our FeSexTe1-x thin films were fabricated via PLD using a Fe0.94Se0.45Te0.55 target, the precisely measured composition indicates a Se-rich FeSexTe1-x (0.6 < x < 0.8) as ascertained through accurate compositional analysis by both wavelength dispersive spectroscopy (WDS) and Rutherford backscattering spectrometry (RBS). We suggest that the origin of the abnormal composition change is the difference in the thermodynamic properties of ternary FeSexTe1-x, based on first principle calculations.

[Clinical intervention research on mental stress-induced myocardial ischemia].

OBJECTIVE: To observe the impact of Xinkeshu on top of standard medication on psychological stress-related emotional and biophysiological parameters in patients with mental stress-induced myocardial ischemia (MSIMI). METHODS: A randomized controlled clinical trial was conducted on 40 patients with MSIMI and patients were randomized into treatment group (n = 21) and control group (n = 19) by random number table method. Patients in the treatment group received Xinkeshu (12 capsules/d) on top of standard therapy, and the control group received placebo on top of standard therapy. Serum homocysteine (Hcy), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were compared between the groups at baseline and after 8 weeks therapy. RESULTS: (1) Baseline data were similar between the 2 groups (all P > 0.05). (2) After 8 weeks, LVFS was significantly increased (from (34.62 ± 5.76)% to (35.90 ± 4.99) %, P = 0.027) and serum Hcy (from (18.08 ± 1.81) µmol/L to (16.06 ± 10.10) µmol/L), PHQ-9 (from 8.14 ± 3.98 to 6.28 ± 2.87) and GAD-7 (from 9.52 ± 4.98 to 6.48 ± 3.84) were significantly reduced in treatment group (all P < 0.05) compared to baseline. In the control group, only GAD-7 was significantly reduced (from 8.89 ± 5.06 to 6.74 ± 4.80, P = 0.003) after 8 weeks therapy compared to baseline (P < 0.05) while other parameters remained unchanged (all P > 0.05). CONCLUSION: Xinkeshu on the top of standard therapy can improve the emotional state and left ventricular systolic function in patients with MSIMI.