MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge,as chronic local inflammation can largely impair bone healing.Here,we used magnesium silicate nanospheres(MSNs)to load microRNA-146a-5p(miR-146a)to fabricate a nanobiomaterial,MSN+miR-146a,which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells(hDPSCs).In addition,miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages(BMMs)under lipopolysaccharide(LPS)stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6(TRAF6),and MSNs could simultaneously promote M2 polarization of BMMs.MiR-146a was also found to inhibit osteoclast formation.Finally,the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring hydrogel.Collectively,the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oralmaxillofacial bone defects.

Benidipine-loaded nanoflower-likemagnesium silicate improves bone regeneration

Regeneration and reconstruction of bone tissue is always a challenge for clinicians due to the uncertainty of bone repair materials in terms of long-term and efficient effects on osteoblasts.Here,we propose a novel strategy combining benidipine,an antihypertensive drug and nanoparticles to synergistically promote the healing of bone defects.Loose and porous benidipine-loaded magnesium silicate nanoparticles were prepared and validated for their biosafety.The nanoparticles were efficiently taken up by preosteoblasts and uniformly distributed around the nucleus.After internalization into cells,the nanosystem is degraded by lysosomes,and the effect of promoting osteogenic differentiation is reflected by the continuous release of benidipine,silicon and magnesium ions.Our results clearly evaluated that the nanoflower-like magnesium silicate delivering benidipine tends to be more appropriate for the bone regeneration in preosteoblasts,indicating that it might be a potential approach in guiding bone repair in clinical applications.

High Water Resistance and Enhanced Mechanical Properties of Bio-Based Waterborne Polyurethane Enabled by in-situ Construction of Interpenetrating Polymer Network

In this study,acrylic acid was used as a neutralizer to prepare bio-based WPU with an interpenetrating polymer network structure by thermally induced free radical emulsion polymerization.The effects of the content of acrylic acid on the properties of the resulting waterborne polyurethane-poly(acrylic acid)(WPU-PAA)dispersion and the films were systematically investigated.The results showed that the cross-linking density of the interpenetrating network polymers was increased and the interlocking structure of the soft and hard phase dislocations in the molecular segments of the double networks was tailored with increasing the content of acrylic acid,leading to enhancement of the mechanical properties and water resistance of WPU-PAA films.Notably,with the increase in content of acrylic acid,the tensile strength,Young’s modulus,and toughness of the WPU-PAA-110 film increased by 3 times,and 8 times,and 2.4 times compared with WPU-PAA-80,respectively.The WPU-PAA-100 film showed the best water resistance,and the water absorption rate at 96 h was only 3.27%.This work provided a new design scheme for constructing bio-based WPU materials with excellent properties.

Decreasing complexity of glucose time series derived from continuous glucose monitoring is correlated with deteriorating glucose regulation

Most information used to evaluate diabetic statuses is collected at a special time-point,such as taking fasting plasma glucose test and providing a limited view of individual’s health and disease risk.As a new parameter for continuously evaluating personal clinical statuses,the newly developed technique“continuous glucose monitoring”(CGM)can characterize glucose dynamics.By calculating the complexity of glucose time series index(CGI)with refined composite multi-scale entropy analysis of the CGM data,the study showed for the first time that the complexity of glucose time series in subjects decreased gradually from normal glucose tolerance to impaired glucose regulation and then to type 2 diabetes(P for trend<0.01).Furthermore,CGI was significantly associated with various parameters such as insulin sensitivity/secretion(all P<0.01),and multiple linear stepwise regression showed that the disposition index,which reflectsβ-cell function after adjusting for insulin sensitivity,was the only independent factor correlated with CGI(P<0.01).Our findings indicate that the CGI derived from the CGM data may serve as a novel marker to evaluate glucose homeostasis.

Smooth muscle AKG/OXGR1 signaling regulates epididymal fluid acid–base balance and sperm maturation

Infertility is a global concern attributed to genetic defects,lifestyle,nutrition,and any other factors that affect the local metabolism and niche microenvironment of the reproductive system.2-Oxoglutarate receptor 1(OXGR1)is abundantly expressed in the testis;however,its cellular distribution and biological function of OXGR1 in the male reproductive system remain unclear.In the current study,we demonstrated that OXGR1 is primarily expressed in epididymal smooth muscle cells(SMCs).Aging and heat stress significantly reduced OXGR1 expression in the epididymis.Using OXGR1 global knockout and epididymal-specific OXGR1 knockdown models,we revealed that OXGR1 is essential for epididymal sperm maturation and fluid acid–base balance.Supplementation ofα-ketoglutaric acid(AKG),the endogenous ligand of OXGR1,effectively reversed epididymal sperm maturation disorders caused by aging and heat stress.Furthermore,in vitro studies showed that AKG markedly stimulated the release of instantaneous intracellular calcium from epididymal SMCs and substantially reduced the pH_(i) value in the epididymal SMCs via OXGR1.Mechanistically,we discovered that AKG/OXGR1 considerably increased the expression of Na^(+)/HCO_(3)^(−)cotransporter(NBCe1)mRNA in the epididymal SMCs,mediated by intracellular calcium signaling.The local AKG/OXGR1 system changed the epididymal fluid pH value and HCO_(3)^(−)concentration,thereby regulating sperm maturation via intracellular calcium signaling and NBCe1 mRNA expression.This study for the first time reveals the crucial role of OXGR1 in male fertility and sheds light on the applicability of metabolic intermediates in the nutritional intervention of reproduction.

Research progress in the application of time in range: more than a percentage

Glucose monitoring is an important part of medical care in diabetes mellitus,which not only helps assess glycemic control and treatment safety,but also assists with treatment adjustment.With the development of continuous glucose monitoring(CGM),the use of CGM has increased rapidly.With the wealth of glucose data produced by CGM,new metrics are greatly needed to optimally evaluate glucose status and guide the treatment.One of the parameters that CGM provides,time in range(TIR),has been recognized as a key metric by the international consensus.Before the adoption of TIR in clinical practice,several issues including the minimum length of CGM use,the setting of the target range,and individualized TIR goals are summarized.Additionally,we discussed the mounting evidence supporting the association between TIR and diabetes-related outcomes.As a novel glucose metric,it is of interest to compare TIR with other conventional glucose markers such as glycated hemoglobin A1c.It is anticipated that the use of TIR may provide further information on the quality of glucose control and lead to improved diabetes management.

Insulin resistance and the metabolism of branched-chain amino acids

Insulin resistance(IR)is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders.IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network.Branched-chain amino acids(BCAAs),namely valine,leucine and isoleucine,are among the nine essential amino acids,accounting for 35%of the essential amino acids in muscle proteins and 40%of the preformed amino acids required by mammals.The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency.Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight,it is only recently that BCAAs are found to be closely associated with IR.This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

Relationship between time in range and corneal nerve fiber loss in asymptomatic patients with type 2 diabetes

Background: Corneal confocal microscopy (CCM) is a noninvasive technique to detect early nerve damage of diabetic sensorimotor polyneuropathy (DSPN). Time in range (TIR) is an emerging metric of glycemic control which was reported to be associated with diabetic complications. We sought to explore the relationship between TIR and corneal nerve parameters in asymptomatic patients with type 2 diabetes (T2DM).Methods: In this cross-sectional study, 206 asymptomatic inpatients with T2DM were recruited. After 7 days of continuous glucose monitoring, the TIR was calculated as the percentage of time in the glucose range of 3.9 to 10.0 mmol/L. CCM was performed to determine corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length (CNFL). Abnormal CNFL was defined as ≤15.30 mm/mm2.Results: Abnormal CNFL was found in 30.6% (63/206) of asymptomatic subjects. Linear regression analyses revealed that TIR was positively correlated with CCM parameters both in the crude and adjusted models (all P< 0.05). Each 10% increase in TIR was associated with a 28.2% (95% CI: 0.595–0.866,P = 0.001) decreased risk of abnormal CNFL after adjusting for covariates. With the increase of TIR quartiles, corneal nerve fiber parameters increased significantly (allP for trend <0.01). The receiver operating characteristic curve indicated that the optimal cutoff point of TIR was 77.5% for predicting abnormal CNFL in asymptomatic patients.Conclusions: There is a significant independent correlation between TIR and corneal nerve fiber loss in asymptomatic T2DM patients. TIR may be a useful surrogate marker for early diagnosis of DSPN.

Association between time in range and cancer mortality among patients with type 2 diabetes:a prospective cohort study

Background:Little was known about the association among time in range(TIR),time above range(TAR),time below range(TBR),and cancer mortality among patients with type 2 diabetes.We aimed to investigate the association among TIR,TAR,TBR,and the risk of cancer mortality among patients with type 2 diabetes.Methods:A total of 6225 patients with type 2 diabetes were prospectively recruited in Shanghai,China.TIR was measured with continuous glucose monitoring at baseline and was defined as the average percentage of time in the target glucose range during a 24 h period.Cox proportion hazard regression analysis was used to determine the association between TIR and the risk of cancer mortality.Results:During a mean follow-up of 7.10 years,we confirmed 237 death events related to cancer.The multivariable-adjusted hazard ratio(HR)for cancer mortality was 1.32(95%confidence interval[CI]:1.01-1.75)in patients with TIR≤70%compared with those with TIR>70%.When TIR was considered as a continuous variable,the multivariable-adjusted HR for cancer mortality associated with each 10%decrease in TIR was 1.07(95%CI:1.02-1.14).In the site-specific analysis,a significant association between TIR as a continuous variable and the risk of hepatocellular cancer was found(HR:1.24;95%CI:1.09-1.41).However,no relationship between hemoglobin A1c and cancer mortality was observed(HR:1.04;95%CI:0.97-1.10).Conclusions:The present study found an inverse association of TIR with the risk of cancer mortality among patients with type 2 diabetes.New evidence of TIR was added into the clinical practice that TIR may be an optimal target of glycemic control among patients with type 2 diabetes.

Metabolomics in human type 2 diabetes research

The high prevalence of diabetes and diabetic complications has caused a huge burden on the modern society.Although scientific advances have led to effective strategies for preventing and treating diabetes over the past several decades,little progress has been made toward curing the disease or even getting it under control,from a public health and overall societal standpoint.There is still a lack of reliable biomarkers indicative of metabolic alterations associated with diabetes and different drug responses,highlighting the need for the development of early diagnostic and prognostic markers for diabetes and diabetic complications.The emergence of metabolomics has allowed researchers to systemically measure the small molecule metabolites,which are sensitive to the changes of both environmental and genetic factors and therefore,could be regarded as the link between genotypes and phenotypes.During the last decade,the progression made in metabolomics has provided insightful information on disease development and disease onset prediction.Recent studies using metabolomics approach coupled with statistical tools to predict incident diabetes revealed a number of metabolites that are significantly altered,including branched-chain and aromatic amino acids,such as isoleucine,leucine,valine,tyrosine and phenylalanine,as diagnostic or highly-significant predictors of future diabetes.This review summarizes the current findings of metabolomic studies in human investigations with the most common form of diabetes,type 2 diabetes.