MicroRNA-27a, downregulated in human obesity, exerts an antiapoptotic function in adipocytes.

Adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue (AT) and thus triggers AT inflammation in obesity. MicroRNA-27a (miR-27a) was shown to mediate the pathological processes of many metabolic disorders; however, whether miR-27a is involved in adipocyte apoptosis of obese AT remains unknown. The present study aimed to investigate the alteration of miR-27a in obese individuals and its antiapoptotic function in adipocytes. In vivo, serum samples and omental adipose tissue from humans as well as epididymal fat pads from mice were collected to detect miR-27a expression. In vitro, 3T3-L1 preadipocytes and mature adipocytes were treated with TNF-α to induce apoptosis and transfected with a mimic for overexpressing miR-27a-3p. The results showed that miR-27a was markedly decreased in the serum and AT of obese human patients and in the AT of high-fat diet-fed mice. Regression analyses revealed that the serum level of miR-27a was correlated with metabolic parameters in human obesity. Notably, TNF-α induced cell apoptosis in both preadipocytes and mature adipocytes, as evidenced by the upregulation of cleaved caspase 3 and cleaved caspase 8 and the ratio of Bax to Bcl-2, while these effects were partly diminished by miR-27a overexpression. In addition, TUNEL and Hoechst 33258 staining verified that miR-27a overexpression markedly inhibited the apoptosis of adipocytes under TNF-α stimulation. Thus, miR-27a was downregulated in the AT of obese subjects with proapoptotic status, and overexpression of miR-27a exerted an antiapoptotic effect on preadipocytes, providing a novel potential target for preventing AT dysfunction.

Fully physically cross-linked double network hydrogels with strong mechanical properties, good recovery and self-healing properties.

Combining a hydrophobic interaction crosslinked curdlan as the first network and hydrophobic interaction crosslinked polyacrylamide as the second network, we have fabricated a curdlan/HPAAm double network (DN) hydrogel using a one-pot method. The resulting DN hydrogel exhibited good mechanical properties, i.e. an elastic modulus of 103 kPa, a tensile fracture strength of 0.81 MPa, a tensile stretch of 25.3 and a compressive stress of 62.5 MPa when the compressive strain increased up to 99%. The DN gel could withstand ten compression tests under 90% compressive strain without observable damage. The DN gel demonstrated 84% stiffness recovery and 97% toughness recovery after the deformed samples were relaxed and stored at 95 °C for 4 h. The stiffness and fracture stress of the DN gel were enhanced after sterilization treatment at 120 °C. Furthermore, the gels exhibited 52% self-healing of fracture stretch after the samples were cut and brought into contact at 95 °C for 4 h. The self-recovery and self-healing properties of the DN gel both originated from the first curdlan network via the reformation of hydrophobic interactions and the second HPAAm network via reformation of the broken hydrophobic associations.

Antidepressant activity of astilbin: involvement of monoaminergic neurotransmitters and BDNF signal pathway.

Depression and related mood disorders are among the world's greatest public health problems. Previous studies have demonstrated that astilbin (AST) has broad pharmacological functions which may modulate numerous pathways, such as antioxidant, scavenging free radicals, anti-inflammatory and so on, similarly to some of other flavonoids. In this study, the antidepressant-like effect of AST was investigated using chronic unpredictable mild stress (CUMS) model of depression in mice. The results showed that chronic administration of AST at doses of 10, 20 and 40 mg/kg (intraperitoneally (i.p.), 21 d) reduced depressive-like behaviors of mice in the forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) without affecting locomotor activity. AST increased the contents of serotonin (5-HT) and dopamine (DA) in the frontal cortex of CUMS mice. Additionally, it was shown that AST treatment restored the CUMS-induced inhibition of extracellular signal-regulated kinase (ERK) 1/2 and AKT phosphorylation in the frontal cortex, conformed to the brain-derived neurotrophic factor (BDNF) expression. Our findings suggest that AST has antidepressant activities and the mechanisms, at least in part, relate to up-regulation of monoaminergic neurotransmitters (5-HT and DA) and activation of the BDNF signaling pathway.

The association of metabolic dysfunction-associated steatotic liver disease (MASLD) with the risk of myocardial infarction: a systematic review and meta-analysis.

Objective While studies have documented how metabolic dysfunction-associated steatotic liver disease (MASLD) can contribute to cardiovascular disease (CVD), whether MASLD is associated with myocardial infarction (MI) remains debateable. Herein, we systematically reviewed published articles and performed a meta-analysis to determine the relationship between MASLD and MI risk.Methods PubMed, MEDLINE, Embase, Web of Science, CNKI, CBM, VIP, and WanFang databases were searched, and the DerSimonian Laird method was used to obtain hazard ratios (HRs) for binary variables to assess the correlation between MASLD and MI risk. Subgroup analyses for the study region, MASLD diagnosis, quality score, study design, and follow-up time were conducted simultaneously for the selected studies retrieved from the time of database establishment to March 2022. All study procedures were independently conducted by two investigators.Results The final analysis included seven articles, including eight prospective and two retrospective cohort studies. The MI risk was higher among MASLD patients than among non-MASLD patients (HR = 1.26; 95% CI: 1.08-1.47, p = 0.003). The results of the subgroup analysis of the study region revealed an association of MASLD with MI risk among Americans and Asians, but not in Europeans. Subgroup analyses of MASLD diagnosis showed that ultrasonography and other (fatty liver index[FLI] and computed tomography [CT)]) diagnostic methods, but not international classification of disease (ICD), increased the risk of MI. Subgroup analysis of the study design demonstrated a stronger relationship between MASLD and MI in retrospective studies but not in prospective studies. Subgroup analysis based on the follow-up duration revealed the association of MASLD with MI risk in cases with < 3 years of follow-up but not with ≥3 years of follow-up.Conclusion MASLD increases the risk of MI, independent of traditional risk factors.

Patency and factors related to patency after percutaneous transluminal angioplasty for inflow arterial stenosis in native arteriovenous fistula dysfunction: a single-center retrospective study.

Controversy still exists regarding how much the inflow arterial percutaneous transluminal angioplasty (PTA) contributed to maintaining fistula function for hemodialysis. We aimed to analyze patency and risk factors after inflow arterial PTA. Hemodialysis patients with inflow arterial primary stenosis who were admitted to our institution from January 2017 to December 2022 were examined. One group had arterial-venous fistula with inflow artery stenosis alone (AVF + iAS) and another group had AVF with inflow artery stenosis and any vein stenosis (AVF + iAS + VS). The characteristics of patients, stenotic lesions, and PTA procedures were recorded. Kaplan-Meier analysis was used to compare primary patency, assisted primary patency, and secondary patency in the two groups. Cox proportional hazard analysis was used to identify risk factors associated with patency. We examined 213 patients, 53 in the AVF + iAS group (51 radial arterial stenosis and 2 ulnar arterial stenosis) and 160 in the AVF + iAS + VS group (159 radial arterial stenosis and 1 ulnar arterial stenosis). Kaplan-Meier analysis indicated the AVF + iAS group had better primary patency and assisted primary patency (both P < 0.05), but the groups had similar secondary patency. Cox proportional hazard analysis indicated that none of the analyzed clinical and biochemical indexes had clinically meaningful effects on primary patency, assisted primary patency, or secondary patency in either group. The patency and safety after PTA for inflow arterial stenosis were satisfactory, and none of the examined risk factors had a major clinical impact on patency. We recommend PTA as treatment for inflow stenosis of an AVF.

Metformin inhibits expression and secretion of PEDF in adipocyte and hepatocyte via promoting AMPK phosphorylation.

OBJECTIVE: Pigment epithelium-derived factor (PEDF) plays an important role in obesity-induced insulin resistance (IR). The study aims to investigate the effect of metformin, a widely used agent to improve IR, on PEDF production both in vivo and in vitro. METHODS: SD rats were divided into normal control group, high fat group (HF group), and metformin group (MET group). Hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity. IR models of 3T3-L1 and HepG2 cells were established and then treated with metformin and inhibitor of AMP activated protein kinase (AMPK). RESULTS: In vivo, the HF group showed increased serum PEDF which is negatively correlated with insulin sensitivity, while the MET group revealed decreased serum PEDF and downregulated PEDF expression in fat and liver, concomitant with significantly improved IR. In vitro, the IR cells showed enhanced PEDF secretion and expression, whereas metformin lowered PEDF secretion and expression, accompanied with increased glucose uptake. Metformin stimulated AMPK phosphorylation in fat and liver of the obese rats, while in vitro, when combined with AMPK inhibitor, the effect of metformin on PEDF was abrogated. CONCLUSIONS: Metformin inhibits the expression and secretion of PEDF in fat and liver via promoting AMPK phosphorylation, which is closely associated with IR improvement.

Random and aligned electrostatically spun PLLA nanofibrous membranes enhance bone repair in mouse femur midshaft defects.

Long-segment bone defects are a common clinical challenge and abstract biomaterials are a promising therapy. Poly-L-lactic acid (PLLA) nanofibrous membranes prepared by electrostatic spinning have a good bone repair potential. However, there are random and aligned surface morphologies of electrostatic spun PLLA nanofibrous membranes, which can affect the migration, proliferation, and differentiation ability of cells. The role of surface morphology in the repair of long bone defects in vivo is currently unknown. In this study, random and aligned electrostatically spun PLLA nanofibrous membranes were prepared, characterised, and implanted into a femur midshaft defect mouse model. The ability of electrostatically spun PLLA nanofibrous membranes to enhance bone repair was tested using X-ray photography, high-resolution micro-computed tomography (micro-CT), and pathological section specimens. The results showed that both random and aligned electrostatically spun PLLA nanofibrous membranes enhanced bone regeneration at bone defects, but the aligned ones exhibited superior results. These results provide a theoretical basis for engineering the surface morphology of bone repair materials.

Stiff and strong hydrogel tube with great mechanical properties and high stability in various solutions.

Hydrogel tubes are widely used in fields such as artificial blood vessels, drug delivery, biomedical scaffolds and cell adhesion, yet their application is often limited by unsatisfactory mechanical properties and poor stability in various solutions. Herein, a novel hydrogel tube exhibiting a remarkable mechanical performance and stability in various solutions is prepared by introducing a dual physically cross-linked double network (DN) hydrogel matrix. The obtained hydrogel tube can withstand ∼60 N load without fracture and be stretched to over twice its original length before and after immersing in various solutions. The great mechanical properties and stability in various solutions of hydrogel tubes are due to the introduction of a dual physically cross-linked poly(acrylamide-co-acrylic acid)/carboxymethylcellulose sodium/Fe3+ DN hydrogel, which possesses high elastic modulus (3.71 MPa), fracture energy (15.4 kJ m-2), and great stability in various solutions. In addition, the hydrogel tubes with different thickness, diameters, shapes and the multiple branched hydrogel tubes can also be fabricated to enable further functionalization for application requirements. Therefore, this new type of hydrogel tube presents tremendous potential for applications in biomedical and engineering fields.

Tough and Stretchable Dual Ionically Cross-Linked Hydrogel with High Conductivity and Fast Recovery Property for High-Performance Flexible Sensors.

As a kind of typical soft and wet material, hydrogel has been increasingly investigated as another way to develop flexible electronics. However, the traditional hydrogel with poor strain and strength performance cannot meet the requirements for stretchable electronics; fabricating a stretchable hydrogel with balanced tensile strength, toughness, and conductivity is still a big challenge. Herein, a new type of physically cross-linked hydrogel with poly(acrylamide-co-acrylic acid)-Fe3+ and chitosan-SO42- dual ionic networks via facile free radical polymerization and soaking processes is developed to fabricate excellent high-performance flexible sensors. The abundant Fe3+ and SO42- ions in the hydrogel can not only construct tough and strong dual ionic networks but also give the hydrogel high conductivity. Consequently, the optimal hydrogel possesses high tensile strength (∼5.1 MPa), large strain capacity (∼1225%), elasticity (∼1.13 MPa), high toughness (∼32.1 MJ/m3), and high conductivity (3.04 S/m at f = 0.1M), as well as rapid self-recovery property. Furthermore, the hydrogel conductor has high stretching sensitivity with a gauge factor of 6.0 at strain of 700% and was able to detect conventional motions of the human body such as the motions of the knuckle, speaking, and swallowing, which indicates that our ionic conductive hydrogels can be used to fabricate excellent high-performance flexible sensors.

Effect of transportation stress on heat shock protein 70 concentration and mRNA expression in heart and kidney tissues and serum enzyme activities and hormone concentrations of pigs.

OBJECTIVE: To determine the enzymatic and hormonal responses, heat shock protein 70 (Hsp70) production, and Hsp70 mRNA expression in heart and kidney tissues of transport-stressed pigs. ANIMALS: 24 pigs (mean weight, 20 +/- 1 kg). PROCEDURES: Pigs were randomly placed into groups of 12 each. One group was transported for 2 hours. The other group was kept under normal conditions and used as control pigs. Sera were used to detect triiodothyronine, thyroxine, and cortisol concentrations and alanine aminotransferase, aspartate aminotransferase, and creatine kinase activities. The heart and kidneys of anesthetized pigs were harvested and frozen in liquid nitrogen for quantification of Hsp70 and Hsp70 mRNA. RESULTS: No significant differences were detected in serum alanine aminotransferase activity and triiodothyronine and cortisol concentrations between groups; however, the serum creatine kinase and aspartate aminotransferase activities and thyroxine concentrations were higher in transported pigs. Densitometric readings of western blots revealed that the amount of Hsp70 in heart and kidney tissues was significantly higher in transported pigs, compared with control pigs. Results of fluorescence quantitative real-time PCR assay revealed that the Hsp70 mRNA transcription in heart tissue, but not kidney tissue, was significantly higher in transported pigs, compared with control pigs. CONCLUSIONS AND CLINICAL RELEVANCE: Transportation imposed a severe stress on pigs that was manifested as increased serum activities of aspartate aminotransferase and creatine kinase and increased amounts of Hsp70 and Hsp70 mRNA expression in heart and kidney tissues. Changes in serum enzyme activities were related to the tissue damage of transport-stressed pigs.

Bisphenol A promotes hepatic lipid deposition involving Kupffer cells M1 polarization in male mice.

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, is considered to promote hepatic lipid deposition. However, the mechanism has not been fully elucidated. The polarization of Kupffer cells (KCs) plays an important role in hepatic inflammation by promoting pro-inflammatory M1 phenotype (M1KCs), which contributes to dysregulated lipid metabolism. The purpose of this study is to investigate the role of KC polarization in BPA-induced hepatosteatosis in male mice. In this study, we examined hepatic lipid contents and quantified M1KC in BPA-treated CD1 mice, and further explored the interaction between KCs and hepatocytes using conditional HepG2 cell culture. BPA treatment significantly increased hepatic fat contents in CD1 mice, accompanied by increased number of pro-inflammatory M1KCs and enhanced secretion of inflammatory cytokines. Increased lipid contents were also observed in HepG2 cells treated with BPA. Interestingly, higher TG contents were observed in HepaG2 cells treated with conditional media from BPA-treated KCs, compared with those treated with BPA directly. Incubation of KCs with BPA promoted the polarization of KCs to pro-inflammatory M1 dominant subtypes, which was blocked by estrogen antagonist ICI182780. Taken together, our results revealed that M1KCs polarization is involved in BPA-induced hepatic fat deposition, which is possibly associated with the estrogen receptor signaling pathway.

Lipopolysaccharide-binding protein cannot independently predict type 2 diabetes mellitus: A nested case-control study.

BACKGROUND: Cross-sectional studies have reported a close association between serum lipopolysaccharide-binding protein (LBP) and many metabolic disorders. However, no longitudinal study has explored the relationship between LBP and type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association between serum LBP levels and the risk of developing T2DM. METHODS: A 5-year nested case-control study of 3510 individuals was performed as part of the Environment, Inflammation and Metabolic Diseases Study (EIMDS). Clinical data were collected at baseline. Serum levels of LBP and other biochemical factors, such as insulin and high-sensitivity C-reactive protein, were detected 5 years later. Subjects were diagnosed as having T2DM on the basis of results of an oral glucose tolerance test (OGTT) and 1998 World Health Organization criteria. Controls were randomly selected to match cases according to age, gender, and body mass index (BMI) in a 1:1 ratio. Odds ratios (OR) for T2DM were calculated using conditional logistic regression analysis. RESULTS: Over a 5-year follow-up period, 255 subjects developed T2DM. There was no significant difference in serum LBP levels between the T2DM and control groups at baseline (19.78 ± 6.40 versus 20.53 ± 6.99 µg/mL; P = 0.207). Subjects were divided into three groups based on tertiles of LBP concentrations (n = 170 in each group; T1 = 1.31-17.16 µg/mL LBP; T2 = 17.21-22.37 µg/mL LBP; T3 = 22.49-40.08 µg/mL LBP). There was no significant association between the risk of developing T2DM and any of the LBP tertiles in either a simple model or after adjusting for general status and biochemical factors. CONCLUSION: After matching for gender, age, and BMI, LBP does not improve prediction of the development of T2DM independently.

AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells.

AIM: It is well known that lipid accumulation and inflammation are two important steps in pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD). However, fewer studies have explored the direct relationship between lipid accumulation and inflammation in early NAFLD. Tumor necrosis factor alpha (TNF-α) is one of the classical inflammatory cytokines. AMP-activated protein kinase (AMPK) is known as a critical regulator of energy homeostasis in metabolic processes. This study aims to investigate the role of TNF-α on lipid deposition of HepG2 cells and examine the modification of AMPK pathway. MAIN METHODS: TNF-α was added in HepG2 cells and lipid accumulation was analyzed by Oil Red O staining and quantitative test of triglyceride (TG). The expressions of phosphorylated AMPK and its pathway (including mTOR and SREBP-1) were determined. Furthermore, an AMPK agonist (metformin or AICAR) or antagonist (compound C) was co-administrated with TNF-α in HepG2 cells to investigate its effect on TNF-α induced lipid deposition. KEY FINDINGS: A significant increment of TG content in HepG2 cells was observed after TNF-α treatment. Meanwhile, substantially suppressed AMPK and ACC phosphorylation, enhanced mTOR and p70S6K phosphorylation, and increased protein expression of FAS and SREBP-1 were found. Co-treatment with metformin or AICAR decreased the TNF-α-induced intracellular TG, accompanied by significantly enhanced AMPK and ACC phosphorylation, suppressed mTOR and p70S6K phosphorylation, and reduced SREBP-1 and FAS expressions. On the contrary, while co-incubated with compound C, AMPK and ACC phosphorylation were suppressed and the inhibitory effect of metformin on HepG2 cell lipid deposition was also attenuated. SIGNIFICANCE: Our results suggest that TNF-α directly induces lipid accumulation in HepG2 cells, at least in part, through the inhibition of AMPK/mTOR/SREBP-1 pathway.

Rosiglitazone inhibits expression and secretion of PEDF in adipose tissue and liver of male SD rats via a PPAR-γ independent mechanism.

Pigment epithelium-derived factor (PEDF) plays an important role in insulin resistance (IR). The study aims to investigate the effect of rosiglitazone, an insulin sensitizer, on PEDF production and release both in vivo and in vitro. Male SD rats were divided into normal control group, high-fat group, and rosiglitazone group. Hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity. IR models of 3T3-L1 adipocytes and HepG2 cells were established by the hyperinsulinemic method. Glucose uptake was examined to validate IR of adipocytes, and phosphorylation of protein kinase B and glycogen synthesis kinase 3ß were examined to validate IR of HepG2 cells. Rosiglitazone, 2-chloro-5-nitro-N-phenylbenzamide (GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ), and compound C (inhibitor of AMP-activated protein kinase [AMPK]) were used for the in vitro intervention. In vivo, the high-fat group showed increased serum PEDF levels, which negatively correlated with insulin sensitivity, whereas the rosiglitazone treatment decreased the serum PEDF and down-regulated PEDF expression in fat and liver of the obese rats, concomitant with significantly enhanced insulin sensitivity. In vitro, the IR cells showed increased PEDF secretion and expression, whereas rosiglitazone lowered PEDF secretion and expression, accompanied with increased insulin sensitivity. Interestingly, combination with 2-chloro-5-nitro-N-phenylbenzamide did not influence the effect of rosiglitazone on PEDF. However, rosiglitazone stimulated AMPK phosphorylation in fat and liver of the obese rats, whereas in vitro, when combined with compound C, the effect of rosiglitazone on PEDF was abrogated. In summary, rosiglitazone inhibits the expression and secretion of PEDF in fat and liver via promoting AMPK phosphorylation rather than peroxisome proliferator-activated receptor-γ, and changes of PEDF induced by rosiglitazone are closely associated with IR improvement.

Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and meta-analysis.

BACKGROUND: Febuxostat has been approved for the treatment of hyperuricemia in patients with/without gout. OBJECTIVES: This meta-analysis and systematic review assessed the efficacy and tolerability of febuxostat in hyperuricemic patients with/without gout. METHODS: Major electronic databases were searched for articles of all publication years (up to February 2012), as were the Web sites of the American College of Rheumatology, the European League Against Rheumatism, and the Chinese State Food and Drug Administration, and clinicaltrials.gov for unpublished studies. Only randomized, controlled trials (RCTs) were included. RESULTS: Ten trials were included. A significantly greater proportion of patients achieved the target serum urate level (sUA ≤6.0 mg/dL) at the final visit in the febuxostat group compared with the placebo (OR = 235.73; P < 0.01) and allopurinol groups (OR = 3.14; P < 0.01). In subgroup analysis, the proportion of patients who achieved target sUA at the final visit was significantly greater in the febuxostat-treated group (40 mg/d) compared with the allopurinol-treated group (100-300 mg/d) (50.9% vs 45.6%; OR = 1.25; 95% CI, 1.05-1.49; P = 0.01). As the dosage was increased (40, 80, 120 mg/d), the proportion of patients who achieved target sUA in the febuxostat-treated group increased gradually (50.9%, 71.4%, 82%, respectively). There was no significant difference in the occurrence of adverse events (AEs) between the febuxostat- and allopurinol-treated groups. CONCLUSION: Febuxostat was effective in reducing serum urate in hyperuricemic patients with/without gout, and febuxostat (40-120 mg/d) was more efficacious compared with allopurinol (100-300 mg/d). The doses of allopurinol to which febuxostat has been compared, although commonly prescribed, are low in the range of approved doses of allopurinol. The tolerability of febuxostat for the treatment of hyperuricemia with/without gout is similar to that of allopurinol.

Effect of intranasal arginine vasopressin on human headache.

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood-brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.