Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

Air Pollution's Impact on the Economic, Social, Medical, and Industrial Injury Environments in China.

In this era of rapid economic development, it is inevitable that economic activities eventually cause serious damage to the environment's air quality, making it the focus of global public health. If the treatment efficiency of medical accidents can be improved, then this can significantly stabilize society and improve production efficiency. Past research has mainly focused on work safety and health issues, seldom discussing economic, social, medical, and environmental pollution issues together, and, most generally, adopted static methods that fail to recognize how air pollution affects the overall economy, society, medical care, and external environment. In order to more deeply understand the changes among social, economic activities, and environmental issues due to air pollution, this study proposes a meta-two-stage undesirable dynamic DDF (Direction Distance Function) that, under an exogenous model, divides the 30 provinces of China into high-income regions and middle-income regions and explores the economic, social, medical, and environmental efficiencies between the two areas to resolve the lack of related static analyses. The empirical results are as follows. (1) The AQI (air quality index) significantly impacts the efficiency of medical injuries in various regions. (2) When the AQI is considered, the medical insurance expenditure efficiency score value of high-income areas is lower than the value without the AQI. (3) When the AQI is considered, the efficiency value of the number of work injury insurance benefits in the middle-income area is lower than the efficiency value without the AQI.

Efficiency assessment of coal energy and non-coal energy under bound dynamic DDF DEA.

The demand for energy has continued to increase because of global economic development, which has led to rising fuel prices and continued pollution problems. China is currently the largest coal consumer and is also the largest emitter of coal-fired CO2 emissions. However, past efficiency studies have been mostly limited to static analyses and have not considered undesirable outputs. Therefore, this study developed a bound dynamic directional distance function (DDF) data envelopment analysis (DEA) model to explore the energy and environmental efficiencies in 30 Chinese provinces from 2011 to 2015, from which it was found that (1) the overall efficiency was the best in the eastern region, but relatively low in the western region; (2) Beijing, Guangdong, Jiangsu, Shandong, Shanghai, Tianjin, Jiangxi, Jilin, and some other regions had efficiencies of 1; (3) the revenue and non-coal indicator efficiencies were reasonably good, but the expenditure and emissions efficiencies were generally poor; and (4) the key direction for primary improvements was found to be the emissions index.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.

Continuous renal replacement therapy for haemodynamic collapse and rhabdomyolysis induced by pheochromocytoma crisis.

Pheochromocytoma associated with pregnancy is not common. Caesarean section may induce pheochromocytoma crisis, resulting in a lethal condition. The clinical picture of pheochromocytoma crisis is extremely variable. In this report, we describe a case of severe pheochromocytoma crisis induced by caesarean section presenting with hyperpyrexia, haemodynamic collapse, muscle weakness, heart failure, and acute kidney injury. Furthermore, we report that the muscle weakness was a manifestation of rhabdomyolysis, resulting from the pheochromocytoma crisis. Standard medical therapy failed to halt the patient's rapidly deteriorating condition. Continuous renal replacement therapy removed catecholamines from the circulation, resulting in improvement of haemodynamics and abrogation of rhabdomyolysis.

[Effect of crucumin on vascular endothelial function in atherosclerotic rabbits].

OBJECTIVE: To observe the effect of curcumin on nitric oxide (NO) in plasma of atherosclerotic rabbits, activity of constitutive nitric oxide synthase (cNOS) and asymmetric dimethylarginine (ADMA), and discuss curcumin's effect against AS and its correlation with ADMA. METHOD: Thirty-eight male Japanese white rabbits were randomly divided into four groups: the control group (eight rabbits fed with standard diets), the model group (ten rabbits fed with high-fat diets), the low dose curcumin group (ten rabbits fed with high-fat diets and 100 mg . kg-1 d -1 ) and the high dose curcumin group (ten rabbits fed with high-fat diets and 200 mg kg-1 d-1 curcumin). At the end of the 12th week, their plasmas were tested for TC, LDL-C, NO, endothelin (ET) , ADMA and activity of aortic cNOS. Aortic tissues were collected for histological examinations. RESULT: The three groups fed with high-fat diets showed higher plasma ADMA and ET than the control group (P <0. 01) , but with decrease in plasma NO concentration and arterial cNOS activity (P <0. 01). Compared with the model group (P <0. 05) , the curcumin groups showed lower plasma ADMA and ET (P <0. 05), but higher plasma NO concentration and arterial cNOS activity than the model group (P <0. 01). There was no significant difference between the two curcumin groups. CONCLUSION: Curcumin may play an important protective role in AS process by reducing plasma ADMA level. [Key words] atherosclerosis; asymmetric dimethylarginine; crucumin; nitric oxide; nitric oxide synthase

[Ryanodine downregulates the expression of p-eNOS (Thr495) and improves the functions of rapamycin treated endothelial outgrowth cells].

OBJECTIVE: To observe the effects of ryanodine on rapamycin treated endothelial outgrowth cells (EOCs). METHODS: The mononuclear cells were harvested from umbilical cord blood by Ficoll density gradient centrifugation, then induced into EOCs and expanded in vitro. The endothelial characteristics of EOCs were identified by immunostaining and fluorescent staining. The EOCs were pretreated with or without ryanodine (10 µmol/L) for 1 h, and then treated with or without rapamycin (10 nmol/L) for 24 h. Proliferation was evaluated by CCK8 and migration was measured by Transwell. The protein expression of EOCs was evaluated by immunobloting technique with total eNOS antibody and phospho-eNOS (Thr495) antibody. RESULTS: Compared with control group, the proliferation and migration capacities of EOCs were significantly reduced while the phosphorylation of eNOS (Thr495) protein was significantly upregulated in rapamycin group (P < 0.05), expression of total eNOS was not affected by rapamycin (P > 0.05). Compared with rapamycin group, the proliferation and migration capacities of EOCs were significantly increased and the phosphorylation of eNOS (Thr495) protein was significantly downregulated in ryanodine + rapamycin group (P < 0.05). The proliferation and migration capacities, the phosphorylation of eNOS (Thr495) protein and the expression of total eNOS were not affected by ryanodine alone (P > 0.05). CONCLUSIONS: Rapamycin reduced proliferation and migration capacities while upregulated the phosphorylation of eNOS (Thr495) protein of EOCs and these effects could be partly reversed by cotreatment with ryanodine.

[Effects of endothelial progenitor cells and endothelial outgrowth cells in repair of injured carotid vessel: a comparative study with rabbits].

OBJECTIVE: To compare the effects of endothelial progenitor cells (EPCs) and endothelial outgrowth cells (EOCs) on the repair of injured vessels. METHODS: Mononuclear cells (MNCs) were isolated from rabbit peripheral blood by density-gradient centrifugation. EPCs and EOCs were obtained from the culture of MNCs and labeled with the cell dye CM-DiI for cells tracking. Eighteen rabbits were made into models of balloon-injured common carotid artery and then divided into 2 equal groups to undergo injection of the suspensions of EPCs or EOCs. Nine rabbits underwent injection of normal saline as control group. Four weeks after transplantation, the rabbits underwent venous injection of Evans blue, and then were killed with the injured vessels taken out. Fluorescence-labeled both types of cells, endothelial regeneration rate and IA/MA ratio were detected. RESULTS: Four weeks after transplantation, fluorescence-labeled EPCs and EOCs were detected within the tunica intima, mostly in the neointima and on the luminal surface of injured vessel. The endothelialization area of denuded vessel of the EPC and EOC groups were 91.6% +/- 3.6% and 89.1% +/- 6.3% respectively, both significantly larger than that of the control group (62.1% +/- 7.5%, both P < 0.01), however, without significant difference between the 2 former groups (P = 0.50). The intima area/media area ratio of the EPC and EOC groups were 0.48 +/- 0.11 and 0.44 +/- 0.06, both significantly lower than that of the control group (0.88 +/- 0.14, both P < 0.01), however, without significant difference between the 2 former groups (P = 0.59). CONCLUSION: Transplantation of both EPCs and EPCs accelerate the reendothelialization and reduce the neointimal formation with similar effects.