Astragalus polysaccharides attenuate rat aortic endothelial senescence via regulation of the SIRT-1/p53 signaling pathway.

BACKGROUND: Astragalus polysaccharides (APS) have been verified to have antioxidative and antiaging activities in the mouse liver and brain. However, the effect of APS on aortic endothelial senescence in old rats and its underlying mechanism are currently unclear. Here, we aimed to elucidate the effects of APS on rat aortic endothelial oxidative stress and senescence in vitro and in vivo and investigate the potential molecular targets. METHODS: Twenty-month-old natural aging male rats were treated with APS (200 mg/kg, 400 mg/kg, 800 mg/kg daily) for 3 months. Serum parameters were tested using corresponding assay kits. Aortic morphology was observed by staining with hematoxylin and eosin (H&E) and Verhoeff Van Gieson (VVG). Aging-related protein levels were evaluated using immunofluorescence and western blot analysis. Primary rat aortic endothelial cells (RAECs) were isolated by tissue explant method. RAEC mitochondrial function was evaluated by the mitochondrial membrane potential (MMP) measured with the fluorescent lipophilic cationic dye JC­1. Intracellular total antioxidant capacity (T-AOC) was detected by a commercial kit. Cellular senescence was assessed using senescence-associated-ß-galactosidase (SA-ß-Gal) staining. RESULTS: Treatment of APS for three months was found to lessen aortic wall thickness, renovate vascular elastic tissue, improve vascular endothelial function, and reduce oxidative stress levels in 20-month-old rats. Primary mechanism analysis showed that APS treatment enhanced Sirtuin 1 (SIRT-1) protein expression and decreased the levels of the aging marker proteins p53, p21 and p16 in rat aortic tissue. Furthermore, APS abated hydrogen peroxide (H2O2)-induced cell senescence and restored H2O2-induced impairment of the MMP and T-AOC in RAECs. Similarly, APS increased SIRT-1 and decreased p53, p21 and p16 protein levels in senescent RAECs isolated from old rats. Knockdown of SIRT-1 diminished the protective effect of APS against H2O2-induced RAEC senescence and T-AOC loss, increased the levels of the downstream proteins p53 and p21, and abolished the inhibitory effect of APS on the expression of these proteins in RAECs. CONCLUSION: APS may reduce rat aortic endothelial oxidative stress and senescence via the SIRT-1/p53 signaling pathway.

Low BMI, blood calcium and vitamin D, kyphosis time, and outdoor activity time are independent risk factors for osteoporosis in postmenopausal women.

Aim: To explore the risk factors of osteoporosis in postmenopausal women in China. Method: This study collected all patient data from January 2014 to December 2015. Basic information and questionnaires were collected from 524 postmenopausal women in Sanya and Hainan Province. The questionnaire was administered to the enrolled participants by endocrinologists. Biochemical parameters were measured using fasting blood samples, and bone density was measured by dual energy X-ray absorptiometry at the department of radiology of Hainan hospital, PLA General Hospital. Participants with an R-value of ≤-2.5 were diagnosed with osteoporosis. After deleting missing values for each factor, 334 participants were divided into the osteoporosis (n=35) and non-osteoporosis (n=299) groups according to the R-values. Results: The participants had a median age of 60.8 years (range: 44-94 years). Among the 334 postmenopausal women included in this study, 35 (10.5%) were diagnosed with osteoporosis. Univariate analysis showed statistically significant differences in age, BMI, type of work, alkaline phosphatase, years of smoking, blood calcium levels, kyphosis, fracture, and asthma between the two groups (P<0.05). In addition, multivariate logistic analysis showed that age (odds ratio [OR]: 1.185, 95% confidence interval [CI]: 1.085-1.293, P<0.001) and kyphosis times (OR:1.468, 95% CI: 1.076-2.001, P=0.015) were positively correlated with postmenopausal osteoporosis, whereas BMI (OR: 0.717, 95% CI: 0.617-0.832, P<0.001), blood calcium levels (OR: 0.920, 95% CI: 0.854-0.991, P=0.027), vitamin D levels (OR: 0.787, 95% CI: 0.674-0.918, P=0.002), and outdoor activity time (OR: 0.556, 95% CI: 0.338-0.915, P=0.021) were negatively correlated with postmenopausal osteoporosis. Conclusion: Low BMI, blood calcium and vitamin D levels, kyphosis time, and outdoor activity time are independent risk factors for osteoporosis in postmenopausal women.

Effects of denosumab on bone mineral density and bone metabolism in patients with end-stage renal disease: A systematic review and meta-analysis.

INTRODUCTION: The effects of denosumab on bone mineral density (BMD) and metabolism in patients with end-stage renal disease (ESRD) remain controversial. Hence, we performed a systematic review and meta-analysis of observational studies. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched in June 2022 to identify studies that evaluated the risk of denosumab-associated hypocalcemia and changes in bone metabolism, changes in BMD from baseline to post-treatment in patients with ESRD. FINDINGS: Twelve studies with 348 participants were included. The pooled incidence of hypocalcemia during denosumab treatment was 35.0% (95% confidence interval [CI], 25%-46%; I2 = 63.6%). There were no significant changes in either the serum calcium or phosphate levels from the baseline to post-treatment period; the mean differences were 0.04 mg/dL (95% CI, -0.12 to 0.20 mg/dL) and -0.39 mg/dL (95% CI, -0.89 to 0.12 mg/dL). We found significant changes in the alkaline phosphatase and parathyroid hormone levels; the standardized mean differences were -2.98 (95% CI, -5.36 to -0.59) and -3.12 (95% CI: -4.94 to -1.29), respectively. Denosumab may increase BMD, with mean differences of 9.10% (95% CI: 4.07%-14.13%) and 9.00% (95% CI: 5.93%-12.07%) for the femoral neck and lumbar spine, respectively. DISCUSSION: Denosumab increased the BMDs of the lumbar spine and femoral neck in patients with ESRD. The onset of hypocalcemia must be carefully monitored during denosumab administration.

Analysis of clinical features and 7-year all-cause mortality in older male patients with non-thyroidal illness syndrome on general wards.

PURPOSE: Older patients with non-thyroidal illness syndrome (NTIS) have a poor prognosis. However, there are few studies on the association of NTIS and mortality among older inpatients on general wards. In a 7-year retrospective observational study, we aimed to investigate the clinical features of NTIS and the association of NTIS and all-cause mortality in older inpatients. METHODS: A total of 959 older male inpatients whose average age was 86.3 ± 8.1 years were enrolled and divided into the NTIS group and non-NTIS group. Cox models were performed to explore the association of thyroid hormone level and mortality. RESULTS: Patients had more respiratory disease and chronic kidney disease in the NTIS than in the non-NTIS group, especially in primary nursing care, respiratory failure and haemodialysis patients; serum total protein, albumin, prealbumin, haemoglobin, uric acid and high-density lipoprotein cholesterol levels were lower, and urea nitrogen and fasting blood glucose levels were higher, in the NTIS than in the non-NTIS group. Patients in the NTIS group had a lower survival rate over 7 years follow-up (P < 0.01). A lower free T3 level was associated with all-cause mortality with a HR of 1.50 (1.36, 1.66). Lower free T4 level was associated with reduced all-cause mortality with a HR of 0.91 (0.88, 0.94) even after adjusting for confounding factors (P < 0.01). CONCLUSIONS: Among older male inpatients, the survival rate was lower in the NTIS group. A reduced free T3 level with low albumin and Hb levels was associated with all-cause mortality; moreover, a higher free T4 in the normal range may be a strong predictor for long-term mortality risk in hospitalised older male patients.

The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study.

BACKGROUND: Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events. METHODS: A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice. RESULTS: Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM. CONCLUSIONS: The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM.

The Role of Peroxisome Proliferator-Activated Receptors in Kidney Diseases.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Accumulating evidence suggests that PPARs may play an important role in the pathogenesis of kidney disease. All three members of the PPAR subfamily, PPARα, PPARß/δ, and PPARγ, have been implicated in many renal pathophysiological conditions, including acute kidney injury, diabetic nephropathy, and chronic kidney disease, among others. Emerging data suggest that PPARs may be potential therapeutic targets for renal disease. This article reviews the physiological roles of PPARs in the kidney and discusses the therapeutic utility of PPAR agonists in the treatment of kidney disease.

Astragalus Polysaccharides Reduce High-glucose-induced Rat Aortic Endothelial Cell Senescence and Inflammasome Activation by Modulating the Mitochondrial Na+/Ca2+ Exchanger.

Vascular endothelial cells play a vital role in atherosclerotic changes and the progression of cardiovascular disease in older adults. Previous studies have indicated that Astragalus polysaccharides (APS), a main active component of the traditional Chinese medicine Astragalus, protect mitochondria and exert an antiaging effect in the mouse liver and brain. However, the effect of APS on rat aortic endothelial cell (RAEC) senescence and its underlying mechanism have not been investigated. In this study, we extracted RAECs from 2-month-old male Wistar rats by the tissue explant method and found that APS ameliorated the high-glucose-induced increase in the frequency of SA-ß-Gal positivity and the levels of the senescence-related proteins p16, p21, and p53. APS increased the tube formation capacity of RAECs under high-glucose conditions. Moreover, APS enhanced the expression of the mitochondrial Na+/Ca2+ exchanger NCLX, and knockdown of NCLX by small interfering RNA (siRNA) transfection suppressed the antiaging effect of APS under high-glucose conditions. Additionally, APS ameliorated RAEC mitochondrial dysfunction, including increasing ATP production, cytochrome C oxidase activity and the oxygen consumption rate (OCR), and inhibited high-glucose-induced NLRP3 inflammasome activation and IL-1ß release, which were reversed by siNCLX. These results indicate that APS reduces high-glucose-induced inflammasome activation and ameliorates mitochondrial dysfunction and senescence in RAECs by modulating NCLX. Additionally, APS enhanced the levels of autophagy-related proteins (LC3B-II/I, Atg7) and increased the quantity of autophagic vacuoles under high-glucose conditions. Therefore, these data demonstrate that APS may reduce vascular endothelial cell inflammation and senescence through NCLX.

Effects of a prolonged diet regimen on autophagic function in rat islets with aging.

The prevalence of type 2 diabetes increases with age-associated increased susceptibility of islet ß-cells and altered dietary patterns, in part because of insufficient compensation of ß-cell functional mass in the face of increasing insulin resistance. However, the underlying mechanisms have not been fully elucidated. In the present study, we investigated the effects of a long-term calorie-restricted (CR) or high-fat (HF) diet compared to a normal ad libitum diet on ß-cell structure-function relationships and autophagy in the islets of 3- and 24-month-old Fischer 344 rats. Aging and the HF diet decreased the ß-cell-to-islet area ratio, disorganized the islet structure, and increased the expression of senescence markers. Aging and the long-term HF diet also decreased autophagy-related proteins, which suggests compromised autophagic function. These findings were further corroborated by increased p62 accumulation and polyubiquitin aggregates observed with aging and the HF diet intervention; these are cardinal markers of attenuated autophagic function. It is important to note that the 24-month-old rats maintained on the CR diet closely mimicked the 3-month-old rats, which indicates that a long-term CR diet can delay islet aging and prevent the decline in the autophagic function of islets during the aging process. Taken together, our results indicate an autophagy-dependent mechanism responsible for islet function in older people or those with altered dietary patterns and lay the foundations for future research leading to novel therapeutic strategies for treating diabetes.

Zebrafish gasdermin E cleavage-engaged pyroptosis by inflammatory and apoptotic caspases.

As the executor of pyroptosis known to date, gasdermins (GSDMs), consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME and pejvakin, might play critical roles in anti-bacterial infection as well as inflammatory diseases. However, zebrafish only harbors a pair of Gsdme (Gsdmea/b), and their activation mechanisms remain largely unknown. Herein, we investigate the activation mechanism of Gsdmea/b cleaved by inflammatory and apoptotic caspases in zebrafish，and found that Gsdmea/b are equally cleaved by Caspase 19b, a sister of Caspy2, but not Caspy. Moreover, the zebrafish apoptotic effector caspases, including Caspase 3a/b and Caspase 7, also can cleave Gsdmea/b at the same sites as inflammatory caspases recognized. Importantly, our results reveal that Caspase 8a/b can cleave Gsdmeb, but only Caspase 8a can cleave Gsdmea. Taken together, these findings suggest that zebrafish Gsdmea/b can concurrently function as GSDMD and GSDME in mammals, which will contribute to better understanding the mechanism of pyroptosis activation in teleost, as well as provide a clue for drug screening model against inflammatory diseases.

Occurrence and depositional history of organochlorine pesticides in the sediments of the Zayandehrud River in the arid region of Central Iran.

In this study, surface sediments along the Zayandehrud River (14 samples), and two dated core sediments (46 samples) from small artificial urban lakes at the middle section of the Zayandehrud River in the Gavkhooni basin in the central arid regions of Iran were analyzed for residual levels of 20 organochlorine pesticide (OCP) compounds. Total OCP concentrations ranged from 0.1 to 50.1 ng g-1 dry weight and from 1.9 to 51.5 ng g-1 dry weight in surface and core sediments, respectively. Dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) were found to be the predominant OCPs in these sediments. The calculated metabolic and isomeric ratios confirmed the aged nature of residual dichlorodiphenyltrichloroethane (DDT) in sediments. Moreover, the isomeric ratios indicated the aged nature of technical HCH (hexachlorocyclohexane), while the contribution of γ- HCH (lindane) as a main source has increased, especially in the last two decades. Past usage, as well as current usage of endosulfan technical mixture in the Gavkhooni basin, has been found in the last four decades. Analyses of sedimentary cores, as natural archives, have shown the successful ban on the use of organochlorine pesticides (especially DDT) in the Gavkhooni basin, and to some extent, in the central plateau of Iran. In general, it can be concluded that natural factors (i.e., floods and wet years) lead to soil leachate and play an essential role in remobilization and transfer of residual OCPs from soil to inland aquatic ecosystems in the Gavkhooni basin, which is an arid region.

Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo.

The bacteria LPS is one of the leading endotoxins responsible for sepsis; its sensing pathway-induced pyroptosis plays an important role in innate immunity. However, excessive pyroptosis might cause immunological diseases, even multiple organ failure and death by undefined mechanisms. Given that the development of acute kidney injury (AKI) in patients with sepsis causes significant morbidity and mortality, the mechanism of pyroptosis in regulating septic AKI remains unknown. In this study, we establish a zebrafish crispant in vivo analysis model and reveal that both caspy2 and gasdermin Eb (GSDMEb) contribute to lethal LPS-induced septic shock. Meanwhile, the in vitro analysis reveals that caspy2 activation can specifically cleave GSDMEb to release its N terminus to mediate pyroptosis, which functions as GSDMD in mammals. Interestingly, we establish an in vivo propidium iodide-staining method and reveal that the caspy2-GSDMEb signaling cascade is essential for enhancing renal tubular damage during lethal LPS-induced septic shock, whereas administration of the zebrafish-specific GSDMEb-derived peptide inhibitor Ac-FEID-CMK can attenuate mortality and septic AKI in vivo. Moreover, we confirm that either caspase-11 or GSDMD deficiency decreases both inflammatory cytokines and kidney dysfunction enzyme release and prolongs survival in a murine model of septic shock. Taken together, these findings demonstrate an evolutionary executor for pyroptosis in zebrafish and reveal that the pyroptosis of renal tubular cells is a major cause of septic AKI, and also provide an ideal in vivo screening model for potential antisepsis therapeutic strategies.

The Edwardsiella piscicida thioredoxin-like protein inhibits ASK1-MAPKs signaling cascades to promote pathogenesis during infection.

It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytosol remains to be resolved. In this study, we identified a new bacterial virulence effector from pathogenic Edwardsiella piscicida, which presents conserved crystal structure to thioredoxin family members and is defined as a thioredoxin-like protein (Trxlp). Unlike the classical bacterial thioredoxins, Trxlp can be translocated into host cells, mimicking endogenous thioredoxin to abrogate ASK1 homophilic interaction and phosphorylation, then suppressing the phosphorylation of downstream Erk1/2- and p38-MAPK signaling cascades. Moreover, Trxlp-mediated inhibition of ASK1-Erk/p38-MAPK axis promotes the pathogenesis of E. piscicida in zebrafish larvae infection model. Taken together, these data provide insights into the mechanism underlying the bacterial thioredoxin as a virulence effector in downmodulating the innate immune responses during E. piscicida infection.

[Establishment of senescent cell model in primary rat aortic endothelial cells].

Objective To establish senescent models in rat aortic endothelial cells (RAECs) induced by high glucose (HG), angiotensin II (AngII), hydrogen peroxide and palmitic acid (PA), and compare the senescence-induced effects of these factors. Methods Primary RAECs were extracted from two-month-old male Wistar rats by issue explant method and identified by CD31 immunofluorescence cytochemistry. RAECs were treated separately by 30 mmol/L (HG), 10 µmol/L AngII, 100 umol/L hydrogen peroxide (H2O2) and 0.5 mmol/L PA. Twenty-four hours later, senescence-associated ß-galactosidase (SA-ß-gal) staining was used to evaluate the senescent state. Real-time quantitative PCR was used to investigate mRNA expression level of senescence-related gene P16. Western blot analysis was performed to determine protein expression levels of P16, P21 and P53. Immunofluorescence cytochemistry was used to detect the expression of P16 protein in cells. The cell viability of RAECs was tested via CCK-8 assay. Results Compared with the control group, positive rate of SA-ß-gal staining in each treatment group increased, especially in H2O2 and PA groups. And mRNA expression level of P16 increased in all four groups. P16 and P21 proteins had high expression in AngII, H2O2 and PA groups, most obviously in H2O2 group. P16 immunofluorescence expression level was enhanced in all groups. The cell viability in HG and AngII groups was similar with the control group, while H2O2 and PA groups had low cell viability. Conclusion The aging mode of RAECs is successfully established by HG, AngII, H2O2 or PA treatment, and H2O2 treatment shows the strongest effect.

Liraglutide protects renal mesangial cells against hyperglycemia­mediated mitochondrial apoptosis by activating the ERK­Yap signaling pathway and upregulating Sirt3 expression.

Diabetic nephropathy results from hyperglycemia­mediated renal glomerular cell death via mitochondrial apoptosis. There is an emerging requirement for novel approaches with mitochondrial protective effects that alleviate the hyperglycemia­induced loss of functional cells during diabetic renal damage. Liraglutide, a type of glucagon­like peptide­1 agonist, has been suggested to inhibit the progression of obesity and hyperglycemia. However, the contributions and mechanism of action of liraglutide on hyperglycemia­mediated cell mitochondrial apoptosis in diabetic kidneys have not been illustrated. The present study demonstrated that liraglutide may protect human renal mesangial cells (HRMCs) against hyperglycemia­induced cell death by inhibiting mitochondrial apoptosis. Liraglutide administration also maintained HRMC viability and promoted HRMC proliferation within a high glucose stress environment. Functional studies demonstrated that hyperglycemia triggered mitochondrial dysfunction, including mitochondrial potential reduction, mitochondrial permeability transition pore opening, reactive oxygen species overproduction and the activation of the mitochondrial apoptotic pathway. However, liraglutide treatment preserved mitochondrial function and prevented activation of mitochondrial apoptosis by upregulating sirtuin 3 (Sirt3) expression. Deletion of Sirt3 abrogated the protective effects of liraglutide on mitochondrial homeostasis following high glucose challenge. In addition, molecular analysis confirmed that liraglutide upregulated Sirt3 via activating the extracellular signal­regulated kinase­Yes­associated protein (ERK­Yap) signaling pathway. Inhibition of the ERK­Yap axis negated the action of liraglutide on Sirt3 activation, leading to mitochondrial injury and HRMC apoptosis. Taken together, the present study illustrated that liraglutide protected renal mesangial cells from hyperglycemia­mediated mitochondrial apoptosis by upregulating Sirt3 expression and activation of the ERK­Yap signaling pathway.

Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function.

Mitochondrial homeostasis is a highly regulated process that serves a critical role in the maintenance of renal structure and function. The growing interest in the field of mitochondrial homeostasis promises to provide more information regarding the mechanisms involved in diabetic renal fibrosis, and aid in the development of novel strategies to combat the disease. In the present study, the effects of melatonin on renal damage in mice with diabetes were evaluated and the underlying mechanisms were investigated. Cellular apoptosis was determined using TUNEL assay and western blotting. Mitochondrial function was measured using fluorescence assay and western blotting. The results indicated that diabetic renal fibrosis was associated with 5'adenosine monophosphate­activated protein kinase (AMPK) downregulation. However, melatonin administration rescued AMPK activity, reduced diabetic renal fibrosis, alleviated glomerular apoptosis and preserved kidney function. The functional experiments demonstrated that melatonin­induced AMPK activation enhanced peroxisome proliferator­activated receptor γ coactivator 1­α (PGC1α) expression, sustained mitochondrial function and blocked mitochondrial apoptosis, leading to protection of the glomerulus against glucotoxicity. However, loss of AMPK and PGC1α negated the protective effects of melatonin on mitochondrial homeostasis, glomerular survival and diabetic renal fibrosis. In summary, the present study revealed that melatonin rescued impaired mitochondrial function and reduced glomerular apoptosis in the context of diabetic renal fibrosis by activating the AMPK/PGC1α pathway.

Edwardsiella piscicida virulence effector trxlp promotes the NLRC4 inflammasome activation during infection.

Edwardsiella piscicida is an important pathogenic bacterium that causes hemorrhagic septicemia in fish. This bacterium could activate NLRC4 and NLRP3 inflammasomes via type III secretion system (T3SS), and inhibit NLRP3 inflammasome via type VI secretion system (T6SS) effector during infection in macrophages. However, the roles of other virulence factors in regulating inflammasome activation during E. piscicida infection remain poorly understood. In this study, we focused on clarification the role of ETAE_RS10155, a thioredoxin-like protein (Trxlp), during bacterial infection in macrophages. We found that mutation of this gene barely influences the bacteria growth and infection capability. Interestingly, the inflammasome activation was reduced in Δtrxlp-infected macrophages, compared with wild-type E. piscicida did. Moreover, Trxlp mainly promotes the NLRC4, but not NLRP3 inflammasome activation during E. piscicida infection. Finally, Trxlp-mediated NLRC4 inflammasome activation is crucial for host surveillance in vivo. Taken together, our results clarify the complex and contextual role of bacterial virulence effector in modulating inflammasome activation, and offer new insights into the warfare between the fish bacterial weapons and host innate immunological surveillance.

Sensing of cytosolic LPS through caspy2 pyrin domain mediates noncanonical inflammasome activation in zebrafish.

The noncanonical inflammasome is critical for cytosolic sensing of Gram-negative pathogens. Here, we show that bacterial infection induces caspy2 activation in zebrafish fibroblasts, which mediates pyroptosis via a caspase-5-like activity. Zebrafish caspy2 binds directly to lipopolysaccharide via the N-terminal pyrin death domain, resulting in caspy2 oligomerization, which is critical for pyroptosis. Furthermore, we show that caspy2 is highly expressed in the zebrafish gut and is activated during infection. Knockdown of caspy2 expression impairs the ability of zebrafish to restrict bacterial invasion in vivo, and protects larvae from lethal sepsis. Collectively, our results identify a crucial event in the evolution of pattern recognition into the death domain superfamily-mediated intracellular lipopolysaccharide-sensing pathway in innate immunity.

Vitamins for Prevention of Contrast-induced Acute Kidney Injury: A Systematic Review and Trial Sequential Analysis.

BACKGROUND: To date, universally accepted preventive measures for contrast-induced acute kidney injury (CI-AKI) do not exist, and they warrant further research. OBJECTIVE: The purpose of this study was to evaluate the efficacy of vitamins, including vitamin C and E, for prevention of CI-AKI. METHODS: We electronically searched the MEDLINE, EMBASE, and Cochrane databases. The outcome of interest was the incidence of CI-AKI. RESULTS: A total of 19 studies were included in this meta-analysis. Pooled analysis showed that vitamin C plus saline [relative risk (RR) = 0.63, 95% confidence interval (CI) 0.49-0.82, p = 0.0005] and vitamin E plus saline (RR = 0.39, 95% CI 0.24-0.62, p < 0.0001) significantly reduced the incidence of CI-AKI compared to saline alone. The effect of vitamin C plus saline was further confirmed by trial sequential analysis (TSA). However, TSA indicated that more trials are required to confirm the efficacy of vitamin E plus saline. There was no significant difference in preventing CI-AKI between vitamin C and N-acetylcysteine (NAC) (RR = 0.90, 95% CI 0.47-1.71, p = 0.75), between vitamin C plus NAC and saline (RR = 0.62, 95% CI 0.30-1.30, p =  0.20), as well as between vitamin C plus NAC and NAC (RR = 0.97, 95% CI 0.49-1.92, p = 0.93). CONCLUSIONS: Vitamin C plus saline administration is effective at reducing the risk of CI-AKI. Evidence for the use of vitamin E plus saline in this context is encouraging, but more trials are required. Furthermore, this meta-analysis and TSA indicated insufficient power to draw a definitive conclusion on the effect of vitamin C plus NAC, versus saline or NAC alone, which needs to be explored further.

The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5'-AMP-activated protein kinase in INS-1 ß-cells under high glucose conditions.

Glucagon-like peptide-1 (GLP-1) is a potent therapeutic agent for the treatment of diabetes and has been proven to protect pancreatic ß-cells from glucotoxicity; however, its mechanisms of action are not entirely understood. Autophagy is a dynamic lysosomal degradation process that can protect organisms against metabolic stress. Studies have shown that autophagy plays a protective role in the survival of pancreatic ß-cells under high glucose conditions. In the present study, we explored the role of autophagy in GLP-1-induced protection of pancreatic ß-cells exposed to high glucose. We demonstrated that the GLP-1 analogue liraglutide increased autophagy in rat INS-1 ß-cells, and inhibition of autophagy abated the anti-apoptosis effect of liraglutide under high glucose conditions. Our results also showed that activation of 5'-AMP-activated protein kinase (AMPK) reduced liraglutide-induced autophagy enhancement and inhibited liraglutide-induced protection of INS-1 ß-cells from high glucose. These data suggest that GLP-1 may protect ß-cells from glucotoxicity through promoting autophagy by the modulation of AMPK. Deeper insight into the molecular mechanisms linking autophagy and GLP-1-induced ß-cell protection may reveal novel therapeutic targets to preserve ß-cell mass.

Abnormal Alterations of Cortical Thickness in 16 Patients with Type 2 Diabetes Mellitus: A Pilot MRI Study.

Objective The aim of this study is to investigate the cerebral cortical thickness changes in type 2 diabetes mellitus (T2DM) using a whole brain cortical thickness mapping system based on brain magnetic resonance imaging (MRI).Methods High resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MR images were obtained from 16 patients with T2DM, as well as from 16 normal controls. The whole brain cortical thickness maps were generated, and the cortical thickness of each brain region was calculated according to gyral based regions of interest (ROI) using an automated labeling system by the Freesurfer software. We compared mean cortical thickness at each brain region by the analysis of covariance with age and sex as covariates. The regional difference of the cortical thickness over the whole brain was compared by the analysis of surface-based cortical thickness.Results Mean cortical thicknesses analysis showed bilateral cerebrum in the patients with T2DM (left: 2.52±0.07 mm; right: 2.51±0.08 mm) were significant thinner than those in the normal controls (left: 2.56±0.09 mm; right: 2.56±0.09 mm) (both P<0.05). Regional cortical thinning in T2DM was demonstrated in the paracentral lobule, postcentral gyrus, lateral occipital gyrus, lingual gyrus, precuneus, superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus and posterior cingulate gyrus, compared to the normal controls. The cortical thickness of left middle cingulate and right inferior temporal gyrus were negatively correlated with the disease course.Conclusion A widespread cortical thinning was revealed in patients with T2DM by the analysis of brain cortical thickness on MR. Our finding supports the idea that T2DM could lead to subtle diabetic brain structural changes.