Impaired Thyroid Hormone Sensitivity Increases Risk of Cardiovascular Events in Patients Undergoing Coronary Angiography.

CONTEXT: Previous studies found inconsistent results on the relationship between thyroid function and cardiovascular risks. OBJECTIVE: This study aimed to investigate the association of thyroid hormone sensitivity with the risk of major adverse cardiovascular events (MACE) and cardiovascular death in a euthyroid population undergoing coronary angiography. METHODS: This prospective cohort study enrolled 1470 euthyroid participants who underwent coronary angiography between March and November of 2013. The participants were followed up from July to November in 2022. Thyrotroph thyroxine resistance index (TT4RI), TSH index (TSHI), and feedback quantile-based index (TFQI) were calculated to evaluate the sensitivity to thyroid hormone. Kaplan-Meier curve and multivariable Cox proportional hazard model were performed to analyze the association between thyroid hormone sensitivity and risk of MACE and cardiovascular death. RESULTS: Among 1089 participants who completed the follow-up, 342 cases of MACE and 77 cardiovascular deaths were identified during a medium follow-up duration of 111 months. In the multivariable Cox proportional hazard model, the higher levels of TFQI (hazard ratio [HR] = 1.41; 95% CI, 1.08-1.84; P for trend = .01), TT4RI (HR = 1.40; 95% CI, 1.06-1.84; P for trend = .02) and TSHI (HR = 1.61; 95% CI, 1.22-2.13; P for trend = .001) were associated with increased risk of MACE. The higher levels of TFQI (HR = 2.21; 95% CI, 1.17-4.17; P for trend = .02) and TSHI (HR = 2.05; 95% CI; 1.08-3.91; P for trend = .03) were also associated with increased risk of cardiovascular death. CONCLUSION: Impaired sensitivity to thyroid hormone is associated with higher risks of MACE and cardiovascular death in a euthyroid population undergoing coronary angiography.

Engineering extracellular vesicles with macrophage membrane fusion for ameliorating imiquimod-induced psoriatic skin inflammation.

INTRODUCTION: Herein, we developed an engineered extracellular vehicle (EV)-based method for ameliorating inflammatory responses in psoriasis. METHODS: EVs, derived from annexin A1 (ANXA1) overexpressing T cells, were co-extruded with M2 macrophage membrane to obtain engineered EVs. In vitro, the effect of engineered EVs on macrophage polarization was evaluated by real-time PCR. In imiquimod (IMQ)-induced psoriasis-like mouse model, the efficacy of engineered EVs in ameliorating psoriatic inflammation was evaluated by Psoriasis Area and Severity Index (PASI) score and immunohistochemistry staining after subcutaneous injection of EVs. RESULTS: The engineered EVs not only preserved the high stability of M2 macrophage membrane but also retained the macrophage reprogramming potential of ANXA1 overexpressed in T cells. In the psoriasis-like mouse model, subcutaneous injection of engineered EVs successfully reduced the PASI score and the levels of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α. Along with high biosafety, the administration of EVs also rescued the histomorphological changes of spleen, liver, and kidney. CONCLUSIONS: The engineered EVs exhibited the potential to alleviate inflammation of psoriasis, providing new insights and potential strategies for the immunotherapies of psoriasis.

Impact of Regional Collaborative Network on the Rescue of Patients with ST-Elevation Myocardial Infarction First Visit to non-PCI Hospitals.

Objective: To assess the effect of a regional collaborative network on the treatment of ST-elevation myocardial infarction (STEMI) patients first admitted to non- percutaneous coronary intervention (PCI) hospitals. Methods: Using data from Kunshan Hospital of Traditional Chinese Medicine's chest pain center database, patients were grouped based on the establishment of the regional collaborative rescue network. Key timepoints and in-hospital complications were analyzed. Results: A total of 152 ST-elevation myocardial infarction patients were included in the study. Compared to control group, symptom-to-balloon time (S-B), time of first medical contact to balloon and inter-hospital referral time in observation group were significantly shorter [(314.03 ± 209.26) min vs (451.27 ± 290.44) min, P = .001], [(115.32 ± 54.73) min vs (191.67 ± 130.30) min, P = .001], [(55.09 ± 37.23) min vs (112.67 ± 95.90) min, P = .001], but time of symptom to first medical contact were not statistically significant[(210.27±217.07) min vs (239.61 ± 200.92) min, P = .136].The incidence of heart failure and total complications during hospitalization decreased [7 (8.14%) vs 13 (19.70%), P = .037] and [14 (16.28%) vs 24 (36.36%), P = .004]. However no statistically significant difference were observed in rate of death during hospitalization [2 (2.33%) vs 3 (4.55%), P = .450], ventricular fibrillation [2 (2.33%) vs 3 (4.55%), P = .450], left ventricular thrombosis [2 (2.33%) vs 4 (6.06%), P = .244] and recurrent myocardial infarction[1 (1.16%) vs 1 (1.52%), P = .851]. Conclusions: The regional cooperative rescue network notably reduces ischemic and referral times for STEMI patients, lowering the incidence of heart failure during their hospital stay.

Folic Acid Protects Against Kidney Damage in Mice with Diabetic Nephropathy by Inhibiting M1 Macrophage Polarization via Nuclear Factor-k-gene Binding Pathway.

Kidney damage is one of the most common complications of diabetes, and inflammation caused by macrophage infiltration plays an important role. Folic acid (FA), a water-soluble vitamin, was previously found to affect inflammation by regulating macrophage polarization. In our study, we aimed to investigate the effect of FA on renal injury in mice with diabetic nephropathy (DN). We found that FA treatment ameliorated diabetic metabolic parameters in mice with DN, including reducing 24-hour food consumption, 24-hour urine volume and 24-hour water intake and increasing body weight and serum insulin. Of note, FA treatment improved renal functional and structural damage in mice with DN. In addition, FA treatment significantly reduced the number of renal infiltrating M1 macrophages, inflammatory cytokine FA stimulation significantly reduced the increase in F4/80+CD86+ cell ratio, inflammatory factor content and p-p65/p65 protein expression induced by high glucose exposure in RAW264.7 cells. All in all, our results indicated that FA protects against kidney damage in mice with DN by inhibiting M1 macrophage polarization, and its mechanism may be related to the inhibition of nuclear factor-k-gene binding (NF-kB) signaling pathway.

FOXP3+ regulatory T cells and the immune escape in solid tumours.

FOXP3+ regulatory T (Treg) cells play critical roles in establishing the immunosuppressive tumour microenvironment, which is achieved and dynamically maintained with the contribution of various stromal and immune cell subsets. However, the dynamics of non-lymphoid FOXP3+ Treg cells and the mutual regulation of Treg cells and other cell types in solid tumour microenvironment remains largely unclear. In this review, we summarize the latest findings on the dynamic connections and reciprocal regulations of non-lymphoid Treg cell subsets in accordance with well-established and new emerging hallmarks of cancer, especially on the immune escape of tumour cells in solid tumours. Our comprehension of the interplay between FOXP3+ Treg cells and key hallmarks of cancer may provide new insights into the development of next-generation engineered T cell-based immune treatments for solid tumours.

Effects of fatty and lean fish intake on stroke risk: a meta-analysis of prospective cohort studies.

BACKGROUND: Fish intake has been postulated to reduce the risk of stroke. However, whether the beneficial effect of fish are mainly linked to fat content, as a source of omega-3 polyunsaturated fatty acids, remains unclear. We conducted a meta-analysis to compare the effect of fatty and lean fish intake on stroke risk. METHODS: We performed a literature search on four database (PubMed, Embase, Scopus, and Cochrane Library) through February 1, 2018 to identify prospective studies of fatty and lean fish in relation to stroke risk. A random-effects model was used to calculate the summary estimates. RESULTS: We identified five prospective studies, including 7 comparisons for fatty fish intake and 5 comparisons for lean fish intake. Compared with the highest category of intake with lowest category, the summary relative risk was 0.88 [95% confidence interval (CI), 0.74-1.04] for fatty fish intake and 0.81 (95% CI, 0.67-0.99) for lean fish intake. No heterogeneity across studies and publication bias were observed. CONCLUSION: Our findings demonstrated that fatty and lean fish intake has beneficial effects on stroke risk, especially lean fish intake. Additional prospective studies are necessary to confirm these observations.

Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice.

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.

Effects of Chronic Whey Protein Supplementation on Atherosclerosis in ApoE-/- Mice.

Whey protein is associated with improvement of metabolic syndrome. This study aimed to evaluate effects of whey protein on atherosclerosis in ApoE-/- mice. Male ApoE-/- mice were fed with a high-fat/cholesterol diet (HFCD), or HFCD supplemented with 10% or 20% whey protein for 18 wk. At the end of experiment, serum lipid profiles and inflammatory cytokines were assayed. Livers were examined using HE staining and Oil Red O staining. Aortas were used for en face and cryosection analyses to observe aortic lesions. Western blotting analysis was used to assess relative protein expression of cholesterol metabolism in the liver and aorta. No significant differences were observed in body weight or food intake among the three groups. Liver examination demonstrated decreased lipid droplets and cholesterol content in the whey-protein-supplemented groups. En face lesion of the aorta revealed a 21.51% and 31.78% lesion reduction in the HFCD supplemented with 10% and 20% whey groups, respectively. Decreased lesion was also observed in cryosection analysis. Whey protein significantly increased the serum high-density lipoprotein cholesterol level by 46.43% and 67.86%. The 20% whey protein significantly decreased serum IL-6 (a proinflammatory cytokine) by 70.99% and increased serum IL-10 (an anti-inflammatory cytokine) by 83.35%. Whey protein potently decreased lipogenic enzymes (ACC and FAS) in the liver and NF-κB expression in the liver and aorta. Whey protein significantly increased protein expression of two major cholesterol transporters (ABCA1 and ABCG1) in the liver and aorta. Thus, chronic whey protein supplementation can improve HFCD-induced atherosclerosis in ApoE null mice by regulating circulating lipid and inflammatory cytokines and increasing expressions of ABCA1 and ABCG1.

Poultry and Fish Consumption in Relation to Total Cancer Mortality: A Meta-Analysis of Prospective Studies.

Observational studies on the association between fish and poultry intake and the risk of total cancer mortality have been reported with mixed results. Thus, we aimed to assess this association by conducting a meta-analysis of prospective studies. We performed a literature search on PubMed database through February 1, 2017 to identify relative prospective studies. A random-effects model was used to calculate the summary estimates. We identified fourteen prospective studies involving 2,378,204 participants and 96,712 cancer mortality events. Comparing the highest category of consumption with lowest category, pooled relative risk (RR) of total cancer mortality was 0.99 (95% confidence interval [CI], 0.94-1.05) for fish (10 studies) and 0.96 (95% CI, 0.93-1.00) for poultry (8 studies), respectively. However, we failed to identify any dose-response association based on a limited number of eligible studies, with a pooled RR of 0.98 (95% CI, 0.92-1.05) and 0.97 (95% CI, 0.88-1.07) for each 100 g per day increment in fish and poultry consumption, respectively. In summary, this meta-analysis indicates that consumption of either fish or poultry is not substantially associated with lower risk of total cancer mortality. The observed weak inverse association for high poultry consumption needs to be verified in additional large prospective studies.

[Establishment of double targets of high throughput screening model for xanthine oxidase inhibitors and superoxide anion scavengers].

A double targets of high throughput screening model for xanthine oxidase inhibitors and superoxide anion scavengers was established. In the reaction system of xanthine oxidase, WST-1 works as the probe for the ultra oxygen anion generation, and product uric acid works as xanthine oxidase activity indicator. By using SpectraMax M5 continuous spectrum enzyme sign reflectoscope reflector, the changes of these indicators' concentration were observed and the influence factors of this reaction system to establish the high throughput screening model were studied. And the model is confirmed by positive drugs. In the reaction system, the final volume of reaction system is 50 µL and the concentrations of xanthine oxidase is 4 mU x mL(-1), xanthine 250 µmol x L(-1) and WST-1 100 µmol x L(-1), separately. The Z'-factor of model for xanthine oxidase inhibitors is 0.537 4, S/N is 47.519 9; the Z'-factor of model for superoxide anion scavengers is 0.507 4, S/N is 5.388 9. This model for xanthine oxidase inhibitors and superoxide anion scavengers has more common characteristics of the good stability, the fewer reagent types and quantity, the good repeatability, and so on. And it can be widely applied in high-throughput screening research.

[Pharmacokinetic comparison of two ozagrel polymorph forms in SD rats].

To enhance the quality and efficiency of ozagrel by investigating the differences between the ozagrel polymorphs in bioavailability. Solid ozagrel in different polymorph forms were orally administered to SD rats. An HPLC method was established to determinate plasma level of ozagrel. The bioavailabilities of two polymorph forms were calculated and compared. The pharmacokinetic parameters of ozagrel, were as follows: Cmax was 32.72 ± 17.04 and 34.01 ± 19.13 mg · L(-1), respectively; AUC0-t was 61.14 ± 14.76 and 85.56 ± 18.08 mg · L(-1) · h, respectively; t½ was 1.53 ± 0.51 and 4.73 ± 3.00 h, respectively. There was no significant difference in pharmacokinetic parameters between form I and II polymorphs of ozagrel while the t½ of form II is longer, which indicates that the use of form II polymorph as pharmaceutical product may prolong the effective action time in clinics. This would help the polymorph quality control in drug production.

[Comparison of extent of postoperative hydrocephalus in patients between intervertional therapy with embolism and craniotomy occlusion in Hunt-Hess III-IV level aneurysm induced subarachnoid hemorrhage and their prognosis].

OBJECTIVE: To analyze and compare the difference and prognosis between vascular embolization and craniotomy occlusion in patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) with Hunt-Hess level III-IV, and acute postoperative hydrocephalus. METHODS: A retrospective study was conducted on 767 patients who had undergone vascular embolization (vascular embolization group, n = 403) or craniotomy occlusion operation (craniotomy occlusion operation group, n = 364), and the patients with postoperative acute hydrocephalus were screened. The clinical data of patients of both groups was analyzed. By judging short-term prognosis in patients with hydrocephalus with Glasgow outcome scale (GOS) score estimated at discharge, the advantages and disadvantages of two surgical procedures were compared. RESULTS: The number of cases with postoperative hydrocephalus in vascular embolization group was 56 (13.90%), while that in craniotomy occlusion group was 33 (9.07%). The difference between the two groups of incidence of hydrocephalus was statistically significant (χ (2) = 4.350, P = 0.037). In 767 patients with aSAH, the incidence of hydrocephalus among the patients after the hematoma removal operation was significantly lower than that of patients without hematoma removal [3.07% (11/358) vs. 19.07% (78/409), χ (2) = 47.635, P = 0.000]. The incidence of hydrocephalus among the patients after ventricular drainage was significantly lower than that of patients without the drainage [2.77% (19/685) vs. 85.37% (70/82), χ (2) = 487.032, P = 0.000]. In 403 cases of vascular embolization group, the incidence of hydrocephalus in the patients after the hematoma removal operation was lower than that of patients without it [8.06% (5/62) vs. 14.96% (51/341), χ (2) = 2.082, P = 0.168]. The incidence of hydrocephalus in the patients after the ventricular drainage was lower than that of patients without drainage [2.59% (9/347) vs. 83.93% (47/56), χ (2) = 266.599, P = 0.000]. In 364 cases of craniotomy occlusion operation group, the incidence of hydrocephalus in the patients after hematoma removal operation was significantly lower than that of patients did not receive [2.03% (6/296) vs. 39.71% (27/68), χ (2) = 95.226, P = 0.000]. The incidence of hydrocephalus among the patients after the ventricular drainage was significantly lower than that of patients without drainage [2.96% (10/338) vs. 88.46% (23/26), χ (2) = 203.852, P = 0.000]. The difference in incidence of hydrocephalus between the patients who had hematoma removal surgery between vascular embolization group and craniotomy occlusion operation group was statistically significant [8.06% (5/62) vs. 2.03% (6/296), χ (2) = 4.411, P = 0.027], while no statistically difference was present in ventricular drainage patients [2.59% (9/347) vs. 2.96% (10/338), χ (2) = 0.085, P = 0.819]. There were 23 patients (41.07%) with good outcome (GOS score 4-5), while 33 (58.93%) with poor outcome (GOS score 1-3) in 56 patients undergone vascular embolization operation. Good result (GOS score 4-5) was shown in 21 (63.64%) and 12 (36.36%) with poor outcome (GOS score 1-3) among 33 patients with hydrocephalus after craniotomy occlusion operation, and the difference was statistically significant (χ (2) = 4.230, P = 0.039). CONCLUSIONS: Hematoma is one of the main factor contributing to the differences in the incidence of postoperative hydrocephalus of Hunt-Hess grade III-IV patients either receiving vascular embolization or craniotomy occlusion operation. Lateral ventricle drainage may not be the factor that contributes to the difference in incidence of hydrocephalus formation between the vascular embolization and craniotomy occlusion operation groups in Hunt-Hess level III-IV patients. The short term prognosis in the craniotomy occlusion operation group is superior to that of endovascular intervention embolization group.

Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor.

Serotonin transporter (SERT) is a critical determinant of synaptic serotonin (5-hydroxytryptamine, 5-HT) inactivation which plays a critical role in the pathology of depression and other mood disorders. Lipopolysaccharide (LPS), a potent activator of the inflammatory system, has been reported to cause depression symptoms by the modulation of SERT in vivo and in vitro. This study is aimed to investigate the underlying mechanism of LPS-induced SERT modulation. The 4-(4-(dimethylamino) styryl)-N-methylpyridinium iodide (ASP) assay was used to detect dynamic 5-HT uptake as read out of SERT activities in RBL-2H3 cells, and cytosol Ca(2+) concentrations ([Ca(2+)]i) and nitric oxide (NO) were examined. Using specific cyclic GMP-dependent protein kinase type I (PKG-I), p38 mitogen-activated protein kinases (p38MAPK) and A3 adenosine receptor (A3AR) inhibitors, SERT expression was evaluated by western blot and immunofluorescence analysis. Results showed that 24 h treatment with LPS stimulated 5-HT transport and up-regulate plasma membrane distribution of SERT in RBL-2H3 cells. LPS treatment increased NO and [Ca(2+)]i, and led to significant increases in levels of phosphorylated calcium/calmodulin-dependent protein kinase type II (CaMK-II), inducible NOS (iNOS) and PKG-I as well as active p38 MAPK. Moreover, PKG-I inhibitor KT5823 or p38MAPK inhibitor SB203580 respectively impaired SERT activation and transposition to plasma membrane by LPS. Notably, A3 adenosine receptor inhibitor MRS1191 also hindered SERT stimulation by LPS. In conclusion, LPS-induced 5-HT uptake and transposition to plasma membrane of SERT in RBL-2H3 cells involves CaMK-II/iNOS/PKG-I and p38 MAPK activation, which may be partially mediated by A3 adenosine receptor activation. This finding provides a novel insight into the interrelationship between LPS and depression.