S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.

Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.

Causal associations between blood lipids and brain structures: a Mendelian randomization study.

The potential causal association between dyslipidemia and brain structures remains unclear. Therefore, this study aimed to investigate whether circulating lipids are causally associated with brain structure alterations using Mendelian randomization analysis. Genome-wide association study summary statistics of blood lipids and brain structures were obtained from publicly available databases. Inverse-variance weighted method was used as the primary method to assess causality. In addition, four additional Mendelian randomization methods (MR-Egger, weighted median, simple mode, and weighted mode) were applied to supplement inverse-variance weighted. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses. After Bonferroni corrections, two causal associations were finally identified: elevated non-high-density lipoprotein cholesterol level leads to higher average cortical thickness (ß = 0.0066 mm, 95% confidence interval: 0.0045-0.0087 mm, P = 0.001); and elevated high-density lipoprotein cholesterol level leads to higher inferior temporal surface area (ß = 18.6077 mm2, 95% confidence interval: 11.9835-25.2320 mm2, P = 0.005). Four additional Mendelian randomization methods indicated parallel results. Sensitivity tests demonstrated the stability. Overall, the present study showed causal relationships between several lipid profiles and specific brain structures, providing new insights into the link between dyslipidemia and neurological disorders.

Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.

OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.Abbreviations: ALS: amyotrophic lateral sclerosis; CI: confidence interval; GWAS: genome-wide association study; IV: instrumental variable; IVW: iverse variance weighted; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; OR: odds ratio; RCT: randomized controlled trial; SNPs: single-nucleotide polymorphisms; UVMR: univariable Mendelian randomization.

No causal relationship between thyroid function and Parkinson's disease: A bidirectional Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent degenerative disease globally. While observational studies have demonstrated a correlation between thyroid function and PD, the causal relationship between these two factors remains uncertain. METHODS: A bidirectional Mendelian randomization (MR) analysis was performed to explore the causal relationship between thyroid function (free thyroxine [FT4], thyroid-stimulating hormone [TSH], hyperthyroidism, and hypothyroidism) and PD. GWAS summary-level statistics of thyroid function and PD were obtained from publicly available GWAS databases. The inverse variance weighted method was the main MR approach to assess causal associations. In addition, two additional MR methods (MR-Egger regression and weighted median) were performed to supplement the IVW. Furthermore, various sensitivity tests were performed to verify the reliability of the MR findings: (i) Heterogeneity was examined by Cochrane's Q test. (ii) Horizontal pleiotropy was assessed by the MR-Egger intercept test and MR-PRESSO global test. (iii) The robustness of MR results was estimated using the leave-one-out method. RESULTS: Various MR results showed that FT4, TSH, hyperthyroidism, and hypothyroidism did not causally affect PD (P > 0.05). Likewise, PD did not causally affect FT4, TSH, hyperthyroidism, and hypothyroidism (P > 0.05). Cochrane's Q test indicated that MR analysis was not affected by significant heterogeneity (P > 0.05). MR-Egger intercept test and MR-PRESSO global test indicated that MR analysis was not affected by a remarkable horizontal pleiotropy (P > 0.05). The leave-one-out method demonstrated the stability of MR results. CONCLUSION: MR analysis did not support a causal relationship between thyroid function and PD.

Mendelian randomization study supports positive bidirectional causal relationships between genetically predicted insomnia symptom and liability to benign prostatic hyperplasia.

BACKGROUND: Sleep quality may be related to benign prostatic hyperplasia (BPH), however causal associations have not been established. This study aimed to evaluate causal relationships between six sleep traits ([i] day time napping, [ii] daytime sleepiness, [iii] insomnia, [iv] long sleep duration, [v] short sleep duration, and [vi] sleep duration per hour) and BPH through a bidirectional Mendelian randomization (MR) study. METHODS: Genome-wide association summary statistics of sleep traits and BPH were downloaded from public databases. Inverse variance weighting (IVW) was used as the main approach for causal inference. For causal estimates identified by IVW, various sensitivity analyses were performed to assess the reliability of the results: (i) four additional MR methods to complement IVW; (ii) Cochran's Q test to assess heterogeneity; (iii) MR-Egger intercept test and MR-PRESSO global test to assess horizontal pleiotropy; and (iv) leave-one-out method to assess stability. RESULTS: Forward MR analyses indicated that genetically predicted insomnia symptom significantly increased BPH risk (OR = 1.267, 95% CI: 1.003-1.601, P = 0.048), while reverse MR analyses identified that genetically predicted liability to BPH significantly increased the incidence of insomnia (OR = 1.026, 95% CI: 1.000-1.052, P = 0.048). In a replicate MR analysis based on summary statistics including exclusively male participants, the finding of increased risk of BPH due to genetically predicted insomnia symptom was further validated (OR = 1.488, 95% CI: 1.096-2.022, P = 0.011). No further causal links were identified. In addition, sensitivity tests demonstrated the reliability of the MR results. CONCLUSION: This study identified that a higher prevalence of genetically predicted insomnia symptoms may significantly increase the risk of BPH, while genetically predicted liability to BPH may in turn increase the incidence of insomnia symptom. Therefore, improving sleep quality and reducing the risk of insomnia could be a crucial approach for the prevention of BPH.

Recurrence and survival of patients with stage III endometrial cancer after radical surgery followed by adjuvant chemo- or chemoradiotherapy: a systematic review and meta-analysis.

OBJECTIVE: To compare recurrence and survival in patients with stage III endometrial cancer after radical surgery, followed by either adjuvant chemoradiotherapy (ACR) or adjuvant chemotherapy (AC). METHODS: We searched for relevant studies in PubMed Central, Embase and the Cochrane Central Register of Controlled Trials. Data were pooled on rates of recurrence as well as rates of progression-free, disease-free and overall survival. Heterogeneity was evaluated using the I2 test. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity. RESULTS: Data from 18,375 patients in 15 retrospective studies and one randomized controlled trial were meta-analyzed. Compared to the AC group, the ACR showed significantly lower risk of local recurrence (OR 0.43, 95%CI 0.32-0.59) and total recurrence (OR 0.72, 95%CI 0.58-0.89). ACR was also associated with significantly better overall survival (HR 0.66, 95%CI 0.57-0.76), progression-free survival (HR 0.56, 95%CI 0.39-0.81) and disease-free survival (HR 0.66, 95%CI 0.53-0.83). CONCLUSIONS: Adding adjuvant radiotherapy to adjuvant chemotherapy after radical surgery may significantly reduce risk of local and overall recurrence, while significantly improving survival of patients with stage III endometrial cancer.

Identification of key lipid metabolism-related genes in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression. METHODS: Comprehensive analyses were performed to determine key DELMRGs in AD compared to controls in GSE122063 dataset from Gene Expression Omnibus. Additionally, the ssGSEA algorithm was utilized for estimating immune cell levels. Subsequently, correlations between key DELMRGs and each immune cell were calculated specifically in AD samples. The key DELMRGs expression levels were validated via two external datasets. Furthermore, gene set enrichment analysis (GSEA) was utilized for deriving associated pathways of key DELMRGs. Additionally, miRNA-TF regulatory networks of the key DELMRGs were constructed using the miRDB, NetworkAnalyst 3.0, and Cytoscape software. Finally, based on key DELMRGs, AD samples were further segmented into two subclusters via consensus clustering, and immune cell patterns and pathway differences between the two subclusters were examined. RESULTS: Seventy up-regulated and 100 down-regulated DELMRGs were identified. Subsequently, three key DELMRGs (DLD, PLPP2, and PLAAT4) were determined utilizing three algorithms [(i) LASSO, (ii) SVM-RFE, and (iii) random forest]. Specifically, PLPP2 and PLAAT4 were up-regulated, while DLD exhibited downregulation in AD cerebral cortex tissue. This was validated in two separate external datasets (GSE132903 and GSE33000). The AD group exhibited significantly altered immune cell composition compared to controls. In addition, GSEA identified various pathways commonly associated with three key DELMRGs. Moreover, the regulatory network of miRNA-TF for key DELMRGs was established. Finally, significant differences in immune cell levels and several pathways were identified between the two subclusters. CONCLUSION: This study identified DLD, PLPP2, and PLAAT4 as key DELMRGs in AD progression, providing novel insights for AD prevention/treatment.

Circulating sex hormone-binding globulin levels and ischemic stroke risk: a Mendelian randomization study.

PURPOSE: Previous studies have presented conflicting findings regarding the protective effects of circulating sex hormone-binding globulin (SHBG) on ischemic stroke (IS). This study aimed to assess the causal effect of SHBG on IS using Mendelian randomization (MR) analysis and to identify potential mediators. METHODS: First, the causal effect of SHBG on any IS (AIS), cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS) was assessed by inverse variance weighed (IVW) method. Two additional MR methods (weighted median and MR-Egger) were used to supplement the IVW results. Subsequently, a two-step MR was further performed to assess whether three glycemic profiles [fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c)] and five lipid profiles (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, total cholesterol, and triglycerides) mediated the causal effect. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses. RESULTS: The IVW results showed that SHBG significantly reduced SVS risk (odds ratio= 0.60, 95% confidence interval: 0.47-0.77, P = 4.60E-05). The weighted median and MR-Egger results were parallel to IVW. However, no significant associations were found between SHBG and AIS, CES, and LAS. Mediation analysis indicated that HbA1c may be involved in SHBG reducing SVS risk. Sensitivity tests demonstrated the reliability of causal estimates. CONCLUSIONS: Circulating SHBG levels may decrease SVS risk by lowering HbA1c levels. Therefore, individuals with low circulating SHBG levels should focus on glycemic control to reduce future SVS risk.

Impact of blood pressure and antihypertensive drug classes on intracranial aneurysm: a Mendelian randomization study.

BACKGROUND: Blood pressure is a risk factor for intracranial aneurysms (IA). Nevertheless, whether various antihypertensive drug classes discriminate in reducing IA risk is unclear. METHODS: Genome-wide association study summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), IA (non-ruptured), and IA [subarachnoid hemorrhage (SAH)] were downloaded. To proxy the effects of antihypertensive drugs, genetic variants associated with SBP adjacent to the coding regions of different antihypertensive drugs were selected. The inverse-variance-weighted (IVW) method was employed as the primary method for causal estimation. In addition, three additional MR methods and sensitivity tests were utilized to assess the reliability. RESULTS: Elevated blood pressure significantly increases the risk of IA: (i) SBP-IA (non-ruptured): odds ratio (OR) = 1.046, 95 % confidence interval (CI): 1.032-1.061, P = 1.05E-10; (ii) SBP-IA (SAH): OR = 1.040, 95 % CI: 1.030-1.050, P = 2.56E-15; (iii) DBP-IA (non-ruptured): OR = 1.082, 95 % CI: 1.056-1.110, P = 3.15E-10; (iv) DBP-IA (SAH): OR = 1.066, 95 % CI: 1.047-1.085, P = 1.25E-12. In addition, among calcium channel blockers (CCBs), beta-blockers (BBs), and thiazide diuretics (TDs), only SBP mediated by TDs target genes significantly increased the risk of IA (non-rupture) (OR = 1.164, 95 % CI: 1.060-1.279, P = 0.001) and IA (SAH) (OR = 1.136, 95 % CI: 1.063-1.214, P = 1.58E-04), while SBP mediated by target genes of BBs or CCBs did not causally associate with IA. CONCLUSION: Elevated blood pressure significantly increases IA risk, while TDs may be a promising antihypertensive medication for reducing IA risk. Further research with larger cohorts is essential for validation.

[Systemic Lupus Erythematosus Combined with Chorea: Report of One Case and Literature Review].

Systemic lupus erythematosus combined with chorea is relatively rare in China,and there are no unified diagnostic criteria or specific ancillary tests.Therefore,it is confirmed by exclusionary clinical diagnosis.To improve the understanding of this disease among rheumatologists,we report the clinical data of a patient with systemic lupus erythematosus combined with chorea admitted to the Department of Rheumatology and Immunology in the First Affiliated Hospital of Jinan University in January 2022.Furthermore,we review the relevant literature in the past 10 years and summarize the clinical features of these cases.

Access to Polysulfides through Photocatalyzed Dithiosulfonylation.

In this study, we outline a general method for photocatalyzed difunctionalization of alkenes, a diene, alkynes, 1,3-enynes, and [1.1.1]propellane using dithiosulfonate reagents (ArSO2 -SSR) with improved atom economy. Both "ArSO2 -" and "-SSR" on the dithiosulfonate are transferred under mild conditions with broad substrate scope, high stereoselectivity, and complete regioselectivity. Significantly, the resulting dithiosulfonylated styrene is a general and practical nucleophilic disulfuration reagent, reacting with a variety of electrophiles efficiently. Both reactions can be conducted on gram scale, rendering the approach highly valuable.

Convergent Synthesis of 1,4-Dicarbonyl Z-Alkenes through Three-Component Coupling of Alkynes, α-Diazo Sulfonium Triflate, and Water.

We report a general protocol for the convergent synthesis of 1,4-dicarbonyl Z-alkenes form alkynes using α-diazo sulfonium triflate and water. The C═O, C═C, and C-H bonds are formed under mild conditions with a wide range of functional groups tolerated. The reaction exhibits excellent Z-selectivity and complete regioselectivity. The resulting 1,4-dicarbonyl Z-alkenes can smoothly undergo follow-up conversion to a variety of heteroaromatic scaffolds. Moreover, the reaction also provides a facile access to the corresponding deuterated Z-alkenes and deuterated heteroarenes with a high level of deuterium incorporation (90-97% D-inc.) by directly using D2O, thus rendering the method highly valuable. The comprehensive mechanistic studies indicate that a free carbyne radical intermediate is formed via the photocatalytic single electron transfer process, and KH2PO4 plays a crucial role in significant improvements on yield and selectivity based on density-functional theory calculations, providing a new direction for radical coupling reactions of diazo compounds.

The Handling of Oxalate in the Body and the Origin of Oxalate in Calcium Oxalate Stones.

Urolithiasis is one of the most common urologic diseases in industrialized societies. More than 80% of renal stones are composed of calcium oxalate, and small changes in urinary oxalate concentrations affect the risk of stone formation. Elucidation of the source of oxalate and its mechanism of transport is crucial for understanding the etiology of urolithiasis. Sources of oxalate can be both endogenous and exogenous. With regard to oxalate transport, tests were carried out to prove the function of solute-linked carrier 4 (SLC4) and SLC26. The molecular mechanism of urolithiasis caused by SLC4 and SLC26 is still unclear. The growing number of studies on the molecular physiology of SLC4 and SLC26, together with knockout genetic mouse model experiments, suggest that SLC4 and SLC26 may be a contributing element to urolithiasis. This review summarizes recent research on the sources of oxalate and characterization of the oxalate transport ionic exchangers SLC4 and SLC26, with an emphasis on different physiological defects in knockout mouse models including kidney stone formation. Furthermore, SLC4 and SLC26 exchangers provide new insight into urolithiasis and may be a novel therapeutic target for modification of urinary oxalate excretion.

[Quality evaluation of Bolbostemmatis Rhizoma by UPLC fingerprint combined with QAMS].

The present study was performed to establish the UPLC fingerprints of Bolbostemmatis Rhizoma and determine the contents of three saponins by quantitative analysis of multi-components by single marker(QAMS), and provide basis for quality evaluation of Bolbostemmatis Rhizoma. The analysis was carried out on an analytical column of Waters Cortecs T3(2.1 mm×100 mm,1.6 µm)with gradient elution by acetonitrile-0.1% phosphoric acid solution, at a flow rate of 0.3 mL·min~(-1). The detection wavelength was 203 nm, the column temperature was 30 ℃ and the injection volume was 1 µL. The UPLC fingerprints of Bolbostemmatis Rhizoma were established and evaluated by similarity calculation, cluster analysis and principal component analysis. The relative calibration factors of toberoside B and toberoside C were determined with toberoside A as internal reference. The content was calculated by relative calibration factors to develop a method of QAMS. Comparing the results of QAMS with those of ESM, the accuracy and feasibility of one-eva-luation and multi-evaluation can be determined. RESULTS:: showed that the fingerprints of 19 batches of Bolbostemmatis Rhizoma have four common peaks with similarities ranging from 0.754 to 1.000. Cluster analysis and principal component analysis classified 19 batches of Bolbostemmatis Rhizoma into three categories, which was consistent with the similarity evaluation results. The relative deviation between the content of tubeicosides B and C in 19 batches of Bolbostemmatis Rhizoma determined by QAMS and ESM is less than 5.0%, indicating that there was no significant difference between the two methods. Therefore, the UPLC fingerprints combined with QAMS and similarity evaluation can be effectively used to evaluate the quality of Bolbostemmatis Rhizoma.

Effects of diabetes mellitus on biomechanical properties of the rabbit cornea.

To investigate the effects of diabetes on the biomechanical behavior of cornea in alloxan-induced diabetic rabbits. Diabetes mellitus (DM) was induced in 20 rabbits using alloxan, while another 20 age- and weight-matched non-diabetic rabbits served as controls. Eyes were enucleated after 8 weeks of inducing diabetes and the whole cornea was removed with a 3 mm wide scleral ring and tested under inflation conditions with an internal pressure range of 2.0-30.0 mmHg to determine their stress-strain behavior using an inverse analysis process. The blood glucose level (BG), advanced glycosylation end products (AGEs), central corneal thickness (CCT) and intraocular pressure (IOP) increased significantly in the DM group. There were statistically significant correlations between BG and AGEs (r = 0.768, p = 0.00), and between AGEs and CCT variation upon induction of DM (r = 0.594, p = 0.00). The tangent modulus (Et) of the cornea at four stress levels (1-4 kPa, equivalent to approximately IOP of 7.5, 15, 22.5 and 30 mmHg, respectively) was significantly higher in diabetic rabbits than in the control group (p < 0.05). Further, Et at stress of 2 kPa (which corresponded to the average IOP for the control group) was significantly correlated with BG (r = 0.378, p < 0.05), AGEs (r = 0.496, p < 0.05) and CCT variation upon induction of DM (r = 0.439, p < 0.05). IOP, as measured by contact tonometry, was also significantly correlated with both CCT (r = 0.315, p < 0.05) and Et at 2 kPa (r = 0.329, p < 0.05), and even after correcting for the effects of CCT and Et, IOP still significantly increased with both AGEs (r = 0.772, p = 0.00) and BG (r = 0.762, p = 0.00). The cornea of diabetic rabbits showed a significant increase in mechanical stiffness as evidenced by increases in corneal thickness and tangent modulus. The Et increase may be explained by a non-enzymatic cross-linking of collagen fibrils mediated by AGEs due to the high blood glucose levels in diabetes. The study also found significant IOP increases with higher blood glucose level even after controlling the effects of both corneal thickness and tangent modulus.

Pharmacokinetics and relative bioavailability of a generic amisulpride tablet in healthy Chinese volunteers
.

OBJECTIVE: To assess and compare the pharmacokinetic properties and bioavailability of a newly developed formulation of amisulpride with those of a conventional formulation in healthy Chinese volunteers under fasting state. MATERIALS AND METHODS: A single-dose, two-sequence crossover study was designed. 20 healthy subjects (14 males and 6 females) were randomized into two groups. A single oral dose of amisulpride (200 mg) was given after an overnight fast of 12 hours. Blood samples were taken at scheduled time spots and separated by a washout period of 14 days. Plasma concentration of amisulpride was measured by high-performance liquid chromatography-fluorescence detector (HPLC-FLD) method. RESULTS: The pharmacokinetic parameters of AUC0-tlast, AUC0-∞, and Cmax for the 20 subjects after a single oral dose of the trial preparation or the reference preparation were 4,767.2 and 4,856.3 ng×h×mL-1; 4,891.7 and 5,043.2 ng×h×mL-1; 584.7 and 586.3 ng×mL-1, respectively. The relative bioavailability was 98.9 ± 14.5%. No significant difference was found among the main pharmacokinetic parameters in the two preparations by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax and AUC0-tlast were 90.7 - 109.1% and 92.5 - 103.6%, respectively, meeting the predetermined criteria (80 - 125%) for bioequivalence. No serious adverse events were reported. CONCLUSION: The study demonstrated that the two preparations met the regulatory criteria for bioequivalence and both formulations were well tolerated.
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Pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers
.

OBJECTIVE: To evaluate the pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers. METHODS: A single-center, randomized, cross-over, two-period study design was conducted in healthy male subjects who were identified as not carrying the HLA-B*58:01 allele. Under fasting conditions, a single oral dose of 300 mg test or reference tablets was given with a 1-week washout period. The blood samples were collected for up to 12 hours after the administration and the plasma concentrations of allopurinol were determined by high performance liquid chromatography. Subject interviews and physical examinations were done over regular intervals to monitor the adverse events. RESULTS: 18 subjects were enrolled in the study, and none dropped out. The main pharmacokinetic parameters of allopurinol test and reference preparations were as follows: AUC0-tlast was 6,725.1 ± 1,390.0 ng×h×mL-1 and 6,425.6 ± 1,257.6 ng×h×mL-1; AUC0-∞ was 7,069.1 ± 1,503.2 ng×h×mL-1 and 6,750.6 ± 1,347.7 ng×h×mL-1; tmax was 1.3 ± 0.8 hours and 1.3 ± 0.8 hours; Cmax was 2,203.7 ± 557.4 ng×mL-1 and 2,310.8 ± 662.8 ng×mL-1; and T1/2 was 2.0 ± 1.6 hours and 1.7 ± 0.7 hours. The relative bioavailability was 105.1 ± 12.6%. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ of both preparations fell within the bioequivalence acceptance criteria (80 - 125%). No adverse events were found or reported during the study. CONCLUSION: The test allopurinol preparations and the reference preparations are bioequivalent and both are well tolerated.
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A High-Saturated-Fat, High-Sucrose Diet Aggravates Bone Loss in Ovariectomized Female Rats.

BACKGROUND: Estrogen deficiency in women and high-saturated fat, high-sucrose (HFS) diets have both been recognized as risk factors for metabolic syndrome. Studies on the combined actions of these 2 detrimental factors on the bone in females are limited. OBJECTIVE: We sought to determine the interactive actions of estrogen deficiency and an HFS diet on bone properties and to investigate the underlying mechanisms. METHODS: Six-month-old Sprague Dawley sham or ovariectomized (OVX) rats were pair fed the same amount of either a low-saturated-fat, low-sucrose (LFS) diet (13% fat calories; 15% sucrose calories) or an HFS diet (42% fat calories; 30% sucrose calories) for 12 wk. Blood, liver, and bone were collected for correspondent parameters measurement. RESULTS: Ovariectomy decreased bone mineral density in the tibia head (TH) by 62% and the femoral end (FE) by 49% (P < 0.0001). The HFS diet aggravated bone loss in OVX rats by an additional 41% in the TH and 37% in the FE (P < 0.05). Bone loss in the HFS-OVX rats was accompanied by increased urinary deoxypyridinoline concentrations by 28% (P < 0.05). The HFS diet induced cathepsin K by 145% but reduced osteoprotegerin mRNA expression at the FE of the HFS-sham rats by 71% (P < 0.05). Ovariectomy significantly increased peroxisome proliferator-activated receptor γ mRNA expression by 136% and 170% at the FE of the LFS- and HFS-OVX rats, respectively (P < 0.05). The HFS diet aggravated ovariectomy-induced lipid deposition and oxidative stress (OS) in rat livers (P < 0.05). Trabecular bone mineral density at the FE was negatively correlated with rat liver malondialdehyde concentrations (R(2) = 0.39; P < 0.01). CONCLUSIONS: The detrimental actions of the HFS diet and ovariectomy on bone properties in rats occurred mainly in cancellous bones and were characterized by a high degree of bone resorption and alterations in OS.

Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice.

AIM: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. METHODS: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1-200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. RESULTS: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. CONCLUSION: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties.

Effects of saturated and monounsaturated fatty acids on cognitive impairment: evidence from Mendelian randomization study.

BACKGROUND: Prior observational studies have suggested correlations between saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) with cognitive function. However, causal relationships remains unclear. METHODS: We assessed the causal impact of two SFAs (palmitic acid [PA] and stearic acid [SA]) and two MUFAs (oleic acid [OA] and palmitoleic acid [POA]) on cognitive function-related traits, and dementia-related traits by univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) analyses. RESULTS: UVMR indicated ß of 0.060 (P = 4.05E-06) for cognitive performance score and 0.066 (P = 4.21E-04) for fluid intelligence per standard deviation (SD) increase in OA level. MVMR indicated: (i) ß of -0.608 (P = 8.37E-05) for fluid intelligence score per SD increase in POA; (ii) ß of 0.074 (P = 0.018) for fluid intelligence score per SD increase in OA; (iii) ß of 0.029 (P = 0.033) for number of incorrect matches in round per SD increase in PA; and (iv) ß of 0.039 (P = 0.032) for number of incorrect matches in round per SD increase in SA. In addition, a secondary MVMR analysis after excluding the effect of polyunsaturated fatty acids suggested that: (i) ß of -0.043 (P = 1.97E-02) for cognitive performance score per SD increase in PA and (ii) ß of -0.079 (P = 1.79E-03) for cognitive performance score per SD increase in SA. CONCLUSIONS: Overall, UVMR and MVMR suggest that OA may be beneficial for cognitive function, while POA, PA, and SA may have detrimental effects on cognitive function.