Exhaustive Hydrodefluorination or Deuterodefluorination of Trifluoromethylarenes via Metal-Free Photoredox Catalysis.

Perfluoroalkyl compounds are persistent environmental pollutants due to their chemical and thermal stability. Hydrodefluorination is one of the most promising strategies for the disposal of fluorine-containing compounds, which has attracted much attention from a broad spectrum of scientific communities. Herein, we disclose a metal-free, visible-light-promoted protocol for the exhaustive hydrodefluorination of a wide variety of trifluoromethylarenes with up to 95% yields. Moreover, methyl-d3 groups can be obtained via deuterium water with a D ratio of up to 94%.

Response to febuxostat according to clinical subtypes of hyperuricemia: a prospective cohort study in primary gout.

BACKGROUND: While xanthine oxidase inhibitors target uric acid production, renal urate underexcretion is the predominant subtypes in gout. This study was to compare treatment response to the XOI febuxostat in a gout cohort according to clinical subtypes of hyperuricemia. METHODS: A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (initially 20 mg daily, escalating to 40 mg daily if not at target) in 644 gout patients with the three major clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal overload subtype, the renal underexcretion subtype, or the combined subtype based on UUE > or ≤ 600 mg/d/1.73 m2 and FEUA < or ≥ 5.5%. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12. RESULTS: Fewer participants with combined subtype achieved the SU target, 45.5% compared with 64.8% with overload subtype (P = 0.007), and 56.6% with underexcretion subtype (P = 0.022). More participants with combined subtype (82%) had febuxostat escalated to 40 mg than those with overload (62%, P = 0.001) or underexcretion subtype (68%, P = 0.001). In all participants, combined subtype hyperuricemia (OR = 0.64, 95%CI 0.41-0.99, P = 0.048) and baseline SU (OR = 0.74, 95%CI 0.62-0.89, P = 0.001) were independently associated with lower rates of achieving SU target. CONCLUSIONS: People with combined subtype have a lower response to febuxostat, compared to those with either overload or underexcretion subtype. Assessment of hyperuricemia subtype may provide useful clinical data in predicting febuxostat response.

Predicting response to CCRT for esophageal squamous carcinoma by a radiomics-clinical SHAP model.

BACKGROUND: Radical concurrent chemoradiotherapy (CCRT) is frequently used as the first-line treatment for patients with locally advanced esophageal cancer. Unfortunately, some patients respond poorly. To predict response to radical concurrent chemoradiotherapy in pre-treatment patients with esophageal squamous carcinoma (ESCC), and compare the predicting efficacies of radiomics features of primary tumor with or without regional lymph nodes, we developed a radiomics-clinical model based on the positioning CT images. Finally, SHapley Additive exPlanation (SHAP) was used to explain the models. METHODS: This retrospective study enrolled 105 patients with medically inoperable and/or unresectable ESCC who underwent radical concurrent chemoradiotherapy (CCRT) between October 2018 and May 2023. Patients were classified into responder and non-responder groups with RECIST standards. The 11 recently admitted patients were chosen as the validation set, previously admitted patients were randomly split into the training set (n = 70) and the testing set (n = 24). Primary tumor site (GTV), the primary tumor and the uninvolved lymph nodes at risk of microscopic disease (CTV) were identified as Regions of Interests (ROIs). 1762 radiomics features from GTV and CTV were respectively extracted and then filtered by statistical differential analysis and Least Absolute Shrinkage and Selection Operator (LASSO). The filtered radiomics features combined with 13 clinical features were further filtered with Mutual Information (MI) algorithm. Based on the filtered features, we developed five models (Clinical Model, GTV Model, GTV-Clinical Model, CTV Model, and CTV-Clinical Model) using the random forest algorithm and evaluated for their accuracy, precision, recall, F1-Score and AUC. Finally, SHAP algorithm was adopted for model interpretation to achieve transparency and utilizability. RESULTS: The GTV-Clinical model achieves an AUC of 0.82 with a 95% confidence interval (CI) of 0.76-0.99 on testing set and an AUC of 0.97 with a 95% confidence interval (CI) of 0.84-1.0 on validation set, which are significantly higher than those of other models in predicting ESCC response to CCRT. The SHAP force map provides an integrated view of the impact of each feature on individual patients, while the SHAP summary plots indicate that radiomics features have a greater influence on model prediction than clinical factors in our model. CONCLUSION: GTV-Clinical model based on texture features and the maximum diameter of lesion (MDL) may assist clinicians in pre-treatment predicting ESCC response to CCRT.

VASN promotes colorectal cancer progression by activating the YAP/TAZ and AKT signaling pathways via YAP.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. Vasorin (VASN) has been reported to be critical in tumor development and angiogenesis. However, VASN has not been reported in CRC, and its role is unclear. In this study, VASN expression is upregulated in CRC compared with the normal tissues, and VASN expression positively correlates with N stage and poor overall survival by analysis of different datasets and 32 CRC clinicopathologic samples. Overexpression of VASN significantly promotes CRC cell progression, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while knockdown of VASN inhibits CRC progression. We found that VASN was associated with the YAP/TAZ and PI3K/AKT pathways by gene set enrichment analysis (GSEA) and gene ontology (GO) analysis. Notably, western blotting, immunofluorescence staining and co-immunofluorescence (co-IP) confirmed that VASN could interact with YAP and activate the YAP/TAZ and PTEN/PI3K/AKT pathways, and knockdown of YAP reversed this effect. Importantly, our findings indicate that VASN interacts with YAP to inhibit YAP phosphorylation and stimulates CRC proliferation, migration, and invasion through activation of the YAP/TAZ-TEAD target gene CTGF and PTEN/PI3K/AKT pathways. Our results also show that knockdown of YAP reverses the cellular phenotype induced by increased VASN. In conclusion, our study reveals that VASN acts as an oncogene to stimulate tumor progression in CRC, providing new insights into the molecular mechanisms of CRC development and representing a possible novel biomarker for CRC.

Association of obesity, triglyceride-glucose and its derivatives index with risk of hyperuricemia among college students in Qingdao, China.

Objective: To analyze and compare the associations of hyperuricemia (HUA) with obesity, triglyceride-glucose (TyG), and its derivatives in college students. To provide early guidance on risk predictors of HUA in college students. Methods: This study was a cross-sectional survey including 23,411 participants (age: 17-20 years). Investigators conducted face-to-face interview surveys and physical examinations. Automated biochemical methods were used to detect biochemical indicators such as serum uric acid (UA). Calculation of obesity, TyG, and their derivatives indices were performed. Logistic regression was used to analyze the relationship between different indexes and hyperuricemia. OR value and 95% CI were also calculated. ROC curve was used for assessing the predictive ability of different indices of hyperuricemia. Results: After adjusting for age, SBP, DBP, ALT, AST, TC, BUN, and CREA, multivariate logistic regression showed that the OR value of LAP in the obesity index was higher, especially in women (male OR: 4.347, 95%CI: 3.807, 4.964; female OR: 4.672, 95%CI: 3.800, 5.744). The other three quartiles of TyG derivatives were highly associated with hyperuricemia in men and women compared with the top quartile (all P< 0.05). The risk of hyperuricemia increased with an increase in quartiles. For college students, all indicators could distinguish the presence of hyperuricemia. For men, the area under the curve (AUC) of TyG-WC was the largest (AUC: 0.694; 95%CI: 0.684-0.704; P<0.05), according to the Maximum Youden index 0.290 with cut point value 477.853. In women, TyG-BMI showed a maximum AUC value of 0.702 (95%CI: 0.685-0.719; P<0.05), according to the maximum Youden index of 0.317 with cut point value 132.446. The TyG-WC, TyG-WHtR, TyG-LAP, and LAP indices also had relatively high AUC. Conclusion: In clinical practice, LAP, TYG, and their related derivatives may be used as sensitive indicators for HUA prediction in college students.

PD-L1/PD-L1 signalling promotes colorectal cancer cell migration ability through RAS/MEK/ERK.

Programmed death ligand 1 (PD-L1) is widely known as an immune checkpoint, and immunotherapy through the inhibition of checkpoint molecules has become an important component in the successful treatment of tumours via programmed death 1 (PD-1)/PD-L1 signalling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) are elusive. We previously found that PD-L1 can bind to PD-L1 and cause cell detachment. However, the detailed molecular mechanisms of how PD-L1 binds to PD-L1 and how it transmits signals to the cell remain unclear. In this study, we disclosed that PD-L1 expression was dramatically upregulated in CRC compared to normal tissues. Ectopic expression of PD-L1 inhibits cell adhesive capacity and promotes cell migration in CRC cell lines, while silencing PD-L1 had the opposite effects and suppressed invasion and proliferation. Mechanistically, PD-L1 was found to promote epithelial-mesenchymal transition (EMT) through the ERK signalling molecule pathway and interacted with the 1-86 aa fragment of KRAS to transduce signals. Collectively, our study demonstrated the role of PD-L1 after binding to PD-L1 in CRC, thereby providing a new theoretical basis for further improving immunotherapy with anti-PD-L1 antibodies.

Single-cell analysis of transcription factor regulatory networks reveals molecular basis for subtype-specific dysregulation in acute myeloid leukemia.

Highly heterogeneous acute myeloid leukemia (AML) exhibits dysregulated transcriptional programs. Transcription factor (TF) regulatory networks underlying AML subtypes have not been elucidated at single-cell resolution. Here, we comprehensively mapped malignancy-related TFs activated in different AML subtypes by analyzing single-cell RNA sequencing data from AMLs and healthy donors. We first identified six modules of regulatory networks which were prevalently dysregulated in all AML patients. AML subtypes featured with different malignant cellular composition possessed subtype-specific regulatory TFs associated with differentiation suppression or immune modulation. At last, we validated that ERF was crucial for the development of hematopoietic stem/progenitor cells by performing loss- and gain-of-function experiments in zebrafish embryos. Collectively, our work thoroughly documents an abnormal spectrum of transcriptional regulatory networks in AML and reveals subtype-specific dysregulation basis, which provides a prospective view to AML pathogenesis and potential targets for both diagnosis and therapy.

Advances in measuring DNA methylation.

DNA methylation is one of the most important components of epigenetics, which plays essential roles in maintaining genome stability and regulating gene expression. In recent years, DNA methylation measuring methods have been continuously optimized. Combined with next generation sequencing technologies, these approaches have enabled the detection of genome-wide cytosine methylation at single-base resolution. In this paper, we review the development of 5-methylcytosine and its oxidized derivatives measuring methods, and recent advancement of single-cell epigenome sequencing technologies, offering more referable information for the selection and optimization of DNA methylation sequencing technologies and related research.

Overexpression of PD-L1 causes germ cells to slough from mouse seminiferous tubules via the PD-L1/PD-L1 interaction.

Spermatogenesis is a cyclical process in which different generations of spermatids undergo a series of developmental steps at a fixed time and finally produce spermatids. Here, we report that overexpression of PD-L1 (B7 homolog1) in the testis causes sperm developmental disorders and infertility in male mice, with severe malformation and sloughing during spermatid development, characterized by disorganized and collapsed seminiferous epithelium structure. PD-L1 needs to be simultaneously expressed on Sertoli cells and spermatogonia to cause spermatogenesis failure. After that, we excluded the influence of factors such as the PD-L1 receptor and humoral regulation, confirming that PD-L1 has an intrinsic function to interact with PD-L1. Studies have shown that PD-L1 not only serves as a ligand but also plays a receptor-like role in signal transduction. PD-L1 interacts with PD-L1 to affect the adhesive function of germ cells, causing malformation and spermatid sloughing. Taken together, these results indicate that PD-L1 can interact with PD-L1 to cause germ cell detachment and male infertility.

Secondary hypogonadism following hand, foot, and mouth disease in an adult: a case report and review of literature.

BACKGROUND: Previous reports have described hypogonadism associated with virus infection such as hantavirus, human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). However, to our best knowledge there has been no case report of secondary hypogonadism following hand, foot, and mouth disease (HFMD). CASE PRESENTATION: A previously healthy 28-year-old man with no history of major physical and psychological trauma, presented with bilateral gynecomastia and erectile dysfunction 2 weeks after HFMD. Laboratory testament showed the level of gonadotropin hormones declined. Imaging examination demonstrated no major abnormal change in pituitary or reproductive system. The diagnosis of hypogonadism was established. Then the patient was ordered to maintain mental health outward of hospital without drug intervention. One month after presentation, his gonadotropin hormone level and sexual desire had recovered, while bilateral gynecomastia and erectile dysfunction symptoms disappeared. CONCLUSIONS: Physicians should notice the possibility for hypogonadism in adult patients with a recent history of HFMD.

Prognostic Value of CD9 in Solid Tumor: A Systematic Review and Meta-Analysis.

Numerous clinical studies investigated how low expression of CD9 predicts poor prognosis of solid tumor. However, the results were inconclusive. This present meta-analysis was therefore performed to determine the prognostic value of CD9 expression in solid tumors. In this meta-analysis, 25 studies involving 5,555 participants were included; the result showed strong significant associations between declined expression of CD9 and all endpoints: overall survival (OS) (hazard ratio (HR) = 1.88, 95% CI = 1.45-2.43, p < 0.000) and time to progression (TTP) (HR = 2.0, 95% CI = 1.38-2.88, p < 0.000). The subgroup analysis was also performed, which revealed that the associations between CD9 downregulated expression related to poor OS in lung cancer and head and neck cancer. Also, low expression of CD9 was significantly connected with poor TTP in patients with head and neck cancer. The adverse prognostic impact of decreased expression of CD9 was observed in patients of different ethnicities. In conclusion, these results showed that declined expression of CD9 was associated with poor survival in human solid tumors. CD9 may be a valuable prognostic predictive biomarker and a potential therapeutic target in human solid tumors.

Regioselective Radical Borylation of α,ß-Unsaturated Esters and Related Compounds by Visible Light Irradiation with an Organic Photocatalyst.

Radical hydroboration reactions have only recently been reported and are still rare. Here we describe a photoredox radical hydroboration of α,ß-unsaturated esters, amides, ketones, and nitriles with NHC-boranes that uses only an organocatalyst and visible light. The conditions are mild, the substrate scope is broad, and the α/ß regioselectivity is high. The reaction requires only the organocatalyst; there is no costly metal, and there are no other additives (base, cocatalyst, initiator).

Geometry transformation of ionic surfactants and adsorption behavior on water/n-decane-interface: calculation by molecular dynamics simulation and DFT study.

Understanding the effect of surfactant structure on their ability to modify interfacial properties is of great scientific and industrial interest. In this work, we have synthesized four amide based ionic surfactants under acidic or basic conditions, including CTHA·HCl, CTEA·HCl, CTHA-Na+ and CTEA-Na+. Experiments have proved that the anionic surfactant with polyethylene oxide groups (CTEA-Na+) had the lowest surface tension on the water/n-decane interface. Molecular dynamics simulations have been applied to investigate the structural effect on the adsorption behavior of four different surfactants. The surface tension, interface thickness, interface formation energy, density profiles, order parameters, radial distribution function on the water/n-decane interfaces were calculated and compared. During the equilibrium states, we found that the interface configuration of two cationic surfactants are almost linear while the two anionic surfactants are changed to bending shapes due to the different positions of the hydrophilic head groups. Further DFT study and wavefunction analysis of surfactants have shown that CTEA-Na+ can form stronger vdW interactions with n-decane molecules due to a more neutral electrostatic potential distribution. Meanwhile, the introduction of polyethylene oxide groups has offered more H-bonding sites and resulted in more concentrated H-bonding interactions with water molecules. The difference of weak interactions may contribute to the conformational change and finally affect the interface properties of these ionic surfactants.

The efficacy and safety of citrate mixture vs sodium bicarbonate on urine alkalization in Chinese primary gout patients with benzbromarone: a prospective, randomized controlled study.

OBJECTIVES: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment. METHODS: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12). RESULTS: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred. CONCLUSION: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks. TRIAL REGISTRATION: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.

Prothrombotic effects of high uric acid in mice via activation of MEF2C-dependent NF-κB pathway by upregulating let-7c.

Serum uric acid is reportedly associated with thrombosis development. However, still unclear is the mechanism of high uric acid in thrombosis with the involvement of let-7c. In an aim to fill this void, we conducted this study by treating mice and human umbilical vein endothelial cells with high uric acid. Analysis indicated that let-7c was upregulated in hyperuricemia patients as well as in mice and human umbilical vein endothelial cells treated with high uric acid. Furthermore, high uric acid inhibited myocyte enhancer factor-2C, but activated nuclear factor-kappa B pathway in human umbilical vein endothelial cells. Then the targeting relationship between let-7c and myocyte enhancer factor-2C was verified. On the one hand, high uric acid shortened activated partial thromboplastin time and prothrombin time of mice and declined tissue plasminogen activator level. Additionally, the treatment prolonged thrombin time and elevated the levels of thrombosis related molecules or proteins such as Fibrinogen and D-dimer. Nevertheless, these alternations could be reversed by inhibition of let-7c and nuclear factor-kappa B pathway or overexpressing myocyte enhancer factor-2C. To sum up, our results uncovered the pro-thrombotic effect of high uric acid in mice by activating myocyte enhancer factor-2C-dependent nuclear factor-kappa B pathway via let-7c upregulation.

Evaluation of febuxostat initiation during an acute gout attack: A prospective, randomized clinical trial.

OBJECTIVE: Urate-lowering treatment (ULT) is recommended in gout management. However, initiation of ULT during an acute gout flare is still inconclusive. This study aimed to evaluate the efficacy and safety of the ULT febuxostat administered at initiation of an acute gout attack. METHODS: A prospective randomized controlled clinical trial was conducted for 12 weeks in primary gout patients who were admitted with acute gout attacks. Subjects were randomly assigned to the febuxostat group in which febuxostat, 40mg daily, was administered in the primary care setting for attacks, or to the control group in which febuxostat, 40mg daily, was administered after the attacks. All patients received adequate anti-inflammatory and analgesic therapies. Serum urate (SU) levels were monitored throughout the study. Pain, measured using a visual analogue scale (VAS), and gout recurrence rate were used as primary outcomes. Flare-related inflammation biomarkers were selected as secondary outcomes. RESULTS: Fifty-two patients completed the study (febuxostat group: n=28; control group: n=24). No significant differences were detected in VAS scores between the two groups over the first 14-day observation period (P>0.05). Administration of febuxostat decreased SU levels significantly during the first 2-week period. However, the gout recurrent rate or gout flare-related inflammation indicators did not change in the febuxostat or control groups. Treatment-related adverse events were mild and similar between groups. CONCLUSION: Initiation of the urate-lowering drug febuxostat during an acute gout attack caused no significant difference in daily pain, recurrent flares, or adverse effects. The treatment significantly decreased SU levels in the early stage and might have potential long-term benefits in these patients.

CaSR participates in the regulation of vascular tension in the mesentery of hypertensive rats via the PLC­IP3/AC­V/cAMP/RAS pathway.

Hypertension is a cardiovascular disease that severely impairs human health; however, its specific etiology and pathogenesis are complex. The present study investigated the effects of the calcium sensing receptor (CaSR) on vascular tone in spontaneously hypertensive rats (SHRs), and clarified the role and mechanism of CaSR in regulating this property with respect to the phospholipase C (PLC)­inositol 1,4,5­triphosphate (IP3)/adenylate cyclase­V(AC­V)/cyclic adenosine monophosphate (cAMP)/renin­angiotensin system (RAS) pathway in these animals. CaSR protein expression in the mesenteric artery (MA) of rats and CaSR protein expression in SHRs were significantly reduced. Based on wire myography studies, vasoconstriction was significantly augmented and vasodilatation was attenuated in SHRs, and this effect was endothelium­independent. The CaSR calcimimetic NPSR568 and inhibitor NPS2143 reduced vasoconstriction and enhanced vasodilation in SHRs. Furthermore, pretreatment with PLC­IP3/AC­V/cAMP/RAS pathway blockers significantly reduced the vasoconstriction response and enhanced the vasodilator response in SHRs and Wistar­Kyoto rats (WKY), and these effects were partially dependent on the endothelium. Additionally, pretreatment with CaSR inhibitors were determined to cooperate with the PLC­IP3/AC­V/cAMP/RAS pathway inhibitors to significantly reduce vasoconstriction and enhance vasodilation in SHRs and WKY. Our results demonstrated that CaSR is functionally expressed in the MA of SHRs, and that CaSR expression is decreased in SHRs. Additionally, vasoconstriction was enhanced while vasodilatation was attenuated in SHRs; these processes were determined to be endothelium­independent. CaSR is involved in the regulation of blood pressure and vascular tension in SHRs and WKYs. In association with mechanistic differences, this effect was proposed to be partially endothelium­dependent and mediated by the PLC­IP3/AC­V/cAMP/RAS pathway.

Baseline urate level and renal function predict outcomes of urate-lowering therapy using low doses of febuxostat and benzbromarone: a prospective, randomized controlled study in a Chinese primary gout cohort.

BACKGROUND: Low doses of febuxostat or benzbromarone are widely used in Asian countries, but lacking studies to compare the efficacy and safety of the two urate-lowering drugs. METHODS: To compare the efficacy and safety of low-dose febuxostat with low-dose benzbromarone in patients with primary gout, a randomized controlled, open-label trial was performed among male patients with primary gout for urate-lowering therapy (ULT) in a dedicated gout clinic in China. Randomization was carried out by a third-party institution according to random number table. Patients were randomly assigned 1:1 to febuxostat group (Feb group) (20 mg daily) or benzbromarone group (Ben group) (25 mg daily) and treated for 12 weeks. General information and biochemical data were collected at baseline and at every visit monthly. Clinical characteristics before and after the ULT were analyzed in the two groups by SPSS and EmpowerStats software. RESULTS: Two hundred forty patients were enrolled and randomized in the two groups, with 214 patients completing 12 weeks' ULT (105 in the Feb group and 109 in the Ben group). After 12 weeks, substantial percentages of patients in both Feb and Ben group achieved the target serum uric acid (sUA) (< 360 µmol/L) and serum urate levels were reduced significantly for both groups (Feb 39.5% and 156.83 µmol/L vs. Ben 35.7% and 163.99 µmol/L). Multivariate analysis suggests baseline sUA level and renal function were associated with the outcome of the rate of achieving target sUA (RAT). Sub-group analysis suggests low doses of febuxostat and benzbromarone rendered better RAT for patients with sUA < 540 µmol/L and creatinine clearance rate (Ccr) ≤ 110 mL min-1 1.73 m-2 at baseline. The drugs were well tolerated, and the incidence of gout flares in Feb group was similar with that in Ben group (22.85% vs. 33.94%). CONCLUSION: Overall, febuxostat 20 mg daily and benzbromarone 25 mg daily reduced sUA, and gout patients with sUA level < 540 µmol/L or Ccr ≤ 110 mL min-1 1.73 m-2 at baseline had better chance to achieve target uric acid levels. The current study suggests sUA level and renal function are key factors to consider when recommending low doses of febuxostat and benzbromarone to gout patients. TRIAL REGISTRATION: Registered with ChiCTR, No. ChiCTR1800019352 (retrospectively registered).

Calcimimetic R568 reduced the blood pressure and improved aortic remodeling in spontaneously hypertensive rats by inhibiting local renin-angiotensin system activity.

Hypertension is a cardiovascular disease that seriously affects human health. Activation of the calcium-sensing receptor (CaSR) inhibits cyclic adenosine monophosphate (cAMP) formation by increasing [Ca2+]i and subsequently inhibiting renin release. The renin-angiotensin system (RAS) plays an important role in the development of essential hypertension (EH). The purpose of this study was to determine the effects of NPSR568 (R568)-activated CaSR on blood pressure (BP), proliferation, and remodeling of vascular smooth muscle cells, and the activity of the RAS in spontaneously hypertensive rats (SHRs). In this study, we treated SHR and Wistar-Kyoto rats with R568 for 8 weeks. The tail-cuff method was used to assess rat BP weekly. Morphological changes in the thoracic aorta were evaluated with hematoxylin-eosin and Masson staining. Western blotting and immunohistochemistry were used to detect the expression of RAS-related proteins and proliferative remodeling proteins in the thoracic aorta. An enzyme-linked immunosorbent assay was used to detect the content of cAMP, the RAS, and the CaSR in plasma and the thoracic aorta. Finally, we found that treatment with R568 for 8 weeks reduced the BP and inhibited arterial vascular proliferation remodeling in SHRs. R568 administration significantly suppressed the activity of local RAS in the thoracic aortas of SHRs. Moreover, R568 treatment reversed the low expression of CaSR in SHRs. R568 may serve as an effective strategy against EH.