Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

BACKGROUND:The extracellular-regulated protein kinase 5(ERK5)signaling protein is essential for the survival of organisms,and resveratrol can promote osteoblast proliferation through various pathways.However,whether resveratrol can regulate osteoblast function through the ERK5 signaling protein needs further verification. OBJECTIVE:To explore the regulatory effect of ERK5 on the proliferation of MC3T3-E1 cells and related secreted proteins,and to further verify whether resveratrol can complete the above process by activating ERK5. METHODS:Mouse MC3T3-E1 preosteoblasts were treated with complete culture medium,XMD8-92(an ERK5 inhibitor),epidermal growth factor(an ERK5 activator),resveratrol alone,XMD8-92+EGF,and resveratrol+XMD8-92,respectively.Western blot assay was used to detect the expression of ERK5 and p-ERK5 proteins,proliferation-related proteins Cyclin D1,CDK4 and PCNA,and osteoblast-secreted proteins osteoprotegerin and receptor activator of nuclear factor-κB ligand in MC3T3-E1 cells of each group.The fluorescence intensity of ERK5,osteoprotegerin and receptor activator of nuclear factor-κB ligand in each group was detected by cell immunofluorescence staining,and cell proliferation was detected by EdU staining,respectively.The appropriate concentration and time of resveratrol intervention in MC3T3-E1 cells were determined by cell morphology observation and cell counting kit-8 assay. RESULTS AND CONCLUSION:The activation of ERK5 signaling protein could effectively promote the proliferation of MC3T3-E1 cells,up-regulate the osteoprotegerin/receptor activator of nuclear factor-κB ligand ratio.The appropriate concentration and time for resveratrol intervention in MC3T3-E1 cells was 5 μmol/L and 24 hours,respectively.Resveratrol could activate ERK5 signaling protein,thereby promoting osteoblast proliferation and up-regulating the osteoprotegerin/RANKL ratio.All these results indicate that resveratrol can promote the proliferation of MC3T3-E1 cells and up-regulate the osteoprotegerin/RANKL ratio by activating the ERK5 signaling protein.

Currently, clinically used drugs for the treatment of gout inflammation, such as colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids, can only relieve the pain of joint inflammation and have severe hepatorenal toxicity and multiple organ adverse reactions. The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a key complex that induces the onset of gout inflammation and has become a crucial target in the development of anti-gout drugs. This article reviews the research progress of anti-gout small molecules targeting the NLRP3 inflammasome and their bioactivity evaluation methods in the past five years, in order to provide information for the development of specific drugs for the treatment of gout inflammation.

BACKGROUND:Fluid shear stress plays an important role in osteoblast proliferation and apoptosis.However,whether Caveolin-1 is involved in the process of fluid shear stress-induced proliferation and apoptosis in osteoblasts is unknown. OBJECTIVE:To explore the role of Caveolin-1 in fluid shear stress-regulated osteoblast proliferation and apoptosis. METHODS:The MC3T3-E1 osteoblasts in good growth status were selected and loaded with fluid shear stress at an intensity of 1.2 Pa for different times(0,30,60,90 minutes).The expression of Caveolin-1 protein was observed and conditions with a time of 60 minutes were screened for the experiment.MC3T3-E1 cells were divided into control group,fluid shear stress group,fluid shear stress+pcDNA 3.1 group(control),fluid shear stress+pcDNA Cav-1 group(plasmid overexpression),and intervened with fluid shear stress and overexpression of Cav-1,respectively.The expression of molecules related to proliferation and apoptosis in MC3T3-E1 cells was detected by qRT-PCR and western blot.In addition,the proliferative activity of MC3T3-E1 cells was detected by cell counting kit-8 and EdU assay;and cell apoptosis was detected by Hoechst 33258 and flow cytometry. RESULTS AND CONCLUSION:The expression of Caveolin-1 in MC3T3-E1 cells was significantly down-regulated after loading fluid shear stress,and the expression level was lowest after 60 minutes.Overexpression of Caveolin-1 attenuated the proliferation-promoting and apoptosis-suppressing effects of fluid shear stress in MC3T3-E1 cells.In conclusion,Caveolin-1 has a vital role in fluid shear stress-regulated osteoblast proliferation and apoptosis,which may offer a potential therapeutic strategy for osteoporosis.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

Objective To evaluate the clinical efficacy and safety of desonide cream in combination with cetirizine hydrochloride for the treatment of skin itching in patients with uremia undergoing hemodialysis.Methods Patients with skin itching associated with uremia and hemodialysis were divided into control group and treatment group by random number table.The control group received oral cetirizine hydrochloride,10 mg per dose,once daily for 8 weeks.Patients in the treatment group were treated with desonide cream appropriate amout for external use on the basis of the treatment in the control group,once in the morning and once in the evening every day,and smeared on the pruritus of the patient's skin for 8 weeks.The clinical efficacy of the two groups were compared,and the pruritus symptoms,sleep quality and safety evaluation of the two groups were compared.Results During the trial,a total of 36 cases dropped out,with 52 cases ultimately included in the treatment and control groups,respectively.Following treatment,the total effective rates in the treatment and control groups were 82.69％(43 cases/52 cases)and 63.46％(33 cases/52 cases),respectively,showing statistically significant difference(P＜0.05).After treatment,the visual analog scale(VAS)scores for the treatment and control groups were(2.87±1.29)and(3.62±1.76)points,respectively;the modified Dou's analogue grading(Dou's VAG)were(18.24±3.23)and(20.13±4.59)points,respectively;the Pittsburgh sleep quality index(PSQI)scores were(9.57±1.72)and(10.34±2.01)points,respectively.Compared with the control group,the above indexes in treatment group were statistically significant(all P＜0.05).The adverse drug reactions of the treatment group were dizziness,nausea and vomiting,and the adverse drug reactions of the control group were dizziness,nausea and vomiting.The total incidence of adverse drug reactions in the treatment group and the control group was 9.62％(5 cases/52 cases)and 7.69％(4 cases/52 cases),respectively,and the difference was no statistically significant(P＞0.05).Conclusion The combination of desonide cream and cetirizine hydrochloride has better efficacy and safety than cetirizine hydrochloride alone in treating the itching symptoms of uremic hemodialysis patients.

Objective To investigate the plasma level of interleukin-31(IL-31)in patients with pulmonary arterial hypertension(PAH)and its clinical relevance.Methods The patients who were diagnosed as PAH in Zhongshan Hospital,Fudan University from January 1,2021 to December 30,2023(PAH group)and the healthy people in the same period(control group)were selected.The clinical data and follow-up records were collected.Plasma levels of IL-31,IL-1β,IL-6,IL-10,IL-12p70,monocyte chemoattractant protein-1(MCP-1),tumor necrosis factor-α(TNF-α)and transforming growth factor-β1(TGF-β1)were detected by enzyme-linked immunosorbent assay(ELISA).Pearson correlation test was used to evaluate the correlations between IL-31 and right cardiac catheterization parameters,echocardiography parameters and blood indices in patients with PAH.Cox proportional hazard model was used to analyze the prognostic factors of patients in PAH group.Results A total of 50 patients with PAH and 22 healthy controls were included.There was no significant difference in age,gender,body mass index and left ventricular ejection fraction between the two groups.Compared with the control group,the plasma level of IL-31 in the PAH group was significantly higher(168.82[149.14,177.26]pg/mL vs 152.76[145.58,159.41]pg/mL,P=0.001).Pearson correlation test showed that the plasma level of IL-31 in PAH patient was positively correlated with mean pulmonary artery pressure(r=0.652,P＜0.001)and pulmonary vascular resistance(r=0.651,P＜0.001),but was negatively correlated with tricuspid annular plane systolic excursion(r=-0.496,P＜0.001).Cox proportional hazard model showed that higher plasma level of IL-31 was an independent predictor of readmission for heart failure/all-cause mortality in patients with PAH(HR=1.130,95％CI 1.052-1.214,P=0.001).Conclusions Plasma level of IL-31 may be significantly increased in patients with PAH and be positively correlated with the severity of PAH,and elevated level of IL-31 is predictive of poor prognosis in PAH patients.

Objective To compare regional pulmonary ventilation and perfusion and ventilation/perfusion(V/Q)matching in different body positions using electrical impedance tomography(EIT).Methods Ten healthy experimental pigs were selected to collect their EIT lung ventilation and perfusion data in supine,prone,left lateral and right lateral positions.The EIT data underwent analysis and image reconstruction using MATLAB R2022b and EIDORS v3.9.The effective regions with ventilation and perfusion were determined and the V/Q matching regions were computed with the maximum pixel value 20％as the threshold.Comparisons were carried out over the V/Q matching indexes including V/Q match％,dead space％and shunt％and ventilation and perfusion distribution in regions of interest(ROIs)including ROI1,ROI2,ROI3 and ROI4 in different body positions.Results The differences in V/Q match％,dead space％and shunt％of the experimental animals in varied positions were not statistically significant(P＞0.05).The regional distribution of pulmonary ventilation and perfusion changed in different positions,and the regional distributions differed in ROIl,ROI2 and ROI3 for ventilation(P＜0.05)and in ROI1 and ROI2 for perfusion(P＜0.05).The ventilation and perfusion regions were distributed consistently with the gravity-dependent areas in supine and prone positions whereas conversely in the right and left lateral positions.Conclusion The V/Q matching indexes of one subject have high test consistency in different body positions;gravity-dependent areas varied with the changes of the body positions,which affected the distribution of pulmonary ventilation and perfusion regions;EIT can be used for measuring the changed pulmonary ventilation and perfusion due to different positions and determining the influences of position changes on pulmonary ventilation and perfusion and V/Q matching.[Chinese Medical Equipment Journal,2024,45(5):1-7]

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Patient 1,a 12-day-old female infant,presented with fever,cough,dyspnea,and elevated infection markers,requiring respiratory support.Metagenomic next-generation sequencing(mNGS)of blood and bronchoalveolar lavage fluid revealed Legionella pneumophila(LP),leading to diagnoses of LP pneumonia and LP sepsis.The patient was treated with erythromycin for 15 days and azithromycin for 5 days,resulting in recovery and discharge.Patient 2,an 11-day-old female infant,presented with dyspnea,fever,elevated infection markers,and multiple organ dysfunction,requiring mechanical ventilation.mNGS of blood and cerebrospinal fluid indicated LP,leading to diagnoses of LP pneumonia,LP sepsis,and LP intracranial infection.The patient was treated with erythromycin for 19 days and was discharged after recovery.Neonatal LP pneumonia lacks specific clinical symptoms,and azithromycin is the preferred antimicrobial agent.The use of mNGS can provide early and definitive diagnosis for severe neonatal pneumonia of unknown origin.