INTRODUCTION: Hydroxychloroquine (HCQ), originally an antimalarial drug, is currently used to treat multiple disorders, especially rheumatic diseases. Given its good efficacy and safety, HCQ is widely administered in pregnant patients. However, the safety profile of HCQ during pregnancy remains controversial due to limited research. In addition, HCQ has been reported to reduce preeclampsia in patients with systemic lupus erythematosus (SLE) and could potentially alleviate the symptom of preeclampsia. However, the clinical profile and molecular mechanism of HCQ in preeclampsia is yet to be fully understood. METHOD: We reviewed the literature on HCQ treatment in pregnancy with rheumatic diseases and preeclamp-sia in PubMed and Web of Science. We also discussed the safety of long-term therapy with HCQ during pregnancy. RESULTS: HCQ mainly modulates autoimmune response through inhibition of lysosomal function, toll-like receptor (TLR) signalling, nicotinamide adenine dinucleotide phosphate-mediated oxidative stress and autophagy. Benefits of HCQ in treating rheumatic diseases, including antiphospholipid syndrome, rheumatoid arthritis and Sjogren's syndrome during pregnancy, has been demonstrated in clinics. In particular, multiple clinical guidelines recommend HCQ as an indispensable therapeutic drug for pregnant patients with SLE. Additionally, it may potentially function in preeclampsia to improve clinical symptoms. CONCLUSION HCQ is effectively used for rheumatic diseases during pregnancy. The benefits of HCQ treatment in rheumatic diseases outweigh the risk of adverse reactions it induces in pregnant women.
Humans ; Hydroxychloroquine/pharmacology* ; Pregnancy ; Female ; Antirheumatic Agents/pharmacology* ; Rheumatic Diseases/drug therapy* ; Pregnancy Complications/drug therapy* ; Pre-Eclampsia/prevention & control* ; Lupus Erythematosus, Systemic/drug therapy* ; Arthritis, Rheumatoid/drug therapy* ; Antiphospholipid Syndrome/drug therapy* ; Sjogren's Syndrome/drug therapy*

Objective To explore the mechanism of Nuanxinkang Powder(aka.NXK,composed of Ginseng Radix et Rhizoma Rubra and Ilex Pubescens Radix)on improving ventricular remodeling in post-infarction mice based on the"metabolic-inflammatory"network regulating macrophage polarization.Methods ①Thirty C57BL/6J male mice were randomly divided into three groups:sham-operation group,model group,and NXK group(1.65 g·kg-1),with 10 mice in each group;the mouse model of myocardial infarction was replicated using left anterior descending coronary artery ligation;and the drug was administered by gavage once a day for 4 consecutive weeks.Masson staining was used to detect collagen deposition in myocardial tissue;ultrasound was used to detect cardiac function in mice:left ventricular ejection fraction(LVEF),left ventricular anterior wall thickness at end-systole(LVAWS)and left ventricular anterior wall thickness at end-diastole(LVAWD);flow cytometry was used to detect distribution of cardiac macrophages in mice;qPCR was used to detect mRNA expressions of lactate dehydrogenase A(LDHA),carnitine palmitoyltransferase 1(CPT-1),glucose transport protein 4(GLUT4),isocitrate dehydrogenase(IDH),and succinate dehydrogenase(SDHa)in heart tissue.②NXK was given 1.15 g·kg-1 NXK suspension to rats by gavage twice a day for 5 consecutive days to prepare NXK-containing serum.Lipopolysaccharide(LPS)-induced RAW 264.7 cells were used to construct a pro-inflammatory macrophage model.The cells were grouped into the following groups:blank serum control group(medium containing 5%blank serum+5%fetal bovine serum),NXK drug-containing serum group(medium containing 5%NXK drug-containing serum+5%fetal bovine serum),lipopolysaccharide group(medium containing 5%blank serum+5%fetal bovine serum+200 μg·mL-1 lipopolysaccharide),NXK drug-containing serum+ lipopolysaccharide group(medium containing 5%NXK drug-containing serum+5%fetal bovine serum+200 μ g·mL-1 lipopolysaccharide),all the groups were intervened for 16 hours.Glycolysis stress test was used to detect the level of glycolysis in RAW 264.7 cells;qPCR was used to detect the mRNA expression of mitochondrial pyruvate carrier(MPC1)in RAW 264.7 cells;and MitoSox Red fluorescent staining was used to detect the level of oxidative stress damage in mitochondria of RAW 264.7 cells.Results ①Compared with the sham-operation group,the blue-stained area of cardiac collagen fibres in mice of the model group was significantly increased,accompanied by thinning of the ventricular wall and enlargement of the left ventricular cavity;cardiac function indexes,such as LVEF,LVAWS,LVAWD,etc.,were all significantly reduced(P＜0.01,P＜0.001);the mRNA expressions of LDHA and CPT-1 were significantly up-regulated in the cardiac tissues of mice(P＜0.05),and the mRNA expressions of GLUT4,IDH and SDHa were significantly down-regulated(P＜0.05,P＜0.01),and CD86 staining positive cell was significantly increased(P＜0.001).Compared with the model group,mice in the NXK group showed a significant decrease in cardiac collagen fiber deposition and an increase in the thickness of the ventricular wall;cardiac function indexes such as LVEF,LVAWS and LVAWD were significantly increased(P＜0.05,P＜0.01,P＜0.001);and the mRNA expressions of LDHA and CPT-1 in the cardiac tissues of the mice were significantly down-regulated(P＜0.01,P＜0.001),mRNA expressions of GLUT4,SDHa and IDH were significantly up-regulated(P＜0.01),and the number of CD86 positive cells was significantly reduced(P＜0.001).②Compared with the blank serum control group,the cytosolic glycolysis level and ROS level of macrophages in the NXK serum-containing group did not change significantly(P＞0.05),whereas the glycolysis level and ROS level of macrophages in the lipopolysaccharide group were significantly increased(P＜0.01),and the mRNA expression of MPC1 was significantly down-regulated(P＜0.001).Compared with the lipopolysaccharide group,the macrophage glycolysis level and ROS level were significantly reduced in the NXK serum-containing + lipopolysaccharide group(P＜0.05,P＜0.01),and mRNA expression of MPC1 was significantly up-regulated(P＜0.001).Conclusion NXK can reduce myocardial fibrosis and ventricular remodeling after myocardial infarction and improve cardiac function in mice,and its mechanism may be related to the down-regulation of mRNA expression of LDHA in cardiac tissues,the up-regulation of mRNA expression of GLUT4,the improvement of cardiac glucose uptake after myocardial infarction,the inhibition of pro-inflammatory macrophage glycolysis,the increase in the expressions of SDHa and IDH to alleviate the accumulation of succinate and citrate,and the reduction of reactive oxygen species(ROS)generation,thereby reducing pro-inflammatory macrophage hyperpolarisation.

Objective:To explore the relationship between the hypertensive snowbirds′ length of migratory stay and their blood pressure control and blood pressure levels.Methods:This study was a cross-sectional study. A population of snowbirds with hypertension was recruited between October and November 2022, and a structured questionnaire was used to collect their self-measured blood pressure and length of stay in Hainan Province. The blood pressure control status is determined based on self-measured blood pressure. According to the self-measured blood pressure to determine whether the blood pressure was well controlled. The associations between snowbirds′ length of stay and their blood pressure control as well as their self-measured blood pressure were analyzed using restricted cubic splines.Results:A total of 362 research subjects were included, 169(46.7%) of whom were male, and their age was (69.7±7.0) years old. The participants′ self-measured systolic blood pressure and diastolic blood pressure were (129.1±16.2) mmHg (1 mmHg=0.133 kPa) and (78.9±10.1) mmHg, respectively. Overall, 174 (48.1%) participants attained adequate blood pressure control. The median length of stay in Wuzhishan City was 7(6, 7) months. There was an inverted U-shaped association between snowbirds′ length of stay and blood pressure control (overall: P=0.023; nonlinearity: P=0.014), where participants with a length of stay of 7 months had the highest rate of blood pressure control. There is a U-shaped curve relationship between length of stay and systolic blood pressure (overall: P=0.001; nonlinearity: P=0.033), and a linear negative correlation with diastolic blood pressure ( β=-1.19, P=0.003). Conclusions:Compared with hypertensive snowbirds with too long or too short lengths of stay, snowbirds who stayed in Wuzhishan City for seven months have better blood pressure control, and systolic blood pressure is also lower.

Objectives:To observe the effect of surgical reduction and posterior lumbar interbody fusion(PLIF)in treating grade n-Ⅲ L5 isthmic spondylolisthesis(IS)with completely collapsed disc space.Methods:The imaging and clinical data of 49 patients with grade n-Ⅲ L5 IS with completely collapsed disc space treated with surgical reduction and PLIF were reviewed.There were 22 males and 27 females,aged 58.0±9.8 years old,with a follow-up period of 31.2±6.9 months.The operational complications were recorded,and low back and leg pain visual analog scale(VAS)score,Oswestry disability index(ODI)preoperatively,1 month and 2 years postoperatively were recorded and compared.The radiographic outcomes,including slippage percentage,pelvic incidence(PI),pelvic tilt(PT),sacral slope(SS),lumbar lordosis(LL),L1-L5 lordosis(L1-5L)and L5-S1 lordosis(L5-S1 L)were measured on standing lateral spinal X-rays preoperatively,1 month and 2 years postoperatively.Before operation and at 2 years after operation the balance conditions of pelvis were evaluated according to Hresko line Y=(0.844835xX)+25.021.With SS as the Y-axis and PT as the X-axis,each case corresponded to a scatter point,and 49 cases constituted the scatter plot.When the scatter point was above the Hresko line,the corresponding case had a balanced pelvis,and when it was be-low the Hresko line,the corresponding case had an unbalanced pelvis.Results:The operation went smoothly in all the patients.Four patients experienced temporary leg pain after surgery,which improved significantly after symptomatic treatment.One patient experienced sacral screw fracture 18 months after surgery,and CT scan showed bone fusion in the L5/S1 segment.And the internal fixation was removed,and there was no sig-nificant low back or leg pain observed during the 3-month follow-up after removal of internal fixation.The VAS score and ODI at 1 month and 2 years after operation reduced significantly compared with those values before operation(P＜0.05).No significant difference was observed between the preoperative and postoperative PIs(P＞0.05).SS increased from 41.6°±4.1° before surgery to 43.7°±4.5° 2 years after surgery(P＜0.05),LL in-creased from 45.1°±9.8° before surgery to 52.2°±7.8° 2 years after surgery(P＜0.05),and L5-S1 L increased from 8.7°±2.6° before surgery to 21.8°±4.3° 2 years after surgery(P＜0.05).SP decreased from 54.3°±8.4° pre-operatively to 9.4°±3.1° 2 years postoperatively(P＜0.05),PT decreased from 18.3°±3.7° preoperatively to 16.7°±4.0° 2 years postoperatively(P＜0.05);L1-5 L decreased from 36.5°±8.3° before surgery to 31.4°±6.7° 2 years after surgery(P＜0.05).There were 31 cases with balanced pelvis and 18 cases with imbalanced pelvis before operation,while there were 42 cases with balanced pelvis and 7 cases with imbalanced pelvis after operation,and the difference was statistically significant(P＜0.05).Conclusions:In treating patients of grade Ⅱ-Ⅲ L5 IS with collapsed disc space,surgical reduction and PLIF can improve the imbalance conditions of pelvis,which can reduce spino-pelvic compensation and achieve satisfactory clinical results.

Objective This study was performed to establish and compare guinea pig models of tuberculosis using intranasal and aerosol infection routes at different doses.The overall goal was to provide a foundation for establishing a standardized guinea pig model of tuberculosis for the study of respiratory tract infection.Methods Twenty-four female guinea pigs were randomly divided into six groups of four guinea pigs each.They were then infected with two doses of Mycobacterium tuberculosis through either the aerosol route(groups A,B,and C)or intranasal route(groups D,E,and F).Aerosol infection groups consist of 3 groups:group A(Aerosol control group,uninfected control group),group B(Aerosol low-dose group,5×102 CFU),and group C(Aerosol high-dose group,5×103 CFU)Intranasal infection groups also consist of 3 groups:group D(Intranasal control group,uninfected control group),group E(Intranasal low-dose group,1×104 CFU),and group F(Intranasal high-dose group,5×104 CFU).The clinical manifestations of the guinea pigs were observed after infection.All guinea pigs were euthanized on day 14.Lung,spleen,and liver tissues were obtained for gross examination and histopathological analysis using hematoxylin-eosin staining to identify characteristic lesions associated with tuberculosis.Acid-fast staining was performed on in situ tissues and organs followed by bacterial culture to analyze the bacterial load.Results The guinea pigs in four infection groups(B,C,E,and F)exhibited macroscopic tuberculosis lesions in the lung,spleen,and liver.Histopathological examination revealed the presence of tuberculous granuloma lesions.Acid-fast staining and bacterial load analysis demonstrated that the bacteria were primarily localized in the lung tissue of aerosol-infected groups B and C,with a few also present in the spleen and liver,and the bacterial load was 104～105 CFU/mL.In intranasal infection groups E and F,bacteria were found in the lung,spleen,and liver with a similar bacterial load of 104～105 CFU/mL.There was no significant difference in lesion severity or bacterial load among groups B,C,E,and F;however,groups B,C,and F showed low standard deviations for both pathology and etiology.Conclusions A guinea pig model of acute tuberculosis was successfully established using two doses administered through distinct routes of infection.Pathological examination and pathogenic analysis demonstrated that an aerosol dose of 5×102 CFU of Mtb effectively established a homogeneous model of acute tuberculosis with good consistency among the animals.Additionally,intranasal infection with 5×104 CFU of Mtb produced a relatively uniform model of tuberculosis.Notably,however,aerosol infection at 5×102 CFU progressed to an acute tuberculosis model more rapidly than intranasal infection at 5×104 CFU.

In the course of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infec-tion,to verify whether ursodeoxycholic acid(UDCA)can reduce angiotensin-converting enzyme 2(ACE2)receptor in BALB/c mice and reduce the risk of infection.UDCA was administered by in-tragastric administration to BALB/c mice for 7 d.During the treatment,the turbinate bones and lungs of mice were taken every day,and the changes of ACE2 content in the turbinate bones and lungs of mice were detected by ELISA.In addition,after 1,4 and 7 d of intragastric prophylaxis,BALB/c mice were infected with SARS-CoV-2 C57MA14 mouse adapted strain and SARS-CoV-2 Omicron DY1.1,respectively,after nasal inoculation,and viral load was detected on the turnings and lungs of mice 3 d after challenge to evaluate the preventive effect.In addition,UDCA was used to treat BALB/c mice infected with SARS-CoV-2 C57MA14 mouse adapted strain after nasal drops by gavage for 3 d,and the viral load of the mouse turbinate and lung was detected to evaluate the therapeutic effect.UDCA can decrease ACE2 content in turbinate and lung of BALB/c mice.How-ever,after 1,4 and 7 d of UDCA intragastric administration,there was no statistical difference in viral load in turbinate and lung of BALB/c mice between the prevention group and the virus con-trol group.There was no significant difference in the viral load of the turbinate and lung between the UDCA treatment group and the viral control group.UDCA could reduce the ACE2 content in the turnings and lungs of aged BALB/c mice,but the daily dose and duration of UDCA treatment had no significant effect on the mice infected with SARS-CoV-2 C57MA14 mouse adapted strain and SARS-CoV-2 Omicron DY1.1.

Cadmium is a non-essential,non-degradable heavy metal element,the accumulation of cadmium can cause kidney damage.The purpose of this study was to reveal the ferroptosis mecha-nism induced by cadmium exposure in porcine kidney PK-15 cells.First of all,cell viability of gradi-ent concentration of cadmium chloride(CdCl2)on PK-15 cells was detected by CCK-8 method to screen suitable work concentration of CdCl2.Secondly,PK-15 cells were treated with 10 μmol/L CdCl2 for 3,6 and 12 h.The contents of lactate dehydrogenase(LDH)malondialdehyde(MDA)were detected by colorimetry,the expression of ferroptosis related protein were detected by West-ern blot,and the content of ferrous ion(Fe2+)was detected by fluorescence probe.Finally,PK-15 cells were pretreated with 10 μmol/L HO-1 inhibitor zinc protoporphyrin(ZnPP)for 6 h,and then treated with 10 μmol/L CdCl2 for 12 h.The morphology of PK-15 cells was observed by phase contrast microscope and the expression of ferroptosis related proteins was detected by West-ern blot.The results showed that CdCl2 treatment caused a significant decrease in cell viability.The levels of LDH,MDA and Fe2+,the protein levels of Nrf2,HO-1 and ALOX5,and the expression level of FTH1 protein were significantly decreased in CdCl2 treatment cells(P＜0.01).ZnPP could significantly improve the ferroptosis of PK-15 cells induced by CdCl2 treatment.Compared with CdCl2 treatment cells,the cell morphology was significantly improved,the protein levels of Nrf2,HO-1 and ALOX5 protein were significantly decreased,and the protein levels of FTH1 protein were significantly increased in ZnPP pretreatment group(P＜0.01).The results showed that cad-mium induced iron overload and lipid peroxidation,which result in ferroptosis in PK-15 cells through Nrf2/HO-1 pathway.

Porcine kidney cell line(PK-15)with HO-1 gene knockout was constructed by CRISPR/Cas9 system to provide experimental materials for exploring the role and molecular mechanism of HO-1 in cadmium-induced ferroptosis in PK-15 cells.Three sgRNA targeting HO-1 gene were de-signed,synthesized and ligated to lentiviral vector Lenti CRISPRv2.The constructed lentiviral plas-mid was transfected into human embryonic cells(HEK293FT)to obtain recombinant lentivirus,which was used to infect PK-15 cells.The monoclonal cell line with HO-1 knockout was obtained by puromycin screening and limited dilution method.The knockout effect was analyzed by sequencing and Western blot detection.The HO-1 gene knockout cells were treated with 10 μmol/L cadmium chloride(CdCl2).The cell viability was detected by CCK-8 method,the cell morpholo-gy was observed by phase contrast microscope,and the content of ferrous ion(Fe2+)was detected by fluorescence probe.The results showed that sgRNA2 possessed the highest editing efficiency.The base insertion or deletion of HO-1 gene and the frameshift of the target gene occurred in all five knockout cells.Western blot results showed that no expression of HO-1 protein was detected,indicating that the PK-15 cell line with HO-1 gene knockout was successfully constructed.After CdCl2 treatment,compared with the control cells,the cell viability was significantly increased and the Fe2+content was significantly decreased in PK-15 cells with HO-1 gene deletion,indicating that HO-1 gene knockout could significantly alleviate the abnormal iron metabolism caused by cadmium treatment.In conclusion,this study successfully constructed a PK-15 cell line knocking out HO-1 gene by using CRISPR/Cas9 gene editing technique,and confirmed that HO-1 plays an important role in iron metabolism abnormality in PK-15 cells induced by cadmium treatment,which lays a foundation for further study on the regulatory mechanism of HO-1 in ferroptosis in PK-15 cells induced by cadmium exposure.

Objective:To establish a nomogram model for predicting the risk of sepsis in diabetic foot patients, and to provide reference for clinical prevention and treatment.Methods:The clinical data of 430 patients with diabetic foot who were hospitalized in Chu Hsien-I Memorial Hospital of Tianjin Medical University from January 2022 to March 2023 were reviewed and collected, including age, gender, past medical history, smoking and drinking history, family history, diabetes course, Texas grade of diabetic foot and laboratory indicators within 24 hours after admission. Patients were divided into sepsis group and non-sepsis group according to the presence or absence of sepsis during hospitalization. The differences in clinical data between the two groups were compared. Multivariate Logistic regression analysis was used to screen the influencing factors of sepsis in patients with diabetic foot during hospitalization, and a nomogram predictive model was established. The performance of the prediction model was evaluated by receiver operator characteristic curve (ROC curve), calibration curve and decision curve analysis (DCA). Internal validation was performed by using Bootstrap method.Results:A total of 430 patients were enrolled, among which 90 patients developed sepsis during hospitalization and 340 patients did not. There were statistically significant differences in diabetes course, Texas grade of diabetic foot, white blood cell count (WBC), neutrophil count (NEU), lymphocyte count (LYM), neutrophil to lymphocyte ratio (NLR), hemoglobin (Hb), albumin (Alb), glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and blood urea nitrogen (BUN) between the two groups. Multivariate Logistic regression analysis showed that diabetes course [odds ratio ( OR) = 2.774, 95% confidence interval (95% CI) was 1.053-7.308, P = 0.039], Texas grade of diabetic foot ( OR = 2.312, 95% CI was 1.014-5.273, P = 0.046), WBC ( OR = 1.160, 95% CI was 1.042-1.291, P = 0.007), HbA1c ( OR = 1.510, 95% CI was 1.278-1.784, P < 0.001), CRP ( OR = 1.007, 95% CI was 1.000-1.014, P = 0.036) were independent risk factors for sepsis in patients with diabetic foot during hospitalization, while Alb was a protective factor ( OR = 0.885, 95% CI was 0.805-0.972, P = 0.011). A nomogram predictive model was constructed based on the above 6 indicators. The ROC curve showed that the area under ROC curve (AUC) of the nomogram predictive model for identifying the sepsis patients was 0.919 (95% CI was 0.889-0.948). The AUC of the nomogram predictive model after internal verification was 0.918 (95% CI was 0.887-0.946). Hosmer-Lemeshow test showed χ2 = 2.978, P = 0.936, indicating that the calibration degree of the predictive model was good. Calibration curve showed that the predicted probability of sepsis was in good agreement with the actual probability. DCA curve showed that the nomogram predictive model had good clinical usefulness. Conclusion:The nomogram predictive model based on the risk factors of diabetes course, Texas grade of diabetic foot, WBC, HbA1c, CRP and Alb has good predictive value for the occurrence of sepsis in patients with diabetic foot during hospitalization, which is helpful for clinical screening of the possibility of diabetic foot patients progressing to sepsis, and timely personalized intervention for different patients.

Objective To investigate the mechanism of Guizhi Tongluo Tablets(GZTLP)on improving atherosclerosis in APOE knockout mice by regulating neutrophil extracellular trapping nets(NETs).Methods After modeling,24 APOE knockout mice aged 8 weeks were randomly divided into 4 groups:GZTLP high-dose group,low-dose group,model control group and normal control group,with 6 mice in each group.GZTLP was given 1.87 mg·g-1 and 0.47 mg·g-1 intragastric administration in high-dose group and low-dose group,respectively.The normal control group and model control group were given 0.9%sodium chloride solution intragastric administration for 6 weeks,and the lipid plaque deposition in aorta was observed by gross oil red O staining.Lipid deposition in aortic root was observed by oil red O staining.The pathological changes of lipid plaques in aortic root were observed by HE staining.The levels of interleukin-1β(IL-1β)and tumor necrosis factor α(TNF-α)in peripheral blood of mice were detected by enzyme-linked immunosorbent assay(ELISA).The expression of lymphocyte antigen 6G(Ly6G),myeloperoxidase(MPO)and citrulinated histone(Cit-H3)in plaques of the aortic arch and the colocalization of Ly6G,MPO and Cit-H3 were detected by immunofluorescence assay.Results Compared with the normal control group,the aorta of mice in the model control group showed serious lipid plaque deposition,morphological damage,and a large number of inflammatory cells infiltration,the contents of serum inflammatory factors IL-1β and TNF-α were increased,and the protein expressions of Ly6G,Cit-H3 and MPO were significantly increased.Compared with model control group,GZTLP group reduced the amount of lipid plaque deposition in aorta,the arrangement of aortic cells was more regular,the inflammatory cell infiltration was improved,and the contents of serum inflammatory factors IL-1β and TNF-α were significantly decreased(P<0.05).The colocalization and the protein expression of Ly6G,MPO and Cit-H3 were significantly decreased in aortic tissues(P<0.01).Conclusions GZTLP can improve atherosclerosis,and its mechanism may be related to the inhibition of neutrophil extracellular trapping nets.