ObjectiveTo investigate the value of different noninvasive diagnostic models in the diagnosis of esophageal and gastric varices since there is a high risk of esophageal and gastric varices in patients with compensated hepatitis B cirrhosis and significant portal hypertension， and to provide a basis for the early diagnosis of esophageal and gastric varices. MethodsA total of 108 patients with significant portal hypertension due to compensated hepatitis B cirrhosis who attended Guangdong Provincial Hospital of Traditional Chinese Medicine from November 2017 to November 2023 were enrolled， and according to the presence or absence of esophageal and gastric varices under gastroscopy， they were divided into esophageal and gastric varices group （GOV group） and non-esophageal and gastric varices group （NGOV group）. Related data were collected， including age， sex， imaging findings， and laboratory markers. The chi-square test was used for comparison of categorical data between groups； the least significant difference t-test was used for comparison of normally distributed continuous data between groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. The receiver operating characteristic （ROC） curve was plotted to evaluate the diagnostic value of five scoring models， i.e.， fibrosis-4 （FIB-4）， LOK index， LPRI， aspartate aminotransferase-to-platelet ratio index （APRI）， and aspartate aminotransferase/alanine aminotransferase ratio （AAR）. The binary logistic regression method was used to establish a combined model， and the area under the ROC curve （AUC） was compared between the combined model and each scoring model used alone. The Delong test was used to compare the AUC value between any two noninvasive diagnostic models. ResultsThere were 55 patients in the GOV group and 53 patients in the NGOV group. Compared with the NGOV group， the GOV group had a significantly higher age （52.64±1.44 years vs 47.96±1.68 years， t=0.453， P<0.05） and significantly lower levels of alanine aminotransferase ［42.00 （24.00 — 17.00） U/L vs 82.00 （46.00 — 271.00） U/L， Z=-3.065， P<0.05］， aspartate aminotransferase ［44.00 （32.00 — 96.00） U/L vs 62.00 （42.50 — 154.50） U/L，Z=-2.351， P<0.05］， and platelet count ［100.00 （69.00 — 120.00）×10⁹/L vs 119.00 （108.50 — 140.50）×10⁹/L， Z=-3.667， P<0.05］. The ROC curve analysis showed that FIB-4， LOK index， LPRI， and AAR used alone had an accuracy of 0.667， 0.681， 0.730， and 0.639， respectively， in the diagnosis of esophageal and gastric varices （all P<0.05）， and the positive diagnostic rates of GOV were 69.97%， 65.28%， 67.33%， and 58.86%， respectively， with no significant differences in AUC values （all P>0.05）， while APRI used alone had no diagnostic value （P>0.05）. A combined model （LAF） was established based on the binary logistic regression analysis and had an AUC of 0.805 and a positive diagnostic rate of GOV of 75.80%， with a significantly higher AUC than FIB-4， LOK index， LPRI， and AAR used alone （Z=-2.773，-2.479，-2.206， and-2.672， all P<0.05）. ConclusionFIB-4， LOK index， LPRI， and AAR have a similar diagnostic value for esophageal and gastric varices in patients with compensated hepatitis B cirrhosis and significant portal hypertension， and APRI alone has no diagnostic value. The combined model LAF had the best diagnostic efficacy， which provides a certain reference for clinical promotion and application.

OBJECTIVE: To investigate the effect of zedoarondiol on neovascularization of atherosclerotic (AS) plaque by exosomes experiment. METHODS: ApoE^-/- mice were fed with high-fat diet to establish AS model and treated with high- and low-dose (10, 5 mg/kg daily) of zedoarondiol, respectively. After 14 weeks, the expressions of anti-angiogenic protein thrombospondin 1 (THBS-1) and its receptor CD36 in plaques, as well as platelet activation rate and exosome-derived miR-let-7a were detected. Then, zedoarondiol was used to intervene in platelets in vitro, and miR-let-7a was detected in platelet-derived exosomes (Pexo). Finally, human umbilical vein endothelial cells (HUVECs) were transfected with miR-let-7a mimics and treated with Pexo to observe the effect of miR-let-7a in Pexo on tube formation. RESULTS: Animal experiments showed that after treating with zedoarondiol, the neovascularization density in plaques of AS mice was significantly reduced, THBS-1 and CD36 increased, the platelet activation rate was markedly reduced, and the miR-let-7a level in Pexo was reduced (P<0.01). In vitro experiments, the platelet activation rate and miR-let-7a levels in Pexo were significantly reduced after zedoarondiol's intervention. Cell experiments showed that after Pexo's intervention, the tube length increased, and the transfection of miR-let-7a minics further increased the tube length of cells, while reducing the expressions of THBS-1 and CD36. CONCLUSION Zedoarondiol has the effect of inhibiting neovascularization within plaque in AS mice, and its mechanism may be potentially related to inhibiting platelet activation and reducing the Pexo-derived miRNA-let-7a level.
Animals ; MicroRNAs/genetics* ; Exosomes/drug effects* ; Plaque, Atherosclerotic/genetics* ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; Humans ; Blood Platelets/drug effects* ; Apolipoproteins E/deficiency* ; Thrombospondin 1/metabolism* ; CD36 Antigens/metabolism* ; Platelet Activation/drug effects* ; Male ; Mice ; Mice, Inbred C57BL

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

Cadmium/metabolism* ; Kidney ; Cells, Cultured ; Mitochondria ; Metallothionein/metabolism* ; Liver

OBJECTIVE To investigate the effects of sacubitril/valsartan on renal function in patients with primary hypertension. METHODS A retrospective study was conducted among patients with primary hypertension who were admitted to PLA Strategic Support Force Characteristic Medical Center from January 2018 to June 2023. Based on their medication， they were divided into two groups： sacubitril/valsartan group and valsartan group. Propensity score matching was used to match baseline data between the two groups. Patients were treated with antihypertensive drugs based on improving their lifestyle. Sacubitril/valsartan group additionally received oral administration of 200 mg Sacubitril/valsartan tablets once daily， while valsartan group additionally received oral administration of 80 mg Valsartan capsules once daily. The increase amplitude of serum creatinine from baseline， the proportion of patients with elevated serum creatinine ＞30%-50% or ＞50%， and the proportion of patients with hyperkalemia （serum potassium ≥5.5 mmol/L） were compared between two groups at 2 months and 6 months after treatment. The trends of changes in serum creatinine， serum potassium and estimated glomerular filtration rate （eGFR） were compared between the two groups before treatment （at baseline）， 2 months and 6 months after treatment. RESULTS After propensity score matching， there were 62 patients in sacubitril/valsartan group and 61 patients in valsartan group； there were no significant differences in baseline characteristics between the two groups before treatment （P＞0.05）， indicating comparability. After 6 months of treatment， the increase of serum creatinine in the sacubitril/valsartan group was significantly lower than that in the valsartan group （P＝0.003）； the proportion of patients with elevated serum creatinine ＞30%-50% in the sacubitril/valsartan group was significantly lower than that in the valsartan group （P＝0.045）. None of the patients experienced hyperkalemia events after 2 months and 6 months of treatment. Repeated measures analysis of variance showed significantly statistical differences in serum creatinine and eGFR between the two groups within 6 months of treatment （P＜0.001）. Patients taking valsartan experienced a continuous increase in serum creatinine levels and a decrease in eGFR， while patients taking sacubitril/valsartan showed a first increase and then a decrease in serum creatinine levels， and a first decrease and then an increase in eGFR with a prolonged duration of medication. CONCLUSIONS Sacubitril/valsartan can delay or even reverse the decline in renal function levels， and limit the deterioration of renal function in patients with primary hypertension， without increasing the risk of hyperkalemia.

Objective To compare the effects of ginsenosides Rg1 and Rb1 on depression-and anxiety-like behaviors in chronic unpredictable stress-induced rats.Methods Seventy male SPF grade SD rats were tested for sugar and water preference after 5 days of adaptation and divided into seven groups according to their preference index:a control group,model group,fluoxetine hydrochloride group,ginsenoside Rg1 24 mg/kg group,ginsenoside Rg1 48 mg/kg group,ginsenoside Rb1 33 mg/kg group,and ginsenoside Rb1 67 mg/kg group.All rats,except for the control group,were subjected randomly to one or two different stimulating factors every day for a total of 35 days.On the 36th day,behavioral experiments including sugar and water preference,open field,novel environment feeding inhibition,elevated cross maze,and forced swimming experiments were conducted to investigate the anti-depression and anti-anxiety effects of the treatments.Serum and hippocampal levels of interleukin(IL)-1β,IL-6,tumor necrosis factor(TNF)-α and serum corticosterone were measured by enzyme-linked immunosorbent assay.Results Compared with the model group,ginsenoside Rg1 and Rb1 significantly increased sucrose consumption in the sucrose preference test and decreased immobility in the forced swimming test.Ginsenoside Rg1(48 mg/kg)significantly reduced the latency to eat in the novelty-suppressed feeding test,and ginsenoside Rg1(24 and 48 mg/kg)significantly increased the percentage of open arm entries and time in the elevated cross maze test.Serum corticosterone levels were significantly decreased in the ginsenoside Rg1 and Rb1 groups,serum IL-1β and IL-6 levels were significantly decreased in the ginsenoside Rg1(48 mg/kg)group,serum TNF-α and IL-6 levels were significantly decreased in the ginsenoside Rb1(33 mg/kg)group,and IL-1β,IL-6,and TNF-α levels in the hippocampus were significantly decreased in the ginsenoside Rg1(48 mg/kg)and Rb1(67 mg/kg)groups.Conclusions Both ginsenosides can regulate the hypothalamic-pituitary-adrenal axis and inhibit neuroinflammation,improving depression-and anxiety-like behaviors in rats induced by chronic unpredictable stress.Ginsenoside Rg1 has a significantly better anti-anxiety effect than Rb1.

Objective To explore the effect of intestinal nitrates on the growth of Klebsiella pneumoniae and its regulatory mechanisms. Methods K. pneumoniae strains with nitrate reductase narG and narZ single or double gene knockout or with NarXL gene knockout were constructed and observed for both aerobic and anaerobic growth in the presence of KNO3 using an automated bacterial growth analyzer and a spectrophotometer, respectively. The mRNA expressions of narG and narZ in K. pneumoniae in anaerobic cultures in the presence of KNO3 and the effect of the binary regulatory system NarXL on their expresisons were detected using qRT-PCR. Electrophoretic mobility shift assays (EMSA) and MST analysis were performed to explore the specific regulatory mechanisms of NarXL in sensing and utilizing nitrates. Competitive experiments were conducted to examine anaerobic growth advantages of narG and narZ gene knockout strains of K. pneumoniae in the presence of KNO3. Results The presence of KNO3 in anaerobic conditions, but not in aerobic conditions, promoted bacterial growth more effectively in the wild-type K. pneumoniae strain than in the narXL gene knockout strain. In anaerobic conditions, the narXL gene knockout strain showed significantly lowered mRNA expressions of narG and narZ (P<0.0001). EMSA and MST experiments demonstrated that the NarXL regulator could directly bind to narG and narZ promoter regions. The wild-type K. pneumoniae strain in anaerobic cultures showed significantly increased expressions of narG and narZ mRNAs in the presence of KNO3 (P<0.01), and narG gene knockout resulted in significantly attenuated anaerobic growth and competitive growth abilities of K. pneumoniae in the presence of KNO3 (P<0.01). Conclusion The binary regulatory system NarXL of K. pneumoniae can sense changes in intestinal nitrate concentration and directly regulate the expression of nitrate reductase genes narG and narZ to promote bacterial growth.

Objective:To explore the predictive value of blood flow velocity changes in superior mesenteric artery (SMA) monitored by ultrasound on feeding intolerance (FI) of enteral nutrition (EN) in mechanically ventilated ICU patients. Methods:One-hundred and eight mechanically ventilated patients in Intensive Care Department of the Second People's Hospital of Nantong from February 2022 to February 2023 were enrolled. SMA blood flow parameters and enteral nutrition tolerance were monitored on the 1st,3rd,and 7th day (D1,D3,D7) after initiation of EN. Differences in SMA blood flow parameters between tolerant and intolerant group,as well as intolerant subgroups (mild,moderate,and severe) were analyzed. The predictive value of SMA blood flow parameters for FI and the risk factors of FI were also evaluated,and the relationship between SMA blood flow parameters and intestinal barrier function were preliminarily explored . Result:The SMA blood flow velocity parameters,peak systolic velocity (PSV) and end diastolic velocity (EDV),were higher at D1,D3,and D7 in the tolerant groups compared to the intolerant group (all P<0.05). Subgroup analysis showed that as the degree of intolerance increased,PSV gradually decreased. EDV at D1,D3,and D7 also gradually decreased with the increased severity of FI (all P<0.05);The AUC of PSV and EDV predicting FI in D1,D3,and D7 patients were 0.752 (95％ CI:0.660～0.830) and 0.773 (95％ CI:0.682～0.848),0.774 (95％ CI:0.683～0.849) and 0.796 (95％ CI:0.708～0.868),0.743 (95％ CI:0.650～0.822) and 0.713 (95％ CI:0.618～0.796). respectively. PSV,norepinephrine use,and blood phosphorus levels were independent prognostic factors for FI at D3. Patients with FI showed a negative correlation between PSV,EDV,and diamine oxidase (PSV:r=-0.857,P<0.001;EDV:r=-0.795,P<0.001). Conclusion:Changes in blood flow velocity in the superior mesenteric artery by ultrasound monitoring can effectively predict enteral nutrition intolerance in mechanically ventilated patients,it might have potential clinical application values in ICU patients.

AIM To study the protective effects and mechanism of pueraria isoflavones on myocardial injury in ovariectomized rats.METHODS Thirty-six rats were randomly divided into the sham operation group,the model group,the estradiol valerate group(0.1 mg/kg)and the low,medium and high dose pueraria isoflavones groups(55,110,220 mg/kg).In contrast to the rats of the sham operation group having their small pieces of adipose tissue removal around the ovaries,rats of the other groups had their bilateral ovaries excised,followed by the 16-week corresponding oral drug administration 2 weeks later at a once daily frequency for,6 days a week.At the end of the 16th week,the rats had their hemodynamics[systolic pressure(SBP),diastolic pressure(DBP),mean pressure(MBP),left ventricular systolic pressure(LVSP),left ventricular diastolic pressure(LVMP),and the maximum rate of increase and decrease of left ventricular pressure during isovolumic contraction(±dp/dtmax)]detected by PowerLab;their cardiac pathological changes observed by HE staining;their levels of creatine kinase(CK),lactate dehydrogenase(LDH),total cholesterol(TC),triglyceride(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C)and glucose(Glu)in plasma detected by biochemical analyzer;their myocardial level of adenosine triphosphate(ATP)detected by colorimetry;their mRNA expressions of glucose transporter 4(GLUT4),lactate dehydrogenase A(LDHA),carnitine palmitoyl transferase-1(CPT-1α),acyl coenzyme A carboxylase(ACC),liver kinase B1(LKB1),adenylate-activated protein kinase(AMPK)and peroxisome proliferator-activated receptor γ coactivator factor 1α(PGC-1α)detected by RT-qPCR;and their myocardial expressions of energy metabolism related proteins LKB1,p-AMPK/AMPK and PGC-1α detected by Western blot.RESULTS Compared with the model group,the pueraria isoflavones groups displayed decreased levels of SBP,DBP,MBP,LVSP,LVMP(P＜0.05,P＜0.01);increased-dp/dtmax(P＜0.05,P＜0.01);improved myocardial fibrinolysis,gap widening and inflammatory infiltration caused by ovariectomy;decreased activities of LDH and CK(P＜0.05);increased myocardial ATP level(P＜0.05,P＜0.01);decreased levels of TC,TG,LDL-C and Glu(P＜0.05,P＜0.01);increased HDL-C level(P＜0.05,P＜0.01);increased myocardial mRNA expressions of GLUT4,LDHA,CPT-1α,ACC,LKB1,AMPK and PGC-1α(P＜0.05,P＜0.01);and increased protein expressions of myocardial LKB1,p-AMPK/AMPK and PGC-1α(P＜0.05,P＜0.01).CONCLUSION Pueraria isoflavones are protective to myocardial injury in ovariectomized rats,and the mechanism may lie in the improvement of energy metabolism-related myocardial proteins via LKB1/AMPK/PGC-1α signaling pathway.

Objective To explore the effect of intestinal nitrates on the growth of Klebsiella pneumoniae and its regulatory mechanisms. Methods K. pneumoniae strains with nitrate reductase narG and narZ single or double gene knockout or with NarXL gene knockout were constructed and observed for both aerobic and anaerobic growth in the presence of KNO3 using an automated bacterial growth analyzer and a spectrophotometer, respectively. The mRNA expressions of narG and narZ in K. pneumoniae in anaerobic cultures in the presence of KNO3 and the effect of the binary regulatory system NarXL on their expresisons were detected using qRT-PCR. Electrophoretic mobility shift assays (EMSA) and MST analysis were performed to explore the specific regulatory mechanisms of NarXL in sensing and utilizing nitrates. Competitive experiments were conducted to examine anaerobic growth advantages of narG and narZ gene knockout strains of K. pneumoniae in the presence of KNO3. Results The presence of KNO3 in anaerobic conditions, but not in aerobic conditions, promoted bacterial growth more effectively in the wild-type K. pneumoniae strain than in the narXL gene knockout strain. In anaerobic conditions, the narXL gene knockout strain showed significantly lowered mRNA expressions of narG and narZ (P<0.0001). EMSA and MST experiments demonstrated that the NarXL regulator could directly bind to narG and narZ promoter regions. The wild-type K. pneumoniae strain in anaerobic cultures showed significantly increased expressions of narG and narZ mRNAs in the presence of KNO3 (P<0.01), and narG gene knockout resulted in significantly attenuated anaerobic growth and competitive growth abilities of K. pneumoniae in the presence of KNO3 (P<0.01). Conclusion The binary regulatory system NarXL of K. pneumoniae can sense changes in intestinal nitrate concentration and directly regulate the expression of nitrate reductase genes narG and narZ to promote bacterial growth.