OBJECTIVE To evaluate the cost-effectiveness of finerenone combined with standard treatment regimen in the treatment of diabetic nephropathy （DN）. METHODS From the perspective of healthcare service providers， a Markov model was established to simulate the dynamic changes of each stage in DN patients who received finerenone combined with the standard treatment regimen or the standard treatment regimen alone based on the phase Ⅲ clinical trial study of finerenone for DN. Markov model was used to perform the cost-effectiveness of long-term effects and the costs of the two therapies with a simulation cycle of 4 months， a simulation period of 15 years and an annual discount rate of 5%. At the same time， one-way sensitivity analysis and probability sensitivity analysis were performed， and the stability of the results was validated. RESULTS Accumulative cost of the standard treatment regimen was 579 329.54 yuan， and the accumulative utility was 8.052 4 quality-adjusted life year （QALYs）； the accumulative cost of finerenone combined with the standard treatment regimen was 332 520.61 yuan， and the accumulative utility was 8.187 4 QALYs. Finerenone combined with the standard treatment regimen was more cost-effective. The results of one-way sensitivity analysis showed that dialysis status utility value， DN stage 3 utility value and DN stage 4 utility value had a great influence on the incremental cost-effectiveness ratio， but did not affect the robustness of the model. The results of probability sensitivity analysis showed that finerenone combined with the standard treatment regimen was more cost-effective with 100% probability. CONCLUSIONS For DN patients， finerenone combined with the standard treatment regimen is more cost-effective as an absolute advantage option.

BACKGROUND:Wogonin is a flavonoid extracted from the root of Scutellaria baicalensis.Previous studies have shown that baicalein has protective effects against cerebral ischemia-reperfusion injury,and can also reduce blood sugar and complications in diabetic mice,but its role and mechanism in diabetic cerebral infarction remain unclear. OBJECTIVE:To explore the effect of wogonin on nerve injury in rats with diabetic cerebral infarction and its mechanism. METHODS:Sprague-Dawley rats were randomly divided into six groups:control group,model group,low-dose wogonin group,medium-dose wogonin group,high-dose wogonin group,and high-dose wogonin+Ras homolog gene family member A(RhoA)activator group.Except for the control group,the other rats were established with diabetes and cerebral ischemia models using intraperitoneal injection of streptozotocin and middle cerebral artery occlusion.Low,medium-and high-dose wogonin groups were intragastrically given 10,20,40 mg/kg wogonin,respectively;high-dose wogonin+RhoA activator group was intragastrically given 40 mg/kg wogonin and intraperitoneally injected 10 mg/kg lysophosphatidic acid;control group and model group were given the same amount of normal saline once a day for 7 consecutive days.Rats in each group were evaluated for neurological deficits and their blood glucose levels were measured after the last dose.TTC staining was applied to detect the volume of cerebral infarction.Hematoxylin-eosin staining was applied to observe pathological changes in brain tissue.ELISA kit was applied to detect tumor necrosis factor-α,interleukin-6,malondialdehyde,and superoxide dismutase levels in brain tissue.Western blot was applied to detect the protein expression of RhoA and Rho-associated protein kinase(ROCK)2 in brain tissue. RESULTS AND CONCLUSION:Compared with the control group,the neuronal structure of rats in the model group was severely damaged,with cell necrosis and degeneration,the neurological deficit score,blood glucose level,and infarct volume were significantly elevated(P<0.05),the levels of tumor necrosis factor-α,interleukin-6,and malondialdehyde,and the protein expression of RhoA and ROCK2 in brain tissue were significantly increased(P<0.05),and the superoxide dismutase level was decreased(P<0.05).Compared with the model group,the low-,medium-,and high-dose wogonin groups showed improved neuronal damage,reduced cell degeneration and necrosis,a significant reduction in neurological deficit score,blood glucose level,infarct volume,and the levels of tumor necrosis factor-α,interleukin-6,and malondialdehyde,and the protein expression of RhoA and ROCK2 in brain tissue,and an increase in the superoxide dismutase level(P<0.05).Compared with the high-dose wogonin group,the high-dose wogonin+RhoA activator group significantly weakened the improvement in the above indexes of rats with diabetic cerebral infarction(P<0.05).To conclude,wogonin can improve the blood glucose level in rats with diabetic cerebral infarction,reduce cerebral infarction and nerve injury,and its mechanism may be related to the inhibition of RhoA/ROCK signaling pathway.

Energy metabolism reconstruction is the new target of the treatment of heart failure. By combing the researches of Chinese medicinals for energy metabolism reconstruction of heart failure， it was found that Chinese medicinal compound formula and single Chinese medicinal have a certain role in regulating energy metabolism， mainly through three aspects， including the optimization of substrate utilization， improvement of mitochondrial structure， function， and homeostasis， and improvement of mitochondrial energy transport， so as to make the energy metabolism of the cardiomyocyte adjusted in the direction of beneficial to the organism， increasing the supply of energy， and improving the cardiac function.

ObjectiveTo study the effects of applying different microbial fertilizers on the growth and rhizosphere soil environment of Codonopsis pilosula and provide a theoretical basis for ecological cultivation of this medicinal plant. MethodsSeven groups were designed， including CK （no application of microbial fertilizer）， T1 （Trichoderma longibrachiatum fertilizer）， T2 （Bacillus subtilis fertilizer）， T3 （Trichoderma viride fertilizer）， T4 （compound microbial fertilizer）， T5 （C. pilosula stems and leaves fermented with compound microbial fertilizer）， and T6 （Scutellaria baicalensis stems and leaves fermented with T. viride fertilizer）. The physiological indicators， yield， and quality of C. pilosula and the physicochemical properties， enzyme activities， and microbial diversity in the rhizosphere soil of different fertilizer treatments were measured. ResultsGroup T1 showed slight decreases in soluble protein content （SPC） and superoxide dismutase （SOD）. Groups T2-T6 showed increases in physiological indicators such as proline （Pro）， soluble solids content （SSC）， SPC， catalase （CAT）， and peroxidase （POD） and a decrease in malondialdehyde （MDA） in C. pilosula leaves. All the fertilizer treatments increased the yield of C. pilosula and the total polysaccharide content in the roots. T1， T2， T3， T4， and T5 increased the total flavonoid content in the roots. Meanwhile， T4 increased the total saponin content in the roots. All the fertilizer treatments reduced the pH and increased the electric conductivity （EC）， soil organic matter （SOM）， and alkaline nitrogen （AN） in the soil. T2 and T5 increased the available phosphorus （AP）， and T3， T4， T5， and T6 increased the available potassium （AK） in the soil. All the fertilizer treatments increased the activities of urease， sucrase， and CAT in the soil. Except that T1 decreased the bacterial diversity in the soil， other fertilizer treatments significantly increased bacterial and fungal diversity in the soil. Different fertilizer treatments significantly affected the composition of bacterial and fungal communities in the soil. At the phylum level， the dominant bacterial phyla included Proteobacteria， Acidobacteriota， and Bacteroideta， and the dominant fungal phyla were Ascomycota， Mortierellomycota， and unclassified_fungi in the rhizosphere soil of C. pilosula after bacterial fertilizer treatment. At the genus level， unclassified Gemmatimonadaceae， Sphingomonas， and unclassified Vicinamibacteraceae were the dominant bacterial genera， while unidentified， unclassified Fungi， and unclassified Sordariomycetes were the dominant fungal genera in the rhizosphere soil. The results of redundancy analysis indicated that the main physicochemical factors affecting changes of microbial communities in the rhizosphere soil of C. pilosula were pH， EC， AK， AN， AP， and soil organic matter （SOM） in the soil. The correlation heatmap showed that Bryobacter had significantly positive correlations with EC， AK， and AN. There was a significantly negative correlation between Fusarium and SOM. In summary， applying an appropriate amount of microbial fertilizer can promote the growth and improve the rhizosphere soil environment of C. pilosula. ConclusionThe compound microbial fertilizer and the C. pilosula stems and leaves fermented with compound microbial fertilizer can improve the soil nutrients， growth， development， yield， and quality of C. pilosula， and thus they can be applied to the artificial cultivation of C. pilosula.

ObjectiveTo study the effects of applying different microbial fertilizers on the growth and rhizosphere soil environment of Codonopsis pilosula and provide a theoretical basis for ecological cultivation of this medicinal plant. MethodsSeven groups were designed， including CK （no application of microbial fertilizer）， T1 （Trichoderma longibrachiatum fertilizer）， T2 （Bacillus subtilis fertilizer）， T3 （Trichoderma viride fertilizer）， T4 （compound microbial fertilizer）， T5 （C. pilosula stems and leaves fermented with compound microbial fertilizer）， and T6 （Scutellaria baicalensis stems and leaves fermented with T. viride fertilizer）. The physiological indicators， yield， and quality of C. pilosula and the physicochemical properties， enzyme activities， and microbial diversity in the rhizosphere soil of different fertilizer treatments were measured. ResultsGroup T1 showed slight decreases in soluble protein content （SPC） and superoxide dismutase （SOD）. Groups T2-T6 showed increases in physiological indicators such as proline （Pro）， soluble solids content （SSC）， SPC， catalase （CAT）， and peroxidase （POD） and a decrease in malondialdehyde （MDA） in C. pilosula leaves. All the fertilizer treatments increased the yield of C. pilosula and the total polysaccharide content in the roots. T1， T2， T3， T4， and T5 increased the total flavonoid content in the roots. Meanwhile， T4 increased the total saponin content in the roots. All the fertilizer treatments reduced the pH and increased the electric conductivity （EC）， soil organic matter （SOM）， and alkaline nitrogen （AN） in the soil. T2 and T5 increased the available phosphorus （AP）， and T3， T4， T5， and T6 increased the available potassium （AK） in the soil. All the fertilizer treatments increased the activities of urease， sucrase， and CAT in the soil. Except that T1 decreased the bacterial diversity in the soil， other fertilizer treatments significantly increased bacterial and fungal diversity in the soil. Different fertilizer treatments significantly affected the composition of bacterial and fungal communities in the soil. At the phylum level， the dominant bacterial phyla included Proteobacteria， Acidobacteriota， and Bacteroideta， and the dominant fungal phyla were Ascomycota， Mortierellomycota， and unclassified_fungi in the rhizosphere soil of C. pilosula after bacterial fertilizer treatment. At the genus level， unclassified Gemmatimonadaceae， Sphingomonas， and unclassified Vicinamibacteraceae were the dominant bacterial genera， while unidentified， unclassified Fungi， and unclassified Sordariomycetes were the dominant fungal genera in the rhizosphere soil. The results of redundancy analysis indicated that the main physicochemical factors affecting changes of microbial communities in the rhizosphere soil of C. pilosula were pH， EC， AK， AN， AP， and soil organic matter （SOM） in the soil. The correlation heatmap showed that Bryobacter had significantly positive correlations with EC， AK， and AN. There was a significantly negative correlation between Fusarium and SOM. In summary， applying an appropriate amount of microbial fertilizer can promote the growth and improve the rhizosphere soil environment of C. pilosula. ConclusionThe compound microbial fertilizer and the C. pilosula stems and leaves fermented with compound microbial fertilizer can improve the soil nutrients， growth， development， yield， and quality of C. pilosula， and thus they can be applied to the artificial cultivation of C. pilosula.

OBJECTIVE To evaluate the cost-effectiveness of finerenone combined with standard of care （SoC） in the treatment of heart failure with mildly reduced ejection fraction （HFmrEF） or preserved ejection fraction （HFpEF）. METHODS Based on a phase Ⅲ clinical trial， a Markov model was constructed from the perspective of China’s healthcare system to compare the treatment outcomes of finerenone combined with SoC regimen versus SoC regimen alone in the treatment of different cardiac functional statuses of HFmrEF/HFpEF. Using quality-adjusted life year （QALY） as the health output index， 3 times China’s per capita GDP in 2023 as the willingness-to-pay （WTP） threshold， a simulation was conducted with a 3-month cycle length and a 10- year time horizon， incorporating an annual discount rate of 5%. The dynamic changes across various stages of HFmrEF/HFpEF treated with finerenone combined with SoC versus SoC alone were simulated to evaluate the long-term effectiveness and costs of the two treatment strategies. Additionally， one-way sensitivity analysis and probabilistic sensitivity analysis were performed， to test the robustness of the results. RESULTS The incremental cost-effectiveness ratio （ICER） of the finerenone combined with SoC regimen versus SoC regimen alone was 179 504.75 yuan/QALY， which was below the WTP threshold set in this study， indicating that the finerenone combined with SoC regimen possessed certain economic advantages. The results of one-way sensitivity analysis showed that the utility value of NYHA Ⅱ status， the drug price of finerenone， the discount rate， and the probability of hospital transfer for both groups had a great influence on ICER， but did not affect the robustness of the model. The probabilistic sensitivity analysis also confirmed the robustness of the model. CONCLUSIONS Under the WTP threshold set in this study， finerenone combined with SoC is cost-effective in the treatment of HFmrEF/HFpEF， compared with the SoC regimen.

The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

Objective:To explore the correlation between IκB kinase-interacting protein(IKBIP)expression in tumor cells within cervical cancer tissues(TCCCT)and the clinical pathological characteristics and prognosis of patients,as well as its impact on the biological behaviors of cervical cancer(CC)cells HeLa and SiHa,and to elucidate its potential mechanism.Methods:GENT2 and Kaplan-Meier plotter databases were utilized to analyze the differential expression of IKBIP mRNA in CC and normal cervical tissues,as well as its correlation with the clinical prognosis of CC patients.The Hallmark reference gene set was chosen for pathway enrichment analysis using the Gene Set Enrichment Analysis(GSEA)software.Immunohistochemistry method was used to detect the IKBIP protein expression in TCCCT and epithelial cells in normal cervical tissue(ECNCT),and analyze the correlations between its expression level and clinicopathological characteristics and prognosis of CC patients.Furthermore,univariate and multivariate Cox regression analyses were performed to identify the risk factors impacting the prognosis of CC patients.The stably transfected cells of CC(HeLa cells and SiHa cells)with IKBIP knockdown were established for the experiment,which were divided into sh-NC group and sh-IKBIP group.The expression of IKBIP protein in various groups was assessed using Western blotting method.The cell proliferation activity and the percentage of 5-ethynyl-2'-deoxyuridine(EdU)positive cells were measured using cell counting kit-8(CCK-8)and EdU methods,while Transwell chamber assay was employed to determine the numbers of migration and invasion cells in various groups.Additionally,the expression levels of E-cadherin,N-cadherin,and Snail proteins in the cells in various groups were analyzed by Western blotting method.Results:The GENT2 database analysis revealed that the expression level of IKBIP mRNA in CC tissue was higher than that in normal cervical tissue(P＜0.001).The GSEA enrichment analysis identified the epithelial-mesenchymal transition(EMT)pathway as the top-ranked pathway in IKBIP high-expression group.The immunohistochemistry results indicated the positive expression rate of IKBIP protein in TCCCT was higher than that in ECNCT(50.5％vs 8.0％),and its over-expression was associated with FIGO stage(2018)and differentiation grade of tumor(P＜0.05).The univariate and multivariate Cox regression analyses suggested that lymph node metastasis(LNM)and high expression of IKBIP were the risk factors affecting the overall survival(OS)and progression-free survival(PFS)of CC patients(P＜0.05).The Western blotting method results showed that compared with sh-NC group,the expression level of IKBIP protein in the cells in sh-IKBIP group was decreased(P＜0.05).The CCK-8 and EdU assay results showed that compared with sh-NC group,the proliferation activity and the percentage of EdU positive cells in sh-IKBIP group were decreased(P＜0.05).The Transwell chamber assay results showed that compared with sh-NC group,the numbers of migration and invasion cells in sh-IKBIP group were significantly decreased(P＜0.05).Additionally,the Western blotting method results indicated that compared with sh-NC group,the expression level of E-cadherin protein in sh-IKBIP group in CC cells was increased(P＜0.05),while the expression levels of N-cadherin and Snail protein were decreased(P＜0.05).Conclusion:The expression of IKBIP protein is significantly up-regulated in HeLa and SiHa cells derived from CC,and it is closely correlated with poor prognosis in CC patients.Suppression of IKBIP protein expression can effectively inhibit the proliferation,invasion and migration capabilities as well as EMT process of CC cells.

Objective:To evaluate the relationship between hippocampal receptor-interacting protein kinase-1 (RIPK1) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes in postoperative neurocognitive dysfunction of aged rats with chronic knee arthritis pain.Methods:Sixty-four healthy male Sprague-Dawley rats, aged 18 months, weighing 500-550 g, were divided into 4 groups ( n=16 each) using a random number table method: chronic knee arthritis pain group (group P), chronic knee arthritis pain+ operation group (group PS), RIPK1 inhibitor necrostatin-1+ chronic knee arthritis pain+ operation group (group NPS), and DMSO+ chronic knee arthritis pain+ operation group (group DPS). The knee arthritis model was prepared by intra-articular injection of monosodium iodoacetate (MIA) 1 mg into the left knee joint, and 12 weeks later exploratory laparotomy was performed under sevoflurane anesthesia. Necrostatin-1 6.25 mg/kg and the equal volume of DMSO were intraperitoneally injected at 1 h before operation in NPS group and DPS group, respectively. Thermal pain threshold was measured at 1 week before MIA injection and 6 and 12 weeks after MIA injection. Morris water maze test was used to evaluate the cognitive function at 7 days after surgery. Hippocampal tissues were obtained for microscopic examination of the pathological changes (after HE staining) and for determination of the expression of RIPK1, phosphorylated RIPK1 (p-RIPK1), NLRP3, activated cysteine-aspartic protease caspase-1 (cl-caspase-1), apoptosis-associated speck-like protein containing a CARD (ASC) (by Western blot) and contents of interleukin-1beta (IL-1β) and IL-18 (by enzyme-linked immunosorbent assay). Results:Thermal pain threshold was significantly decreased at 6 and 12 weeks after MIA injection as compared with that before injection ( P<0.05), and there was no significant difference in thermal pain threshold among the four groups ( P>0.05). Compared with P group, the escape latency was significantly prolonged, the time of staying at the original platform quadrant was shortened, the number of crossing the original platform was reduced, the expression of RIPK1, p-RIPK1, NLRP3, cl-caspase-1 and ASC was up-regulated, and the contents of IL-1β and IL-18 were increased ( P<0.05), and pathological changes of hippocampal neurons were marked in PS group, DPS group and NPS group. Compared with PS group and DPS group, the escape latency was significantly shortened, the time of staying at the original platform quadrant was prolonged, the number of crossing the original platform was increased, the expression of RIPK1, p-RIPK1, NLRP3, cl-caspase-1 and ASC was down-regulated, the contents of IL-1β and IL-18 were decreased ( P<0.05), and pathological changes of hippocampal neurons were significantly attenuated in NPS group. Conclusions:Postoperative hippocampal RIPK1 function is enhanced in aged rats with chronic knee arthritis pain, which then activates NLRP3 inflammasomes, triggering neuroinflammation, and this process may be involved in the mechanism of postoperative neurocognitive dysfunction.

Objective:To investigate the factors influencing the success of external cephalic version.Methods:Pregnant women who underwent an external cephalic version due to breech or transverse presentation by the same operator in the Third Affiliated Hospital of Zhengzhou University from July 2015 to July 2021 were selected as the study objects. Univariate analysis and logistic regression analysis were used to explore the clinical factors influencing the success of the external cephalic version. The receiver operating characteristic (ROC) curve was used to analyze the best cut-off value of gestational week and amniotic fluid index at the time of operation and to evaluate the predictive value of the influencing factors on the success of the external cephalic version.Results:(1) A total of 118 cases finally entered this study. Among the 118 cases,77 cases (65.3%) succeeded in the external cephalic version, among which the success rate was 49.1% (27/55) for primipara and 79.4% (50/63) for multipara. The vaginal delivery rate was 56.8% (67/118). (2) Complications occurred in 19 (16.1%) of the 118 cases. The main complications were abnormal fetal heart rate (13 cases, 11.0%), umbilical cord presentation, and fetal position reversion (two cases and 1.7% in each), and the serious complications were intrauterine fetal death and placental abruption (one case and 0.8% in each).The complication rate of patients with successful external cephalic version was 7.8% (6/77), which was lower than that of those who failed the external cephalic version [31.7%(13/41)] ( χ 2=11.33, P=0.001). (3) Multivariate analysis showed that gestational week at surgery before 38, amniotic fluid index >11.10 cm, and multipara were the factors affecting the success of the external cephalic version [ OR(95% CI)=0.561(0.351-0.897), 1.173(1.018-1.351) and 4.201(1.547-11.404), all P<0.05]. (4) The area under the ROC curve of the combination of the gestational week at surgery, amniotic fluid index, and parity was 0.744 (95% CI: 0.640-0.848, P<0.001), and the Youden index was 0.518, with a sensitivity of 70.0% and a specificity of 81.8%. Conclusion:Gestational weeks, amniotic fluid index, and multipara are related to the success of the external cephalic version, and the combination of the three has certain predictive power for the success of the surgery.