ObjectiveTo explore the therapeutic effect of Xuebijing injection （XBJ） on severe acute pancreatitis induced acute lung injury （SAP-ALI） by regulating formyl peptide receptors （FPRs）/nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） inflammatory pathway. MethodsSixty rats were randomly divided into a sham group， a SAP-ALI model group， low-， medium-， and high-dose XBJ groups （4， 8， and 12 mL·kg^-1）， and a positive drug （BOC2， 0.2 mg·kg^-1） group. For the sham group， the pancreas of rats was only gently flipped after laparotomy， and then the abdomen was closed， while for the remaining five groups， SAP-ALI rat models were established by retrograde injection of 5% sodium taurocholate （Na-Tc） via the biliopancreatic duct. XBJ and BOC2 were administered via intraperitoneal injection once daily for 3 d prior to modeling and 0.5 h after modeling. Blood was collected from the abdominal aorta 6 h after the completion of modeling， and the expression of interleukin （IL）-1β， IL-6， and tumor necrosis factor-α （TNF-α） in plasma was measured by enzyme-linked immunosorbent assay （ELISA）. The amount of ascites was measured， and the dry-wet weight ratios of pancreatic and lung tissue were determined. Pancreatic and lung tissue was taken for hematoxylin-eosin （HE） staining to observe pathological changes and then scored. The protein expression levels of FPR1， FPR2， and NLRP3 in lung tissue were detected by the immunohistochemical method. Western blot was used to detect the expression of FPR1， FPR2， and NLRP3 in lung tissue. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of FPR1， FPR2， and NLRP3 in lung tissue. ResultsCompared with the sham group， the SAP-ALI model group showed significantly decreased dry-wet weight ratio of lung tissue （P<0.01）， serious pathological changes of lung tissue， a significantly increased pathological score （P<0.01）， and significantly increased protein and mRNA expression levels of FPR1， FPR2， and NLRP3 in lung tissue （P<0.01）. After BOC2 intervention， the above detection indicators were significantly reversed （P<0.01）. After treatment with XBJ， the groups of different XBJ doses achieved results consistent with BOC2 intervention. ConclusionXBJ can effectively improve the inflammatory response of the lungs in SAP-ALI rats and reduce damage. The mechanism may be related to inhibiting the expression of FPRs and NLRP3 in lung tissue， which thereby reduces IL-1β and simultaneously antagonize the release of inflammatory factors IL-6 and TNF-α.

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.

The incomplete degradation of tumour cells by macrophages (Mϕ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mϕ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mϕ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mϕ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mϕ phagosomes, causing Mϕ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mϕ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mϕ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mϕ to degrade tumour cells by suppressing NOX2.

Traumatic brain injury (TBI), as a significant central nervous system damage disease with high frequency in the world, leads to a huge number of patients with impaired health and lower quality of life every year. Lung injury is a common and dangerous consequence, which dramatically raises the mortality of patients. Discovering the pathophysiology of lung injury after TBI and discovering viable therapeutic targets has become an important need for clinical diagnosis and therapy. Neurotransmitters, as the fundamental chemical agents of the nervous system for signal transmission, not only govern neuronal activity and apoptosis in TBI but also significantly influence the pathophysiological mechanisms of lung injury subsequent to TBI. The imbalance is intricately linked to the onset and progression of lung damage. This paper systematically reviews the clinical characteristics and predominant pathogenesis of lung injury following TBI, emphasizing the role of key neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh), in lung injury post-TBI. It examines their influence on inflammatory response, vascular permeability, and pulmonary circulation function. Additionally, the paper evaluates the research advancements and potential applications of targeted therapeutic strategies for various neurotransmitter systems, such as receptor antagonists, transporter inhibitors, and neurotransmitter analogues. This research aims to offer a theoretical framework for clarifying the neural regulatory mechanisms of lung injury following TBI and to establish a basis for the development of novel therapeutic strategies and enhancement of the prognosis of the patients.
Humans ; Brain Injuries, Traumatic/metabolism* ; Neurotransmitter Agents/metabolism* ; Lung Injury/metabolism* ; gamma-Aminobutyric Acid/metabolism* ; Glutamic Acid/metabolism* ; Norepinephrine/metabolism* ; Dopamine/metabolism* ; Acetylcholine/metabolism*

Hormesis effect has been observed in the secondary metabolite synthesis of microorganisms induced by rare earth elements. However, the underlying molecular mechanism remains unclear. To analyze the molecular mechanism of the regulatory effect of Rhodotorula mucilaginosa in the presence of lanthanum chloride, different concentrations of lanthanum chloride were added to the fermentation medium of Rhodotorula mucilaginosa, and the carotenoid content was subsequently measured. It was found that the concentrations of La³⁺ exerting the promotional and inhibitory effects were 0-100 mg/L and 100-400 mg/L, respectively. Furthermore, the expression of 33 genes and the synthesis of 55 metabolites were observed to be up-regulated, while the expression of 85 genes and the synthesis of 123 metabolites were found to be down-regulated at the concentration range of the promotional effect. Notably, the expression of carotenoid synthesis-related genes except AL1 was up-regulated. Additionally, the content of β-carotene, lycopene, and astaxanthin demonstrated increases of 10.74%, 5.02%, and 3.22%, respectively. The expression of 5 genes and the synthesis of 91 metabolites were up-regulated, while the expression of 35 genes and the synthesis of 138 metabolites were down-regulated at the concentration range of the inhibitory effect. Meanwhile, the content of β-carotene, lycopene, and astaxanthin decreased by 21.73%, 34.81%, and 35.51%, respectively. In summary, appropriate concentrations of rare earth ions can regulate the synthesis of secondary metabolites by modulating the activities of various enzymes involved in metabolic pathways, thereby exerting the hormesis effect. The findings of this study not only contribute to our comprehension for the mechanism of rare earth elements in organisms but also offer a promising avenue for the utilization of rare earth elements in diverse fields, including agriculture, pharmaceuticals, and healthcare.
Lanthanum/pharmacology* ; Rhodotorula/genetics* ; Carotenoids/metabolism* ; Hormesis/drug effects* ; Fermentation ; Multiomics

Objective To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.Methods Tumor associated fibroblasts(CAFs)co-cultured with breast cancer cells were treated with metformin,and the changes in expressions of hypoxia-inducible factor-1α(HIF-1α),p-AMPK,stroma-derived factor-1(SDF-1)and interleukin-8(IL-8)in the CAFs were detected using ELISA,RT-qPCR or Western blotting;Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1,IL-8 and TGF-β1.The effects of HIF-1α shRNA or overexpression plasmid,AMPK shRNA,and treatment with OG(a proline hydroxylase inhibitor)or 2-OXO(a proline hydroxylase activator)were examined on p-AMPK,HIF-1α,SDF-1 and IL-8 expressions and invasiveness of the CAFs.Results Metformin treatment significantly increased the expression levels of p-AMPK,SDF-1 and IL-8(P<0.05)and decreased HIF-1α expression(P<0.05)without affecting AMPK expression level(P>0.05)in the CAFs.The invasion ability of metformin-treated breast cancer cells was significantly decreased(P<0.05).Exogenous SDF-1 and IL-8,HIF-1α overexpression,and OG-induced upregulation of HIF-1α all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion(P<0.05)and HIF-1α,SDF-1 and IL-8 expressions in CAFs(P<0.05).Transfection with HIF-1α shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells(P<0.05).P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1α expression in CAFs and on invasion of breast cancer cells(P<0.05).Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1α expression in CAFs and invasiveness of the breast cancer cells(P<0.05).Conclusion Metformin suppresses HIF-1α expression in CAFs to block tumor-stromal cross talk in breast cancer.

Objective To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.Methods Tumor associated fibroblasts(CAFs)co-cultured with breast cancer cells were treated with metformin,and the changes in expressions of hypoxia-inducible factor-1α(HIF-1α),p-AMPK,stroma-derived factor-1(SDF-1)and interleukin-8(IL-8)in the CAFs were detected using ELISA,RT-qPCR or Western blotting;Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1,IL-8 and TGF-β1.The effects of HIF-1α shRNA or overexpression plasmid,AMPK shRNA,and treatment with OG(a proline hydroxylase inhibitor)or 2-OXO(a proline hydroxylase activator)were examined on p-AMPK,HIF-1α,SDF-1 and IL-8 expressions and invasiveness of the CAFs.Results Metformin treatment significantly increased the expression levels of p-AMPK,SDF-1 and IL-8(P<0.05)and decreased HIF-1α expression(P<0.05)without affecting AMPK expression level(P>0.05)in the CAFs.The invasion ability of metformin-treated breast cancer cells was significantly decreased(P<0.05).Exogenous SDF-1 and IL-8,HIF-1α overexpression,and OG-induced upregulation of HIF-1α all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion(P<0.05)and HIF-1α,SDF-1 and IL-8 expressions in CAFs(P<0.05).Transfection with HIF-1α shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells(P<0.05).P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1α expression in CAFs and on invasion of breast cancer cells(P<0.05).Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1α expression in CAFs and invasiveness of the breast cancer cells(P<0.05).Conclusion Metformin suppresses HIF-1α expression in CAFs to block tumor-stromal cross talk in breast cancer.

Objective To investigate the relationship between systemic immune-inflammation index(SII),red blood cell distribution width(RDW),albumin(ALB)ratio(RAR)and severity of disease and respiratory failure in patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD).Methods A total of 110 patients with AECOPD were divided into the severe group(n=37)and the non-severe group(n=73).They were also divided into the respiratory failure group(n=26)and the non-respiratory failure group(n=84)according to whether they had respiratory failure.Platelet count(PLT),neutrophil count(NEU),lymphocyte count(LYM),RDW,ALB,SII and RAR were compared between different groups.Multiple Logistic regression method was used to analyze influencing factors of severe and concurrent respiratory failure.Receiver operating characteristic(ROC)curves were plotted to analyze the predictive value of indicators for severe condition and respiratory failure.Results Compared with the non-severe group,there were increased NEU,SII,RDW and RAR,and decreased PLT and LYM in the severe group(P＜0.05).Compared with the non-respiratory failure group,there were increased NEU,SII,RDW and RAR,and decreased LYM and ALB in the respiratory failure group(P＜0.05).Multivariate Logistic regression analysis showed that increased SII and RAR were independent risk factors for severe condition or respiratory failure in patients with AECOPD.ROC curves indicated that the area under the curve(AUC)of SII combined with RAR for predicting severe condition and respiratory failure in patients with AECOPD were 0.882(0.806-0.935)and 0.908(0.837-0.954),both of which were higher than those of SII or RAR alone(P＜0.05).Conclusion Combination of SII and RAR can effectively help to evaluate the condition and the occurrence of respiratory failure in patients with AECOPD.

Objective To explore the functional changes of the glial lymphatic system in patients with spontaneous intracerebral hemorrhage(sICH)by MR diffusion tensor imaging(DTI).Methods The clinical and imaging data of 32 sICH patients(sICH group)and 31 healthy volunteers(control group)were retrospectively collected,and the diffusivity values of DTI in different direc-tions were collected from all the subjects,the diffusion tensor imaging analysis along the perivascular space(DTI-ALPS)index was calculated,the difference of DTI-ALPS index values between the sICH group and the control group was compared,the changes in the function of the glial lymphatic system in sICH patients were evaluated,and the correlation between DTI-ALPS index and clinical indi-cators in sICH patients was further analyzed.Results The DTI-ALPS index of cerebral hemispheres on the lesions side of sICH group was significantly lower than that on the unaffected side(P＜0.01,t=-5.03),and lower than that on the left side of control group(P＜0.01,t=-9.85)and the right side(P＜0.01,t=-8.80).In addition,vascular endothelial growth factor(VEGF)tes-ting was performed in 8 of the 32 patients,and the levels[(187.40±19.11)pg/mL]were significantly higher than the normal range(0-142.20 pg/mL).Conclusion Through the quantitative analysis of the DTI-ALPS index,the damage to the function of the glial lymphatic system of sICH can be reflected,and perhaps the mechanism of pathophysiological changes in the brain after sICH can be reflected from a new perspective by using MR DTI technology.