OBJECTIVE To form an expert consensus addressing clinical issues regarding the use of parenteral direct thrombin inhibitors （DTIs） in special populations. METHODS Led by the Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital（the Affiliated Hospital of UESTC）， a multidisciplinary working group was formed comprising experts from multiple fields， including clinical pharmacy， cardiac surgery， obstetrics， pediatrics and evidence-based medicine. Through literature review and the Delphi method， clinical questions regarding the efficacy and safety of parenteral DTIs used in special populations were identified. A structured design was adopted using the “Population-Intervention-Comparison-Outcome” （PICO） framework；systematic searches were conducted in CJFD， PubMed， Embase and other databases. Relevant evidence from randomized controlled trials，cohort studies and systematic reviews were included and synthesized. Evidence quality was assessed using the Grading of Recommendations Assessment，Development and Evaluation （GRADE） approach， and recommendations were formulated through three rounds of Delphi surveys and expert consensus meetings. RESULTS &CONCLUSIONS Seven clinical questions were ultimately selected （with a consensus rate exceeding 90%）， resulting in the formulation of seven recommendations on the use of parenteral DTIs in special populations， including children， pregnant women， patients with hepatic or renal impairment， patients with mesenteric venous thrombosis， and individuals with thrombophilia. These recommendations clarify the preferred agents， dosing ranges， monitoring parameters， and safety management strategies for parenteral DTIs in these special populations. This expert consensus， which is formulated based on the best available evidence， provides evidence-based guidance for standardized and individualized use of parenteral DTIs in special populations.

Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Objective To investigate the intervention effect of Xiao'er Zhixiao Pingchuan Granules(XEZXPCG)on ovalbumin(OVA)-induced airway remodeling in asthmatic mice and its potential mechanism by regulating macrophage migration inhibitory factor(MIF)and inhibiting the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.Methods A total of 96 SPF-grade male BALB/c mice were randomly divided into blank,model,XEZXPCG low/medium/high-dose groups(2.05,4.10,and 8.20 g/kg),adeno-associated virus(AAV)NC shRNA,AAV MIF shRNA(MIF gene silencing),and LY294002(PI3K/Akt inhibitor,1 mg/kg)groups(12 mice in each group).Asthma models were established through OVA sensitization and challenge.Airway resistance and the proportions of inflammatory cells(eosinophils and macrophages)in bronchoalveolar lavage fluid(BALF)were detected.Serum inflammatory factor(OVA-IgE,interleukin[IL]-1β,IL-6,tumor necrosis factor-alpha,and interferon-gamma)levels and BALF were quantified.Hematoxylin and eosin,Masson,and periodic acid-Schiff staining were used to evaluate airway wall thickness(Wat/Phm),smooth muscle area(Wam/Phm),collagen deposition,and goblet cell metaplasia.Western blotting,immunofluorescence,and real-time fluorescence-qPCR were used to detect MIF protein and mRNA expressions,as well as activation markers of the PI3K/Akt pathway and cell cycle-related proteins(including cyclin-dependant kinase 6[CDK6],Cyclin D1,Cyclin D3,and p21),in lung tissues.Results Compared to the model group,a XEZXPCG medium or high-dose significantly reduced airway resistance(P<0.05),improved the imbalance of eosinophil and macrophage proportions in BALF,and decreased inflammatory factor levels in serum and BALF(P<0.05).XEZXPCG medium or high-dose alleviated airway epithelial damage,goblet cell hyperplasia,and collagen fiber deposition,and reduced the Wat/Phm and Wam/Phm(P<0.05),with effects comparable to those of the AAV MIF shRNA and LY294002 groups.XEZXPCG medium and high-inhibited MIF protein/mRNA expression(P<0.05),downregulated Akt phosphorylation(P<0.05),upregulated p21 protein expression,and downregulated Cyclin D1,Cyclin D3,and CDK6 expressions(P<0.05).Conclusion XEZXPCG alleviates airway inflammation and improves airway remodeling in OVA-induced asthmatic mice by inhibiting MIF expression,downregulating the PI3K/Akt signaling pathway,and regulating cell cycle progression.XEZXPCG enhances airway remodeling through MIF-mediated PI3K/Akt pathway regulation.

Objective To investigate the intervention effect of Xiao'er Zhixiao Pingchuan Granules(XEZXPCG)on ovalbumin(OVA)-induced airway remodeling in asthmatic mice and its potential mechanism by regulating macrophage migration inhibitory factor(MIF)and inhibiting the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.Methods A total of 96 SPF-grade male BALB/c mice were randomly divided into blank,model,XEZXPCG low/medium/high-dose groups(2.05,4.10,and 8.20 g/kg),adeno-associated virus(AAV)NC shRNA,AAV MIF shRNA(MIF gene silencing),and LY294002(PI3K/Akt inhibitor,1 mg/kg)groups(12 mice in each group).Asthma models were established through OVA sensitization and challenge.Airway resistance and the proportions of inflammatory cells(eosinophils and macrophages)in bronchoalveolar lavage fluid(BALF)were detected.Serum inflammatory factor(OVA-IgE,interleukin[IL]-1β,IL-6,tumor necrosis factor-alpha,and interferon-gamma)levels and BALF were quantified.Hematoxylin and eosin,Masson,and periodic acid-Schiff staining were used to evaluate airway wall thickness(Wat/Phm),smooth muscle area(Wam/Phm),collagen deposition,and goblet cell metaplasia.Western blotting,immunofluorescence,and real-time fluorescence-qPCR were used to detect MIF protein and mRNA expressions,as well as activation markers of the PI3K/Akt pathway and cell cycle-related proteins(including cyclin-dependant kinase 6[CDK6],Cyclin D1,Cyclin D3,and p21),in lung tissues.Results Compared to the model group,a XEZXPCG medium or high-dose significantly reduced airway resistance(P<0.05),improved the imbalance of eosinophil and macrophage proportions in BALF,and decreased inflammatory factor levels in serum and BALF(P<0.05).XEZXPCG medium or high-dose alleviated airway epithelial damage,goblet cell hyperplasia,and collagen fiber deposition,and reduced the Wat/Phm and Wam/Phm(P<0.05),with effects comparable to those of the AAV MIF shRNA and LY294002 groups.XEZXPCG medium and high-inhibited MIF protein/mRNA expression(P<0.05),downregulated Akt phosphorylation(P<0.05),upregulated p21 protein expression,and downregulated Cyclin D1,Cyclin D3,and CDK6 expressions(P<0.05).Conclusion XEZXPCG alleviates airway inflammation and improves airway remodeling in OVA-induced asthmatic mice by inhibiting MIF expression,downregulating the PI3K/Akt signaling pathway,and regulating cell cycle progression.XEZXPCG enhances airway remodeling through MIF-mediated PI3K/Akt pathway regulation.