Objective : To investigate the protective effect of dimethyl fumarate(DMF) on maternal intrahepatic cholestasis(ICP) during pregnancy induced by di(2-ethylhexyl) phthalate(DEHP) exposure and its mechanism. Methods : Thirty-two 8-week-old female institute of cancer research(ICR) mice were randomly divided into 4 groups: Ctrl group, DEHP group, DMF group and DEHP+DMF group. DEHP and DEHP+DMF groups were treated with DEHP(200 mg/kg) by gavage every morning at 9:00 a.m. DMF and DEHP+DMF groups were treated with DMF(150 mg/kg) from day 13 to day 16 of gestation by gavage. After completion of gavage on day 16 of pregnancy, maternal blood, maternal liver, placenta, and amniotic fluid were collected from pregnant mice after a six-hour abrosia. The body weight of the mother rats and the body weight of the fetus rats were sorted and analyzed; the levels of total bile acid(TBA), alkaline phosphatase(ALP), aspartate aminotransferase/alanine aminotransferase(AST/ALT) in serum and TBA in liver, amniotic fluid and placenta were detected by biochemical analyzer; HE staining was used to observe the pathological changes of liver tissue; Quantitative reverse transcription PCR(RT-qPCR) was used to detect the expression levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-6, IL-1, IL-18 and NOD-like receptor thermal protein domain associated protein 3(NLRP3) in the liver; Western blot was used to detect the expression of the nuclear factor KappaB(NF-κB) and NLRP3. Results : Compared with the control group, the body weight of the DEHP-treated dams and pups decreased(P<0.05); the levels of TBA, ALP, AST/ALT in the serum of dams and the levels of TBA in the liver, amniotic fluid, and placenta of dams increased(P<0.05); the histopathological results showed that liver tissue was damaged, bile ducts were deformed, and there was inflammatory cell infiltration around them; the levels of inflammation-related factors TNF-α, IL-6, IL-1, IL-18 and NLRP3 transcription in maternal liver increased(P<0.05); the expression of NF-κB and NLRP3 protein in maternal liver significantly increased( P<0. 05). Compared with the DEHP group,the body weight of both dams and fetuses significantly increased in DEHP + DMF group( P<0. 05); the levels of TBA,ALP,AST/ALT in the serum of dams and amniotic fluid of fetuses decreased( P<0. 05); the degree of liver lesions was improved; the transcription levels of inflammation-related factors TNF-α,IL-6,IL-1,IL-18 and NLRP3 in maternal liver decreased( P<0. 05); the expression of NF-κB and NLRP3 protein in maternal liver significantly decreased( P<0. 05). Conclusion DMF can effectively protect the DEHP exposure to lead to female ICP,and its mechanism may be through inhibiting the NF-κB/NLRP3 pathway and reducing liver inflammation.

Objective To investigate the protective effect of folic acid against cholestatic liver injury in mice induced by bis(2-ethylhexyl)phthalate(DEHP)exposure and its mechanism.Methods ICR mice were randomly divided into control group,high-dose folic acid(H-FA)group,DEHP group,DEHP+low-dose folic acid(DEHP+L-FA)group,and DEHP+high-dose folic acid(DEHP+H-FA)group,with 6 mice in each group.The mice in the H-FA group,the DEHP+L-FA group,and the DEHP+H-FA group were given folic acid by gavage at the corresponding dose,and those in the control group and the DEHP group were given an equal volume of PBS solution by gavage.After 2 hours,the mice in the DEHP group,the DEHP+L-FA group,and the DEHP+H-FA group were given corn oil containing 200 mg/kg DEHP,and those in the control group and the H-FA group were given an equal volume of pure corn oil,by gavage for 4 weeks.Body weight and food intake were recorded every day,and blood and liver tissue samples were collected.A biochemical analyzer was used to measure the serum levels of total bile acid(TBA)and alkaline phosphatase(ALP);HE staining was used to observe the histopathological changes of liver tissue;kits were used to measure the content of malondialdehyde(MDA)and superoxide dismutase(SOD)in the liver;LC-MS/MS was used to measure serum bile acid profiles;Western blot was used to measure the expression levels of proteins associated with hepatic bile acid metabolism.A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups.Results Compared with the control group,the daily food intake of the mice in the DEHP group decreased significantly,and the body weight decreased significantly from day 10(P＜0.05),and compared with the DEHP group,the DEHP+L-FA group and the DEHP+H-FA group had basically unchanged body weight and daily food intake(P＞0.05).Compared with the control group,the DEHP group had significant increases in liver weight index and the serum levels of TBA and ALP(all P＜0.05),with enlarged portal area,bile duct deformity and hyperplasia,and a small amount of inflammatory cell infiltration in liver tissue;compared with the DEHP group,the DEHP+L-FA group and the DEHP+H-FA group had a significant reduction in liver weight index(P＜0.01),and the DEHP+H-FA group had significant reductions in the serum levels of TBA and ALP(P＜0.05),with a significant improvement in liver histomorphology and structure after folic acid intervention.Compared with the control group,the DEHP group had a significant reduction in the content of SOD(P＜0.05)and a significant increase in the content of MDA in the liver(P＜0.01),and compared with the DEHP group,the DEHP+H-FA group had significant reductions in the content of MDA and SOD(P＜0.05).Compared with the control group,the DEHP group had significant increases in the serum levels of α-muricholic acid(α-MCA),β-muricholic acid(β-MCA),deoxycholic acid(DCA),lithocholic acid(LCA),taurocholic acid(TCA),taurodeoxycholic acid(TDCA),tauroursodeoxycholic acid(TUDCA),tauro-β-muricholic acid(T-β-MCA),tauro-α-muricholic acid(T-α-MCA),taurohyodeoxycholic acid(THDCA),and taurolithocholic acid(TLCA)(P＜0.05)and a significant reduction in ursodeoxycholic acid(UDCA)(P＜0.05);compared with the DEHP group,the DEHP+H-FA group had significant reductions in the serum levels of DCA,LCA,TCA,TDCA,TUDCA,T-β-MCA,T-α-MCA,THDCA,and TLCA(P＜0.05).Compared with the control group,the DEHP group had significant increases in the protein expression levels of FXR and CYP3A11 in the liver(P＜0.01)and significant reductions in the protein expression levels of CYP7A1 and MRP2(P＜0.01);compared with the DEHP group,the DEHP+L-FA group and the DEHP+H-FA group had significant reductions in the protein expression levels of FXR and CYP3A11 in the liver(P＜0.05)and a significant increase in the protein expression level of MRP2(P＜0.05),and the DEHP+H-FA group had a significant increase in the protein expression level of CYP7A1(P＜0.05).Conclusion Folic acid has a protective effect against cholestatic liver injury in mice induced by DEHP exposure,possibly by regulating bile acid synthesis,catabolism,and transport and maintaining bile acid homeostasis.

In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

This video presents a case of L4–5 unstable spondylolisthesis treated with full-endoscopic transforaminal lumbar interbody fusion (Endo-TLIF), emphasizing the GUARD (Glider Used as a Rotary Device) technique for nerve root protection. This innovative approach involves controlled rotation of the cage glider before cage insertion to minimize the risk of nerve root injury, a significant complication in Endo-TLIF procedures. The GUARD technique, validated in previous cadaveric studies, provides enhanced safety during cage insertion by protecting the nerve root. A 48-year-old woman with a 3-year history of progressive low back pain and bilateral lower extremity radiculopathy (right-sided predominance) was diagnosed with L4–5 unstable spondylolisthesis and spinal stenosis. After failure of conservative management, she underwent uniportal full-endoscopic facet-resecting transforaminal lumbar interbody fusion using the GUARD technique. Postoperatively, the patient experienced significant symptomatic improvement and resolution of radiculopathy, without any intraoperative nerve root injury or postoperative neurological deficits. This case demonstrates the effectiveness of the GUARD technique in reducing neurological complications and improving patient outcomes.

This video presents a case of L4–5 unstable spondylolisthesis treated with full-endoscopic transforaminal lumbar interbody fusion (Endo-TLIF), emphasizing the GUARD (Glider Used as a Rotary Device) technique for nerve root protection. This innovative approach involves controlled rotation of the cage glider before cage insertion to minimize the risk of nerve root injury, a significant complication in Endo-TLIF procedures. The GUARD technique, validated in previous cadaveric studies, provides enhanced safety during cage insertion by protecting the nerve root. A 48-year-old woman with a 3-year history of progressive low back pain and bilateral lower extremity radiculopathy (right-sided predominance) was diagnosed with L4–5 unstable spondylolisthesis and spinal stenosis. After failure of conservative management, she underwent uniportal full-endoscopic facet-resecting transforaminal lumbar interbody fusion using the GUARD technique. Postoperatively, the patient experienced significant symptomatic improvement and resolution of radiculopathy, without any intraoperative nerve root injury or postoperative neurological deficits. This case demonstrates the effectiveness of the GUARD technique in reducing neurological complications and improving patient outcomes.

This video presents a case of L4–5 unstable spondylolisthesis treated with full-endoscopic transforaminal lumbar interbody fusion (Endo-TLIF), emphasizing the GUARD (Glider Used as a Rotary Device) technique for nerve root protection. This innovative approach involves controlled rotation of the cage glider before cage insertion to minimize the risk of nerve root injury, a significant complication in Endo-TLIF procedures. The GUARD technique, validated in previous cadaveric studies, provides enhanced safety during cage insertion by protecting the nerve root. A 48-year-old woman with a 3-year history of progressive low back pain and bilateral lower extremity radiculopathy (right-sided predominance) was diagnosed with L4–5 unstable spondylolisthesis and spinal stenosis. After failure of conservative management, she underwent uniportal full-endoscopic facet-resecting transforaminal lumbar interbody fusion using the GUARD technique. Postoperatively, the patient experienced significant symptomatic improvement and resolution of radiculopathy, without any intraoperative nerve root injury or postoperative neurological deficits. This case demonstrates the effectiveness of the GUARD technique in reducing neurological complications and improving patient outcomes.

This video presents a case of L4–5 unstable spondylolisthesis treated with full-endoscopic transforaminal lumbar interbody fusion (Endo-TLIF), emphasizing the GUARD (Glider Used as a Rotary Device) technique for nerve root protection. This innovative approach involves controlled rotation of the cage glider before cage insertion to minimize the risk of nerve root injury, a significant complication in Endo-TLIF procedures. The GUARD technique, validated in previous cadaveric studies, provides enhanced safety during cage insertion by protecting the nerve root. A 48-year-old woman with a 3-year history of progressive low back pain and bilateral lower extremity radiculopathy (right-sided predominance) was diagnosed with L4–5 unstable spondylolisthesis and spinal stenosis. After failure of conservative management, she underwent uniportal full-endoscopic facet-resecting transforaminal lumbar interbody fusion using the GUARD technique. Postoperatively, the patient experienced significant symptomatic improvement and resolution of radiculopathy, without any intraoperative nerve root injury or postoperative neurological deficits. This case demonstrates the effectiveness of the GUARD technique in reducing neurological complications and improving patient outcomes.