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.

BACKGROUND:Acellular cartilage extracellular matrix is effective in the treatment of osteoarthritis,but its efficacy is limited when applied alone.Oxymatrine alleviates interleukin-1β-induced chondrocyte apoptosis and extracellular matrix degradation.OBJECTIVE:To observe the effect of different doses of oxymatrine combined with acellular cartilage extracellular matrix injection in knee cavity on osteoarthritis in rats.METHODS:The femoral cartilage of SD rats was obtained.The acellular cartilage extracellular matrix was prepared by physical,chemical and enzyme methods.Fifty SD rats were selected and divided into sham operation group,osteoarthritis group,simple material group,low-dose drug group,and high-dose drug group by random number table method,with 10 rats in each group.The latter four groups were treated with modified Hulth method to establish the rat model of osteoarthritis.After successful modeling,acellular cartilage extracellular matrix homogenate was injected into the knee cavity of rats in the simple material group.Acellular cartilage extracellular matrix homogenate containing 50,100 μg oxymatrine was injected into the knee cavity of rats in the low-dose drug group and the high-dose drug group,respectively.Samples were taken 4 weeks after injection for relevant detection.RESULTS AND CONCLUSION:(1) Compared with the sham operation group,the concentrations of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in the joint effusion were increased (P<0.05),and the concentration of superoxide dismutase in the joint effusion was decreased (P<0.05) in the osteoarthritis group.Compared with osteoarthritis group,the levels of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in joint effusion were decreased (P<0.05),while the level of superoxide dismutase was increased (P<0.05) in the low-dose drug group and high-dose drug group,and the changes were more significant in high-dose drug group.(2) TUNEL staining showed that compared with sham operation group,apoptotic chondrocytes increased in osteoarthritis group.Compared with the osteoarthritis group,the apoptotic chondrocytes decreased in the simple material group,the low-dose drug group,and the high-dose drug group,and the decrease was more significant in the high-dose drug group.(3) Hematoxylin-eosin staining and immunohistochemical staining showed that the knee cartilage was seriously degraded,the expression of type Ⅱ collagen was decreased (P<0.05),and the expression of matrix metalloproteinase-9 was increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the knee cartilage degeneration of rats in the simple material group,the low-dose drug group,and the high-dose drug group was significantly improved;the expression of type Ⅱ collagen was increased (P<0.05) and the expression of matrix metalloproteinase 9 was decreased (P<0.05),and the improvement was most significant in the high-dose drug group.(4) Western blot assay showed that compared with sham operation group,the expression of Nrf2,HO-1,and Bcl-2 protein in cartilage tissue decreased (P<0.05);expression levels of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the protein expression levels of Nrf2,HO-1,and Bcl-2 were increased (P<0.05),and the protein expressions of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were decreased (P<0.05) in the low-dose and high-dose drug groups.The improvement was more significant in the high-dose drug group.(5) In conclusion,intracavicular injection of acellular cartilage extracellular matrix and oxymatrine can promote the synthesis of extracellular matrix,inhibit inflammation and oxidative stress,and suppress chondrocyte apoptosis,and play a therapeutic role in osteoarthritis,which may be related to the activation of Nrf2/HO-1 pathway.

BACKGROUND:Acellular cartilage extracellular matrix is effective in the treatment of osteoarthritis,but its efficacy is limited when applied alone.Oxymatrine alleviates interleukin-1β-induced chondrocyte apoptosis and extracellular matrix degradation.OBJECTIVE:To observe the effect of different doses of oxymatrine combined with acellular cartilage extracellular matrix injection in knee cavity on osteoarthritis in rats.METHODS:The femoral cartilage of SD rats was obtained.The acellular cartilage extracellular matrix was prepared by physical,chemical and enzyme methods.Fifty SD rats were selected and divided into sham operation group,osteoarthritis group,simple material group,low-dose drug group,and high-dose drug group by random number table method,with 10 rats in each group.The latter four groups were treated with modified Hulth method to establish the rat model of osteoarthritis.After successful modeling,acellular cartilage extracellular matrix homogenate was injected into the knee cavity of rats in the simple material group.Acellular cartilage extracellular matrix homogenate containing 50,100 μg oxymatrine was injected into the knee cavity of rats in the low-dose drug group and the high-dose drug group,respectively.Samples were taken 4 weeks after injection for relevant detection.RESULTS AND CONCLUSION:(1) Compared with the sham operation group,the concentrations of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in the joint effusion were increased (P<0.05),and the concentration of superoxide dismutase in the joint effusion was decreased (P<0.05) in the osteoarthritis group.Compared with osteoarthritis group,the levels of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in joint effusion were decreased (P<0.05),while the level of superoxide dismutase was increased (P<0.05) in the low-dose drug group and high-dose drug group,and the changes were more significant in high-dose drug group.(2) TUNEL staining showed that compared with sham operation group,apoptotic chondrocytes increased in osteoarthritis group.Compared with the osteoarthritis group,the apoptotic chondrocytes decreased in the simple material group,the low-dose drug group,and the high-dose drug group,and the decrease was more significant in the high-dose drug group.(3) Hematoxylin-eosin staining and immunohistochemical staining showed that the knee cartilage was seriously degraded,the expression of type Ⅱ collagen was decreased (P<0.05),and the expression of matrix metalloproteinase-9 was increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the knee cartilage degeneration of rats in the simple material group,the low-dose drug group,and the high-dose drug group was significantly improved;the expression of type Ⅱ collagen was increased (P<0.05) and the expression of matrix metalloproteinase 9 was decreased (P<0.05),and the improvement was most significant in the high-dose drug group.(4) Western blot assay showed that compared with sham operation group,the expression of Nrf2,HO-1,and Bcl-2 protein in cartilage tissue decreased (P<0.05);expression levels of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the protein expression levels of Nrf2,HO-1,and Bcl-2 were increased (P<0.05),and the protein expressions of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were decreased (P<0.05) in the low-dose and high-dose drug groups.The improvement was more significant in the high-dose drug group.(5) In conclusion,intracavicular injection of acellular cartilage extracellular matrix and oxymatrine can promote the synthesis of extracellular matrix,inhibit inflammation and oxidative stress,and suppress chondrocyte apoptosis,and play a therapeutic role in osteoarthritis,which may be related to the activation of Nrf2/HO-1 pathway.

Objective:To investigate the effects of personalized intermittent energy restriction (IER) diet on sleep related gut microbiome in obese patients.Methods:In this single-arm clinical trial, a total of 35 obese patients who visited Henan Provincial People′s Hospital from April to November 2018 were recruited as research subjects. They underwent a strict 32-day IER diet intervention, divided into 4 stages of 8 days each. Nutritional recipes were formulated and nutritious meals were provided to each obese patient with timed meals, including 55% carbohydrates, 15% protein, and 30% fat per meal. In stages 1, 2, 3, and 4, patients were provided with 2/3, 1/2, 1/3, and 1/4 of their previous calorie intake every other day, respectively, with meals at 8:00 and 16:00. During the remaining time, patients were allowed unrestricted eating at home. Physiological indicators (weight, body mass index, body fat percentage, waist circumference, hip circumference, fasting blood glucose, glycosylated hemoglobin, blood pressure, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein and Pittsburgh Sleep Quality Index (PSQI) scores were observed before and after the intervention. Gut microbiota changes were analyzed using metagenomic sequencing technology, and Spearman′s correlation analysis was used to assess the correlation between significantly different bacterial species and PSQI scores.Results:After the intervention, the body weight, body mass index, and PSQI scores of obese patients were all significantly lower than before intervention [(89.92±14.98) vs (97.53±15.67) kg, (31.94±3.95) vs (34.64±4.05) kg/m 2, (3.43±1.16) vs (5.42±2.27)], the abundance of gut microbiota was significantly higher after the intervention (all P<0.05). There were 45 significantly different bacterial species before and after the intervention, of which 6 bacterial species ( Enterobacter cloacae, Escherichia coli, Odoribacter splanchnicus, Oribacterium sinus, Streptococcus gordonii, and Streptococcus parasanguinis) showed significantly positive correlations with PSQI scores ( r=0.476, 0.475, 0.369, 0.391, 0.401, 0.423) (all P<0.05), and they were mainly enriched in the glutamate and tryptophan synthesis pathways. Conclusions:The personalized IER diet intervention can improve the sleep of obese patients while reducing weight, possibly mediated by changes in gut microbiota through the glutamate and tryptophan pathways.

Objective:To investigate the feasibility and clinical effects of the chimeric multi-paddled anteriolateral thigh perforator flap (ALTP) for reconstruction of complex defects in extremities, which was pedicled with the descending branch of lateral circumflex femoral artery (d-LCFA).Methods:From August, 2010 to December, 2017, 11 cases of severe soft-tissue defects were repaired with this flap, including 4 cases of car accident trauma, 2 of machine injury, 2 of fall injuries, 1 of ploughing machine injury, 1 of crushing injury, and 1 of spoke injury. The injuries accompanied with different degrees of infections, dead space and left huge soft-tissue defects after radical debridement (10.0 cm×9.0 cm-20.0 cm×18.0 cm) . Dead cavity was filled by the muscular flap, and the large area soft-tissue defects were repaired by chimeric multi-paddled perforator flap. Appearance, colour and texture of the flap, recurrence of infection and knee extension were recorded at 1, 3, 6, 9 and 12 months follow-up.Results:After the operation, all recipient sites had no hematoma and no infection. Eight flaps survived successfully, and donor sites healed primarily. One flap had partial necrosis because of a mechanical stretch of the perforator during the operation, then repaired by the ipsilateral chimeric perforator flap based on d-LCFA. One flap occurred vascular crisis on the second day after the surgery, and it was rescued and survived completely after surgical exploration. The other flap which repaired wound on hand had partial necrosis too, and then repaired with posterior interosseous artery perforator flap. The follow-up periods ranged from 2 to 32 (mean, 10.2) months. All flaps had satisfactory appearance and texture. Only linear scars left at the donor sites. There were no motion limitations at the hip and knee joints of the effected leg.Conclusion:The anteriolateral thigh perforator flap combined with multi-paddled and chimeric techniques can reduce donor site morbidities, simplify the anastomosis of blood vessel, and improve the appearance and effects of the recipient site. It is a feasible method in repairing severe soft tissue defects of limbs.

Objective To investigate the feasibility and clinical effects of deep femoral artery third perforating artery perforator flap for reconstruction of soft tissue defect in lower limbs.Methods From September,2008 to October,2016,8 cases of soft tissue defect in lower limbs which were repaired by deep femoral artery third perforating artery perforator flap,including 4 cases of traffic accident trauma,2 cases of chronic ulcer,1 case of a fall injury,1 case of the scar after fracture operation.The area of wounds was 8.0 cm×7.0 cm-19.0 cm×8.0 cm.Seven patients were accompanied by different degrees of infections.The deep femoral artery third perforating artery perforator flap was designed to repair,including 5 cases of pedicled flaps and 3 cases of free flaps.The flap's appearance,color,texture,infection recurrence and the recovery of lower limb function were recorded at 1,3,6,9 and 12 months followed-up.Results One flap suffered partial necrosis due to cross-zone backflow disorder,the ipsilateral medial sural artery pedicled perforator flap was used to repair.The rest of the flaps survived successfully.Skin graft was used to close the donor site in 1 case,and other donor sites were closed directly.All patients had no postoperative hematoma or secondary infection.The followed-up periods ranged from 2 to 28 months (mean,8.1 months).All flaps had satisfied appearance and texture.There were no complications such as paresthesia and numbness in the donor sites.And no motion limitations in hip and knee joint of the operated leg.Conclusion Deep femoral artery third perforating artery perforator flap can be used for both free flaps and pedicled flaps,which is a feasible method to repair soft tissue defect in lower limbs.

Objective To investigate the feasibility and clinical effects of chimeric perforator flap based on the descending branch of lateral circumflex femoral artery (d-LCFA) for reconstructing the three-dimensional tissue defect in lower extremities. Methods From May, 2008 to June, 2017, 79 cases of soft tissue defects with dead space were repaired by using a d-LCFA chimeric perforator flap, in which 33 cases of car accident trauma, 12 cases of chronic tibial osteomyelitis, 10 cases of plowing machine injury, 9 cases of chronic calcaneal osteomyelitis, 6 cases of falling injury, 5 cases of crushing injury, 3 cases of spoke injury, and 1 case of suppurative knee arthritis. These patients were accompany with different degrees of infection and dead space after radical debridement. The dead cavity was filled by muscular flap, and perforator flap covered the superficial wound. Recording the flap 's appearance, color, texture, osteomyelitis recurrence and the patient 's knee extension at 1, 3, 6, 9 and 12 months followed-up. Results Seventy-five flaps survived without complications, and the donor sites were closed directly. All patients had no post-operative hematoma or secondary infection. Vascular crisis occurred in 2 days after the operation in 4 flaps, 1 flap had an arterial crisis on the second-postoperative-day, and the flap was necrotic after surgical exploration. The deep cir-cumflex iliac artery chimeric perforator flap was used for repairing. Three flaps with venous crisis during 48 h after operation, in which 2 flaps survived eventually after surgical exploration, and another flap was necrosis and repaired by skin graft. The followed-up periods ranged from 3 months to 30 months (mean, 9.7 months). All flaps had satisfied with appearance and texture. There were no osteomyelitis recurrence and any ranges of motion limitations in the hip and knee joints of the operated leg. Conclusion The chimeric perforator flap with d-LCFA merely anastomosed 1 group vascular pedicle can make the dead space be filled and cover the superficial wound simultaneously. It is an ideal option for reconstructing the skin defect with dead space in lower extremity, which can improve the quality of restoration of recipient site and reduce the damage of donor site.

Currently,although surgical aortic valve replacement (SAVR) is still the golden standard in treatment of severe aortic stenosis according to the guideline,transcatheter aortic valve implantation (TAVI) is gradually becoming a common treatment for patients who are prohibitive or in high risk for SAVR.Recently,the valve manufacturers,including medical companies in China,are making their utmost to develop valve device,leading remarkable results achieved by TAVI.With the complications being controlled,TAVI displays promising future.It is likely that TAVI is expected to become a substitute for SAVR to treat patients with aortic stenosis or even aortic regurgitation.

Objective To study the effect of different dialysis modalities on pruritus in elderly maintenance hemodialysis patients.Methods Totally 51 patients were randomly divided into hemoperfusion combined with hemodialysis group (HD+ HP),hemodiafiltration group (HDF) and hemodialysis group (HD).Plasma β2-microglobulin(β2-MG) and intact parathyroid hormone (iPTH) were measured by means of radio immunoassay at pre and post dialysis,4 weeks and 8 weeks after dialysis,cutaneous pruritus was scored.The remission rate of itching was calculated at 8 weeks after dialysis.The parameters were compared among different groups.Results The level of plasma β2-MG was lower in HD+HP group after dialysis than pre dialysis [(13.48±3.05)mg/L vs.(16.27±4.73) mg/L,t＝2.044,P＜0.05],at 4 weeks and 8 weeks after dialysis,its levels were decreased to (10.97±3.25)mg/L(t＝3.808,P＝0.002)and (6.47±2.35)mg/L(t＝7.650,P＝0.000),respectively.The levels of iPTH were also found decrease from(887.5 ± 242.7)ng/L to (688.3 ±223.4)ng/L(t＝3.384,P＝0.004)at 4 weeks and (467.2±102.5) ng/L(t＝6.578,P＝0.000) at 8weeks after dialysis in HD+HP group (all P＜0.01).There were differences of the levels of plasma β2-MG and iPTH at 4 weeks and 8 weeks after dialysis in HDF group (all P＜ 0.05),but no differences of the levels of plasma β2-MG and iPTH during every period were found in HD group(all P＞0.05).The scores of cutaneous pruritus were decreased from (21.17± 5.01) scores to (13.37±2.85) scores(t＝ 5.580,P＝0.000)at 4 weeks and (8.52±4.38) scores(t＝7.838,P＝0.000)at 8 weeks after dialysis in HD+ HP group,and also the scores at 4 and 8 weeks after dialysis in HDF group (all P＜0.01),but there were no significant differences of the scores during every period in HD group (all P＞0.05).The remission rate of itching was better in HD+ HP group than in HDF group [88.24％ (15/17 cases) vs.58.82％ (10/17 cases),x2＝14.44,P＝0.000],better in HDF group than in HD group 23.53％ (4/17 cases) (x2 ＝4.37,P＝0.037).Conclusions HD+HP is superior to HDF in efficiently clear β2-MG and iPTH,and relief cutaneous pruritus,but HD can poorly clear β2-MG and iPTH or relief itching.

Objective To isolate and identify the Dengue virus(DEN)from the sera of patients with unknown fever in summer and autumn in Dushan and Xingyi areas of Guizhou province,China.Methods From June 2005 to October 2005.356 blood samples were collected from patients with unknown fever in Dushan and Xingyi areas of Guizhou province.The serum samples were inoculated on the C6/36 cell monolayers.After three blind passages,the cytopathie effect(CPE)Was observed.Identification of DEN antigen was earried out by indirect immunofluorescence assay(IFA)with the monoclonal antibody(McAb)against DENl-4 virus.The total RNA was extracted from the serum and tested by RT-PCR with the universal primer for DEN NS region.And determination of the RNA sequenee Was performed,and phylogenetic analysis was carried out.Results Three serum samples caused CPE and were proved as DEN2 positive by IFA,RT-PCR and senquence determination.The phylogenetic tree analysis showed that the isolated virus strains had the closest relations with the systemic evolution of the strains DEN2-43 and DEN2-44.Conclusion DEN infections exist in the population of Dushan and Xingyi of Guizhou,China.