Research progress on multi-target regulation strategies of tumor microenvironment based on nano-drug delivery system / 药学学报

Tumor microenvironment (TME) is composed of endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), extracellular matrix (ECM) and other components of the complex biological environment. TME interacts with the tumor cells through a large amount of signaling pathways, participates in the process of tumor progression, invasion, and metastasis. Hence, TME has become a potential therapeutic target for cancer treatment, exhibiting excellent therapeutic potential and research value in the field of cancer treatment. Currently, the novel nanotechnology has been widely applied in anticancer therapy, and nanotechnology-mediated drug delivery system is being explored to apply in TME modulation to inhibit tumor progression. Nanotechnology-mediated drug delivery has many advantages over traditional therapeutic modalities, including longer circulation times, improved bioavailability, and reduced toxicity. This review summarized the research of targeted nano-drug delivery based on TME regulation, including regulation strategies based on CSCs, CAFs, immune cells, ECM, tumor vascularization, exosomes, and microbiota. In addition, we summarized the advantages, opportunities, and challenges of TME regulation strategy compared with traditional treatment strategy, which provides a reference for the application of nano-drug delivery system based on TME regulation strategy in tumor precision therapy.

Application of trifoliate flap design of radial forearm flap in reconstruction of defects after mouth floor cancer resection / 中华肿瘤杂志

Objective: To evaluate the effect of trifoliate flap design of radial forearm flap in reconstruction of defects after mouth floor cancer resection. Methods: From June 2016 to December 2019, 12 patients with defect after resection of mouth floor cancer were treated with trifoliate flap design of radial forearm flap. All of these patients were T2 stage, included 9 well-differentiated squamous cell carcinoma (SCC) and 3 moderate differentiated SCC. The defect size ranged from 8.0 cm×6.0 cm to 5.0 cm×4.5 cm after resection of tumor and neck dissection. All defects were repaired with trifoliate flap design of radial forearm flap. The flap size ranged from 8.0 cm×2.0 cm to 4.0 cm×1.5 cm, the donor site was sutured directly on Z plasty. Results: All flaps completely survived well. Both the wound and the donor site were stage Ⅰ healing. With the average follow-up of 38.6 months, the swallowing and speech function were satisfactory. Conclusions: Trifoliate flap design of radial forearm flap can effectively repair the postoperative defect of mouth floor cancer, and the donor site can be directly sutured on Z plasty. This technique can avoid forearm scar caused by skin grafting and the formation of the second donor site.

Therapeutic effect of Fanzhen Jieci needling on discogenic sciatica: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the therapeutic effect between Fanzhen Jieci (warming acupuncture plus fast needling) combined with conventional acupuncture and simple conventional acupuncture on discogenic sciatica.@*METHODS@#A total of 76 patients with discogenic sciatica were randomized into a Fanzhen Jieci group and a conventional acupuncture group, 38 cases in each one. Conventional acupuncture was applied at Shenshu (BL 23), Dachangshu (BL 25), L1-L5 Jiaji (EX-B 2) and Huantiao (GB 30) on the affected side, etc. in the conventional acupuncture group. On the basis of the treatment in the conventional acupuncture group, Fanzhen Jieci was applied at L1-L5 Jiaji (EX-B 2) and Huantiao (GB 30) on the affected side in the Fanzhen Jieci group, i.e. warming acupuncture was applied at L1-L5 Jiaji (EX-B 2), and fast needling was applied at Huantiao (GB 30) on the affected side for a depth of 40-60 mm, so as to introduce a sensation of electric shock transmitting to lower limb, and then the needle was immediately withdrawn. The treatment was given once every other day, 3 times a week for 3 weeks in both groups. The visual analogue scale (VAS) score of leg and low back pain, the Oswestry disability index (ODI) score and the 36-item short form health survey (SF-36) score before and after treatment were compared between the two groups.@*RESULTS@#Compared before treatment, the VAS scores of leg and low back pain and the ODI scores after treatment were decreased in both groups (P<0.001), the changes of the VAS scores of leg and low back pain in the Fanzhen Jieci group were larger than those in the conventional acupuncture group (P<0.05). After treatment, except for the role emotional and health transition scores, the various scores of SF-36 were increased compared before treatment in the Fanzhen Jieci group (P<0.01); except for the role physical, role emotional and health transition scores, the various scores of SF-36 were increased compared before treatment in the conventional acupuncture group (P<0.01). After treatment, the physical functioning, role physical, bodily pain, mental health and general health scores of SF-36 in the Fanzhen Jieci group were higher than those in the conventional acupuncture group (P<0.05).@*CONCLUSION@#Fanzhen Jieci combined with conventional acupuncture can effectively relieve the pain and improve the mental state in patients with discogenic sciatica, its therapeutic effect is superior to simple conventional acupuncture.

Stress Distributions of Hip Cartilage During Gait Cycle and its Effects in Curved Periacetabular Osteotomy / 医用生物力学

Objective To study stress distributions of the cartilage around the hip joint in stress environment of complete gait cycle, and explore the optimal correction angle of bone block in curved periacetabular osteotomy (CPO), so as to provide theoretical references for clinical operation. Methods Based on CT scans from a healthy volunteer and a patient with development dysplasia of hip (DDH), the three-dimensional (3D) model including pelvis and proximal femur was reconstructed. The cortical bone and cancellous bone were distinguished by dividing the masks, and the material attributes were assigned to the finite element model. A total of 100 different postoperative models were obtained by simulating CPO in DDH model, by adjusting lateral center edge angle (LCEA) and anterior center edge angle (ACEA). According to hip joint stresses in complete gait cycle, the model was loaded respectively, and stress changes of normal, preoperative and postoperative acetabular cartilage were analyzed and compared. ResultsThe minimum peak contact stresses of acetabular cartilage of DDH patient at heel landing phase, start phase of single leg support, mid phase of single leg support, end phase of single leg support and double support phase after simulated CPO operation were 5.273, 6.128, 7.463, 6.347, 6.582 MPa, which were decreased by 2.159, 2.724, 2.249, 2.164, 2.119 MPa,respectively, compared with those before operation. The contact area between femoral head and acetabulum was significantly increased after operation, but it was still smaller than that of normal volunteers. Conclusions The optimal correction angle of LCEA and ACEA can be obtained by using finite element method, and the simulation of CPO surgery on different patients is of great significance to improve surgical accuracy and efficiency.

Relationship between Rev-erbα and NLRP3 inflammasome during myocardial ischemia-reperfusion in diabetic rats / 中华麻醉学杂志

Objective:To evaluate the relationship between nuclear receptor subfamily 1, group D, member 1 (Rev-erbα) and NOD-like receptor protein 3 (NLRP3) inflammasome during myocardial ischemia-reperfusion (I/R) in diabetic rats.Methods:SPF-grade healthy male Sprague-Dawley rats, weighing 210-240 g, in which 1% streptozotocin 60 mg/kg was intraperitoneally injected to develop the model of type 1 diabetes mellitus.Eighteen non-diabetic rats were divided into 2 groups by the random number table method: non-diabetic sham operation group (NS group, n=6) and non-diabetic myocardial I/R group (NIR group, n=12). Thirty diabetic rats were divided into 3 groups by the random number table method: diabetic sham operation group (DS group, n=6), diabetic myocardial I/R group (DIR group, n=12), and diabetic myocardial I/R + Rev-erbα inhibitor SR8278 group (DIR+ SR group, n=12). Myocardial I/R model was developed by ligation of left anterior descending coronary artery for 30 min followed by reperfusion for 120 min.In DIR+ SR group, SR8278 2 mg/kg was injected via the femoral vein at 1 h before ischemia.At the end of reperfusion, blood samples from the right carotid artery were collected for determination of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI) levels (by enzyme-linked immunosorbent assay). Then the rats were sacrificed, hearts were removed and myocardial tissues were obtained for determination of the percentage of myocardial infarct size (by TTC method) and expression of Rev-erbα, NLRP3 and IL-1β (by Western blot) and for microscopic examination of pathologic changes (by HE staining). Results:Compared with sham-operated rats, the serum concentrations of CK-MB, LDH and cTnI were significantly increased, the expression of Rev-erbα, NLRP3 and IL-1β in myocardial tissues was up-regulated ( P<0.05), and the pathological injury of myocardial tissues was obvious in myocardial I/R rats.Compared with NIR group, the percentage of myocardial infarct size and levels of serum CK-MB, LDH and cTnI were significantly increased, the expression of Rev-erb α, NLRP3 and IL-1β was up-regulated ( P<0.05), and the pathological injury of myocardial tissues was aggravated in DIR group.Compared with DIR group, the percentage of myocardial infarct size and serum CK-MB, LDH and cTnI levels were significantly decreased, the expression of Rev-erbα, NLRP3 and IL-1β was down-regulated ( P<0.05), and the pathological injury of myocardial tissues was reduced in DIR+ SR group. Conclusions:Rev-erbα can promote activation of NLRP3 inflammasome and is involved in the pathophysiological mechanism of myocardial I/R injury in diabetic rats.

Role of phosphoglycerate mutase 5 in myocardial ischemia-reperfusion injury in diabetic rats: relationship with mitochondrial quality / 中华麻醉学杂志

Objective:To evaluate the role of phosphoglycerate mutase 5 (phosphoglycerate mutase family member 5, PGAM5) in myocardial ischemia-reperfusion (I/R) injury in diabetic rats and the relationship with mitochondrial quality.Methods:SPF healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-220 g, were used in this study.Type 1 diabetes mellitus was induced by 1% streptozotocin diluted in citrate buffer solution 60 mg/kg.The rats were continuously fed for 8 weeks after successful establishment of the model.Seventy-two rats with type 1 diabetes mellitus were divided into 4 groups ( n=18 each) by a random number table method: diabetic sham operation group (DS group), diabetic myocardial I/R group (DIR group), diabetic myocardial I/R plus AAV9-PGAM5 shRNA group (DIR+ PGAM5 shRNA group), and diabetic myocardial I/R plus AAV9-GFP group (DIR+ GFP group). The myocardial I/R model was established by ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h starting from 8 weeks after establishment of type 1 diabetes mellitus model.AAV9-PGAM5 shRNA and AAV9-GFP 2×10 12 μg/kg were slowly injected via tail vein 3 weeks before ischemia.In group AAV9-PGAM5 shRNA, left ventricular systolic pressure (LVSP) and the maximum rate of increase or decrease in left ventricular systolic pressure (±dp/dt max) were monitored and recorded at the end of reperfusion, and then blood samples from the the right carotid artery were collected for determination of serum troponin Ⅰ(cTnI), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels (by enzyme-linked immunosorbent assay). The animals were sacrificed and hearts were obtained for determination of myocardial infarct size (by Evans Blue plus TTC double staining method) and expression of PGAM5, autophagy-related proteins (LC3B, p62), dynamin-related protein 1 (Drp1), and mitochondrial autophagy receptor protein (FUNDC1) (by Western blot) and for microscopic examination of pathological changes of myocardial tissues (by HE staining). Results:Compared with group DS, the LVSP and ±dp/dt max were significantly decreased, the serum levels of cTnI, CK-MB and LDH were increased, myocardial infarct size was increased, the expression of PGAM5, LC3B, Drp1 and FUNDC1 was up-regulated, and the expression of p62 was down-regulated in group DIR and group DIR+ GFP ( P<0.05). Compared with group DIR, LVSP and ±dp/dt max were significantly increased, the serum levels of cTnI, CK-MB and LDH were decreased, myocardial infarct size was decreased, the expression of PGAM5, LC3B, Drp1 and FUNDC1 was down-regulated, and the expression of p62 was up-regulated in group DIR+ PGAM5 shRNA ( P<0.05), and no significant change was found in the parameters mentioned above in group DIR+ GFP ( P>0.05). Conclusion:PGAM5 is involved in the myocardial I/R injury in diabetic rats, which is related to the reduction of mitochondrial quality.

Effect of TBK1 overexpression on hypoxia-reoxygenation injury in isolated mouse cardiomyocytes subjected to high glucose: relationship with mitochondrial autophagy / 中华麻醉学杂志

Objective:To evaluate the effect of TBK1 overexpression on hypoxia-reoxygenation (H/R) injury in isolated mouse cardiomyocytes subjected to high glucose and the relationship with mitochondrial autophagy.Methods:Normally cultured log-phase HL-1 mouse cardiomyocytes were inoculated in a 6-well plate at a density of 1×10 6 cells/ml and were divided into 4 groups ( n=10 each) using a random number table method: control group (group C), high glucose group (group HG), high glucose and H/R group (group HG+ H/R), and TBK1 overexpression group (group TBK1). The cells were incubated in culture medium with 1% fetal bovine serum and 1% double antibody for 24 h when the cell density reached 50%.When the cell density reached 80%, pcDNA3.1 (+ ) was used as a vector to achieve TBK1 overexpression.The cells were cultured with high glucose medium (33 mmol/L) for 24 h, exposed to 94% N 2+ 5% CO 2+ 1% O 2 for 24 h in an incubator at 37℃ followed by 12 h reoxygenation in an incubator containing 5% CO 2 at 37°C to establish the model of H/R injury to cardiomyocytes subjected to high glucose.After reoxygenation, CCK-8 assay was used to detect cell viability, the activity of lactic dehydrogenase (LDH) in supernatant was detected using LDH kit, mitochondrial contents were determined using Mito-Tracter green fluorescent probe, and the expression of TBK1 and mitophagy-related proteins PINK1, Parkin, LC3B and P62 was detected by Western blot. Results:Compared with group C, the cell viability was significantly decreased, the activity of LDH in supernatant was increased, mitochondrial contents were decreased, the expression of TBK1, PINK1, Parkin and LC3B was down-regulated, and the expression of P62 was up-regulated in HG group and HG+ H/R group ( P<0.05). Compared with group HG, the cell viability was significantly decreased, the activity of LDH in supernatant was increased, mitochondrial contents were decreased, the expression of TBK1, PINK1, Parkin and LC3B was down-regulated, and the expression of P62 was up-regulated in group HG+ H/R ( P<0.05). Compared with group HG+ H/R, the the cell viability was significantly increased, the activity of LDH in supernatant was decreased, mitochondrial contents were increased, the expression of TBK1, PINK1, Parkin and LC3B was up-regulated, and the expression of P62 was down-regulated in group TBK1 ( P<0.05). Conclusion:The mechanism by which TBK1 overexpression reduces the H/R injury is related to restoring mitophagy in isolated mouse cardiomyocytes subjected to high glucose.

Role of HIF-1α in renal injury induced by myocardial ischemia-reperfusion in diabetic rats: relationship with SLC7A11 / 中华麻醉学杂志

Objective:To evaluate the role of hypoxia-inducible factor-1α (HIF-1α) in the renal injury induced by myocardial ischemia-reperfusion (I/R) in diabetic rats and its relationship with solute carrier family7 member11 (SLC7A11).Methods:SPF-grade healthy male Sprague-Dawley rats, aged 4 weeks, weighing 100-130 g, were fed with high-fat and high-sucrose diet freely.The weight of the rats was measured once a week.After the weight of the animals reached 240 g, 1% streptozotocin (STZ)-citrate buffer 35 mg/kg was injected intraperitoneally to induce type 2 diabetes mellitus.After injection of STZ, the animals were fed with high-fat and high-sucrose diet continuously.Blood samples were collected from the tail vein for determination of blood glucose concentrations 1 week later.When random blood glucose was ≥16.7 mmol/L for 3 times, the model of type 2 diabetes mellitus was considered to be established successfully.After the model was established successfully, the animals were fed with high-fat and high-sucrose diet continuously for 6 weeks.Eighteen rats with type 2 diabetes mellitus were selected and divided into 3 groups ( n=6 each) using a random number table method: diabetic sham operation group (group DS), diabetic myocardial I/R group (group DIR) and diabetic myocardial I/R+ HIF-1α agonist DMOG group (DIR+ DMOG group). Twelve non-diabetic rats were divided into 2 groups ( n=6 each) using a random number table method: non-diabetic sham operation group (NS group) and non-diabetic myocardial I/R group (NIR group). The rat myocardial I/R injury model was established by ligating the anterior descending branch of the left coronary artery for 30 min followed by 120 min reperfusion in anesthetized rats.Blood samples were collected from the right internal carotid artery at 120 min of reperfusion for determination of the serum creatinine (Cr), urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) concentrations (by enzyme-linked immunosorbent assay). Renal tissues were obtained for examination of the pathological changes (by HE staining method) and for determination of the expression of HIF-1α and SLC7A11 (by Western blot). The damage to the renal tubules was scored. Results:Compared with group NS, the concentrations of serum Cr, BUN and NGAL and renal tubular damage score were significantly increased in group DS and group NIR, the expression of HIF-1α and SLC7A11 was down-regulated in group DS, and the expression of HIF-1α and SLC7A11 was up-regulated in group NIR ( P<0.05). Compared with group DS, the concentrations of serum Cr, BUN and NGAL and renal tubular damage score were significantly increased, and the expression of HIF-1α and SLC7A11 was up-regulated in group DIR ( P<0.05). Compared with group NIR, the concentrations of serum Cr, BUN and NGAL and renal tubular damage score were significantly increased, and the expression of HIF-1α and SLC7A11 was down-regulated in group DIR ( P<0.05). Compared with group DIR, the concentrations of serum Cr, BUN and NGAL and renal tubular damage score were significantly decreased, and the expression of HIF-1α and SLC7A11 was up-regulated in group DIR+ DMOG ( P<0.05). Conclusion:HIF-1α is involved in the renal injury induced by myocardial I/R, which is related to regulation of the expression of SLC7A11 in rats.

Role of Notch1/Hes1 signaling pathway in high glucose and hypoxia-reoxygenation injury to cardiomyocytes / 中华麻醉学杂志

Objective:To evaluate the role of Notch1/hairy and enhancer of split homolog1(Hes1) signaling pathway in high glucose and hypoxia-reoxygenation (H/R) injury to cardiomyocytes.Methods:H9c2 cardiomyocytes were cultured in low-glucose DMEM culture medium supplemented with 10% fetal bovine serum.The cells were divided into 6 groups ( n=12 each) using a random number table method: control group (group C), H/R group, H/R+ Jagged-1 group (group H/R+ J), high glucose group (group HG), high glucose+ H/R group (group HG+ H/R) and high glucose+ H/R+ Jagged-1 group (group HG+ H/R+ J). The cells were incubated in low-glucose culture medium for 72 h in group C. After incubated in low-glucose culture medium for 72 h, the cells were exposed to 24-h hypoxia in an incubator filled with 95% N 2-5% CO 2 at 37℃, immediately followed by 6-h reoxygenation in an incubator filled with 95% O 2-5% CO 2 at 37℃ in group H/R.In group H/R+ J, Jagged-1 (Notch1/Hes1 signaling pathway specific activator) 5μg/ml was added to low-glucose culture medium and the cells were incubated for 72h before H/R.In group HG, H9c2 cardiomyocytes were incubated in high-glucose culture medium containing 33 mmol/L glucose for 72 h. In group HG+ H/R, the cells were incubated in high-glucose medium for 72 h before H/R.In group HG+ H/R+ J, Jagged-1 5μg/ml was added to high-glucose culture medium, and the cells were incubated for 72 h before H/R.At 6 h of reoxygenation, the supernatant of the culture medium was collected for detection of the activities of superoxide dismutase (SOD) and lactic dehydrogenase (LDH), the cell viability (by CCK-8 assay) and the cell apoptosis rate (by flow cytometry) and for determination of expression of Notch1, Hes1 and c-caspase-3 (by Western blot). Results:Compared with group C, the cell survival rate and SOD activity were significantly decreased, and apoptosis rate and LDH activity were increased in H/R, H/R+ J and HG groups, expression of Notch1, Hes1 and c-caspase-3 was up-regulated in H/R and H/R+ J groups, and the expression of Notch1 and Hes1 was down-regulated and c-caspase-3 expression was up-regulated in group HG ( P<0.05). Compared with group H/R, the cell survival rate and SOD activity was significantly increased, apoptosis rate and LDH activity were decreased, expression of Notch1 and Hes1 was up-regulated, and c-caspase-3 expression was down-regulated in group H/R+ J, and the cell survival rate and SOD activity were significantly decreased, apoptosis rate and LDH activity were increased, expression of Notch1 and Hes1 was down-regulated, and c-caspase-3 expression was up-regulated in group HG+ H/R ( P<0.05). Compared with group HG, the cell survival rate and SOD activity were significantly decreased, and apoptosis rate and LDH activity were increased in HG+ H/R and HG+ H/R+ J groups ( P<0.05), and expression of Notch1 and Hes1 was down-regulated, and c-caspase-3 expression was up-regulated in group HG+ H/R ( P<0.05). Compared with group HG+ H/R, the cell survival rate and SOD activity were significantly increased, apoptosis rate and LDH activity were decreased, expression of Notch1 and Hes1 was up-regulated, and c-caspase-3 expression was down-regulated in group HG+ H/R+ J ( P<0.05). Compared with group H/R+ J, the cell survival rate and SOD activity were significantly decreased, apoptosis rate and LDH activity were increased, expression of Notch1 and Hes1 was down-regulated, and c-caspase-3 expression was up-regulated in group HG+ H/R+ J ( P<0.05). Conclusion:Activation of Notch1/Hes1 signaling pathway is the endogenous protective mechanism of high glucose and H/R injury to cardiomyocytes.

Role of NRF2 in myocardial ischemia-reperfusion injury in diabetic rats: relationship with ferroptosis / 中华麻醉学杂志

Objective:To evaluate the role of nuclear factor E2-related factor 2 (NRF2) in myocardial ischemia-reperfusion (I/R) injury and the relationship with ferroptosis in diabetic rats.Methods:Forty-eight SPF healthy adult male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-220 g, were divided into 5 groups by a random number table method: sham operation group (group S, n=6), myocardial I/R group (group NIR, n=12), diabetes mellitus+ sham operation group (group DS, n=6), diabetes mellitus+ myocardial I/R group (group DIR, n=12) and diabetes mellitus+ myocardial I/R+ NRF2 agonist sulforaphane group (group DIR+ SFN, n=12). Type 1 diabetes mellitus was induced by intraperitoneal injection of 1% streptozotocin-citrate buffer 60 mg/kg.Sulforaphane 500 μg·kg -1·d -1 was injected intraperitoneally before ischemia for 3 consecutive days in group DIR+ SFN.At the 8th week after establishing the model, myocardial I/R was produced by occlusion of the anterior descending branch of the left coronary artery for 30 min followed by reperfusion.At 2 h of reperfusion, the left ventricular systolic pressure (LVSP), HR, and the maximum rate of increase and decrease of left ventricular systolic pressure (±dp/dt max) were recorded.Blood samples were taken from the carotid artery and the animals were then sacrificed for determination of concentration of cardiac troponin I (cTnI) in serum (using enzyme-linked immunosorbent assay), myocardial Fe 2+ and malondialdehyde (MDA) contents, superoxide dismutase (SOD) activity (by colorimetry) and myocardial infarct size (using TTC) and for determination of expression of NRF2, ferroportin1 (FPN1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) (by Western blot), and the pathological changes of lung tissues were observed by hematoxylin-eosin staining. Results:Compared with group S, LVSP, HR, and ±dp/dt max were significantly decreased, serum cTnI concentration and myocardial Fe 2+ and MDA contents were increased, SOD activity was decreased, expression of ACSL4 was up-regulated and expression of NRF2 and FPN1 was down-regulated in group NIR ( P<0.05). Compared with group DS, LVSP, HR, and ±dp/dt max were significantly decreased, serum cTnI concentration and myocardial Fe 2+ and MDA contents were increased, SOD activity was decreased, expression of ACSL4 was up-regulated and expression of NRF2 and FPN1 was down-regulated in group DIR ( P<0.05). Compared with group NIR, LVSP, HR, and ±dp/dt max were significantly decreased, serum cTnI concentration and myocardial Fe 2+ and MDA contents were increased, SOD activity was decreased, myocardial infarct size was increased, expression of ACSL4 was up-regulated and expression of NRF2 and FPN1 was down-regulated in group DIR ( P<0.05). Compared with group DIR, LVSP, HR, and ±dp/dt max were significantly increased, serum cTnI concentration and myocardial Fe 2+ and MDA contents were decreased, SOD activity was increased, myocardial infarct size was decreased, expression of ACSL4 was down-regulated and expression of NRF2 and FPN1 was up-regulated in group DIR+ SFN ( P<0.05). Conclusion:NRF2 is involved in the process of myocardial I/R injury, which is related to promoting ferroptosis in diabetic rats

Establishment of HPLC Fingerprint ，Chemical Pattern Recognition Analysis and Content Determination of the Leaves of Toricellia angulata from Different Regions / 中国药房

OBJECTIVE：To provide reference for the quality control of the leaves of Toricellia angulata . METHODS ：HPLC method was adopted. The determination was performed on Agela Promosil C 18 column with 0.2％ phosphoric acid solution-acetonitrile（gradient elution ）as mobile phase at the flow rate of 1.0 mL/min. The detection wavelength was set at 210 nm，and column temperature was 35 ℃. The sample size was 10 μL. HPLC fingerprint of 10 batches of the leaves of T. angulata was established and similarity evaluation was conducted by using Similarity Evaluation System of TCM Chromatographic Fingerprint（2004 edition）. The chromatographic peak was identified by comparing with the chromatogram of reference substance. Cluster analysis ，PCA and PLS-DA were used to identify chemical patterns ，and the quality differential markers were screened. The contents of hyperoside and isoquercitrin were determined by the same HPLC. RESULTS ：The similarities of HPLC fingerprint of 10 batches of the leaves of T. angulata with control fingerprint were 0.923-0.983. A total of 11 common peaks were identified ，and the peaks 4 and 5 were hyperoside and isoquercitrin ，respectively. Results of cluster analysis ，PCA and PLS-DA showed that 10 batches of leaves of T. angulata could be divided into two categories ，Y10 was clustered into one category ，and others were clustered into one category. PLS-DA analysis showed that 6 common peaks （peaks 4，3，10，2，6 and 11） with variable importance projection （VIP）greater than 1 were selected. Average contents of hyperoside and isoquercitrin in 10 batches of the leaves of T. angulata were 0.47-6.97，0.21-1.87 mg/g，respectively. CONCLUSIONS ：Established HPLC fingerprint and the method for content determination are stable and reliable ，and can be used for the quality control of the leaves of T. angulata from different areas. Six quality differential markers including hyperoside in the leaves of T. angulata from different areas are qnyz202034） preliminarily screened.

Blood eosinophils and mortality in patients with acute respiratory distress syndrome: A propensity score matching analysis / 世界急诊医学杂志（英文）

@#BACKGROUND: The effect of blood eosinophils (EOSs) on mortality in acute respiratory distress syndrome (ARDS) patients and whether corticosteroids affect this effect are unclear. METHODS: The Medical Information Mart for Intensive Care III database (version 1.4) was used to extract data. Patients with ARDS were selected for inclusion. Cox regression models using the backward stepwise method and propensity score matching (PSM) were used to assess the relationship between blood EOS counts and 28-day mortality. RESULTS: A total of 2,567 patients with ARDS were included, and the 28-day mortality rate was 24.19%. The crude 28-day mortality was significantly lower in patients with EOS counts ≥2% (18.60% [85/457] vs. 25.40% [536/2,110], P=0.002) than in those with EOS counts <2%. In the Cox regression model, the EOS counts ≥2% showed a significant association with the decreased 28-day mortality (hazard ratio [HR] 0.731; 95% confidence interval [95% CI] 0.581-0.921, P=0.008). In the corticosteroid non-use subgroup, EOS counts ≥2% was significantly related to decreased 28-day mortality (HR 0.697, 95% CI 0.535-0.909, P=0.008), but the result was not significant in the corticosteroid non-use subgroup model (P=0.860). A total of 457 well-matched pairs were obtained by a 1:1 matching algorithm after PSM. The 28-day mortality remained significantly lower in the EOS counts ≥2% group (18.60% [85/457] vs. 26.70% [122/457], P=0.003). CONCLUSIONS: Higher EOS counts are related to lower 28-day mortality in ARDS patients, and this relationship can be counteracted by using corticosteroids.

Biomechanical Study of the Open-Type Stent Retriever / 医用生物力学

Objective To simulate the process of thrombus removal from the open-type stent retrievers, so as to provide theoretical references for the design and clinical application of the open-type stent retrievers. Methods Finite element models of the open-type stent retrievers with 3,4,5 supporting units (K3,K4,K5), the crimping tools, simulated vessels and simulated thrombus (three types) were established. Radial displacement load was applied on the crimping tool until the stent was crimped to 0.5 mm, and the maximum principal strain (MPS) peak and radial force (RF)of the stent were analyzed. When displacement of the crimping tool was restored, the stent self-expanded and contacted with blood vessels, and MPS of the stent and von Mises stress (VMS) of blood vessels were analyzed. Axial displacement was applied to proximal end of the stents to allow the stent to drive the clots to migrate, and the blood vessel VMS and withdrawal force of the stents (the ability to capture thrombus) were analyzed. ResultsThe MPS peaks for 3 types of stent retrievers during crimping process were 6.94%, 8.30% and 5.48%, which were all smaller than the 12% fracture limit. When the outer diameter of the stent was 3 mm (equal to the inner diameter of blood vessels), the K4 stent had the largest RF. The results of self-expanding release process showed that the larger the number of support units, the greater the VMS of blood vessels. At the stage of thrombus migration and removal,the VMS of blood vessels was generally small and concentrated on the thrombus. The withdrawal force of the stent reached the maximum at the initial stage of thrombus migration and removal, then gradually decreased. The peak withdrawal force of the K4 stent was larger than that of the K5 and K3 stent. Conclusions Although the MPS and VMS for 3 types of open-type stent retrievers were within the safe range, the K4 stent showed better performance in RF and withdrawal force with the three types of thrombus. The research findings can provide the analysis methods and ideas for optimizing the open-type stent retrievers, to avoid clinical complications such as vascular injury and improve safety and effectiveness of the stent retrievers.

Preoperative Planning of Acetabular Arc Osteotomy Using Finite Element Method / 医用生物力学

Objective In order to simulate different angles of acetabular blocks that need to be adjusted during operation, the optimal angle was determined through analyzing the contact stress and contact area of cartilage around the hip joint, so as to provide an individual scheme for acetabular osteotomy. Methods The finite element models for development dysplasia of hip (DDH) and normal pelvis were established to investigate morphological characteristics of the acetabulum and the causes of stress concentration. To simulate osteotomy for the DDH model, a total of 20 postoperative osteotomy models were obtained through the combination of different angles for anterior rotation and lateral rotation of acetabular blocks, and the differences in optimal results of the models during simulated one legged-standing were compared and analyzed. Results The maximum contact pressure of acetabular cartilage in normal model was 7.85 MPa. The maximum contact pressure of acetabular cartilage in DDH model was 13.42 MPa. The optimal contact pressure after simulated osteotomy decreased to 8.49 MPa, and the contact distribution was improved more significantly. Conclusions Changing the anterior rotation angle can significantly improve the contact pressure distribution and size, as well as stay away from the preoperative lesion area, which has a positive impact on postoperative outcomes. Personalized osteotomy plan based on actual situation of each patient before the operation is crucial for the surgical effect.

Origanum vulgare L. leaf extract alleviates finasteride-induced oxidative stress in mouse liver and kidney

Objective: To investigate the hepatorenoprotective effects of Origanum vulgare L. against finasteride-induced oxidative injury in the liver and kidney of mice. Methods: Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI/MS) analysis was utilized to yield a fingerprint of Origanum vulgare polyphenolic constituents. Thirty BALB/c mice received 0.5 mL/day distilled water, finasteride (25 mg/kg/day for 10 d), and 100, 200, or 400 mg/kg/day finasteride + Origanum vulgare extract with 6 mice per group for five weeks. On day 36, liver and kidney function as well as pro- and anti-inflammatory (IFN-γ, IL-12, IL-6, TNF-α, IL-1β, and IL-10) cytokines were measured. The total antioxidant status, nitric oxide (NO), and malondialdehyde levels as well as the activities of NO synthase and catalase were also evaluated. Histopathological study was conducted to assess the effect of Origanum vulgare extract on finasteride-induced renal and hepatic toxicities. Results: Twenty-five major polyphenolic compounds were identified in the Origanum vulgare extract by LC-ESI/MS. Origanum vulgare extract, especially at 200 and 400 mg/kg/day doses, significantly improved liver and kidney biochemical indices, decreased inflammatory cytokines, increased total antioxidant status and NO synthase and catalase activities, as well as decreased plasma NO and malondialdehyde levels in a dose-dependent manner as compared to the finasteride group. Histopathological results further confirmed the protective effect of Origanum vulgare extract. Conclusions: Origanum vulgare extract ameliorates finasteride-induced hepatic and renal biochemical and histopathological alterations, and restores antioxidant/oxidant balance.

Effects of traditional Chinese exercises and general aerobic exercises on older adults with sleep disorders: A systematic review and meta-analysis / 中西医结合学报

BACKGROUND@#Sleep disorders are common in older adults and have a negative influence on their physical and mental health. General aerobic exercises (GAEs) have long been used in the treatment of sleep disorders as a non-pharmacological measure. However, there is no consensus on the efficacy of traditional Chinese exercises (TCEs) for treating sleep disorders in older adults and the difference between TCEs and GAEs.@*OBJECTIVE@#This study assessed the effects of TCEs and GAEs on the sleep quality of older adults and the differences between these two interventions.@*SEARCH STRATEGY@#PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine disc, China National Knowledge Infrastructure, China Science Journal Database and Wanfang Data were searched from their inception to August 2020.@*INCLUSION CRITERIA@#Randomized controlled trials (RCTs) that evaluated the effects of TCEs and GAEs on older adults with sleep disorders were included.@*DATA EXTRACTION AND ANALYSIS@#Data were extracted by two researchers working independently. The risk bias of included studies was assessed using the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 and the quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. The Pittsburgh Sleep Quality Index (PSQI) was used to estimate sleep quality. Meta-analyses were performed to assess the total PSQI score of the exercise intervention as the primary outcome, and the scores of subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleep medication and daytime dysfunction were assessed as secondary outcomes. Subgroup, sensitivity, and meta-regression analyses were conducted to assess the contribution of covariables to heterogeneity.@*RESULTS@#A total of 22 RCTs (including 1747 participants) were included in the meta-analysis. The results indicated that TCEs (weighted mean difference [WMD] = -2.14, 95% confidence interval [CI] [-2.82, -1.46], P < 0.001; heterogeneity: P < 0.001, I@*CONCLUSION@#Current evidence shows that both TCEs and GAEs, as complementary and non-pharmacological approaches, help to improve the sleep quality in older adults with potentially clinical implications; however, there was not enough evidence to conclude the difference between them. More rigorous and high-quality RCTs are needed to arrive at reliable conclusions.

Origanum vulgare L. leaf extract alleviates finasteride-induced oxidative stress in mouse liver and kidney

Objective: To investigate the hepatorenoprotective effects of Origanum vulgare L. against finasteride-induced oxidative injury in the liver and kidney of mice. Methods: Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI/MS) analysis was utilized to yield a fingerprint of Origanum vulgare polyphenolic constituents. Thirty BALB/c mice received 0.5 mL/day distilled water, finasteride (25 mg/kg/day for 10 d), and 100, 200, or 400 mg/kg/day finasteride + Origanum vulgare extract with 6 mice per group for five weeks. On day 36, liver and kidney function as well as pro-and antiinflammatory (IFN-γ, IL-12, IL-6, TNF-α, IL-1β, and IL-10) cytokines were measured. The total antioxidant status, nitric oxide (NO), and malondialdehyde levels as well as the activities of NO synthase and catalase were also evaluated. Histopathological study was conducted to assess the effect of Origanum vulgare extract on finasteride-induced renal and hepatic toxicities. Results: Twenty-five major polyphenolic compounds were identified in the Origanum vulgare extract by LC-ESI/MS. Origanum vulgare extract, especially at 200 and 400 mg/kg/day doses, significantly improved liver and kidney biochemical indices, decreased inflammatory cytokines, increased total antioxidant status and NO synthase and catalase activities, as well as decreased plasma NO and malondialdehyde levels in a dose-dependent manner as compared to the finasteride group. Histopathological results further confirmed the protective effect of Origanum vulgare extract. Conclusions: Origanum vulgare extract ameliorates finasteride-induced hepatic and renal biochemical and histopathological alterations, and restores antioxidant/oxidant balance.

Three-dimensional chromosome conformation capture and its derived technologies / 生物工程学报

Linear chromatin is compacted into eukaryotic nucleus through a complex and multi-layered architecture. Consequently, chromatin conformation in a local or long-distance manner is strongly correlated with gene expression. Chromosome conformation capture (3C) technology, together with its variants like 4C/5C/Hi-C, has been well developed to study chromatin looping and whole genome structure. In this review, we introduce new technologies including chromosome capture combined with immunoprecipitation, nuclei acid-based hybridization, single cell and genome sequencing, as well as their application.

A new strategy based on acid-alkali complexation for rapidly and accurately fishing phytochemicals in sennae folium / 中草药·英文版

Objective: There are some anthraquinones, anthraquinones and flavonones in Sennae Folium which exhibited significant acidity, such as sennoside A/B and sennoside C/D. The current strategies used in separating these components are mainly based on conventional column chromatography which is time consuming, laborious and costly. This study is aimed at exploring a method of precipitation extraction of acid components in Sennae Folium. Using alkaloid as a “hook”, it is reasonable to use the principle of “acid-alkali complexation” to "fish" the acidic components in Sennae Folium. Methods: Isothermal titration calorimeter (ITC) was used to measure the extraction efficiency of different alkaloids. Then, alkaloid determined by ITC was mixed with extracting solution of Sennae Folium to form complex. High performance liquid chromatography coupled with mass spectrometry (HPLC-MS2) was used to investigate the ingredients “fished” by berberine (Ber). The mechanism of “fishing” process was explained by ITC, optical activity, fluorescence spectrometry and scanning electron microscope. Results: The ITC results proved that the choice of “hook” was particularly important in the process of “fishing”. Among the hooks, the fishing efficiency of the isoquinoline alkaloids (Ber) was the highest, reaching 10.3%. Nine ingredients were detected and determined by HPLC-MS2, and the main components were sennoside A/B and sennoside C/D. Based on ITC test of Ber and sennoside A, the combination mechanism of the two ingredients was a chemical reaction with a nearly binding ratio (2:1). Fluorescence and optical properties of the active ingredients were changed after complexation. By scanning electron microscope, we found that two types of components had obviously self-assembled behavior during the formation process. Conclusion: Ber successfully “fished” the main acidic components, sennoside A/B and sennoside C/D, from Sennae Folium. Combined with different characterizations, the “fishing” process was determined as a chemical association reaction induced by electrostatic interaction or π-π stacking. Therefore, with special identification ability, the “fishing” process had the potential of practical application.

The Effect of Pelvic Modeling on Outcome in Preoperative Planning for Bernese Acetabular Osteotomy / 医用生物力学

Objective To explore the influence of different model scopes on acetabular stress distribution and optimal osteotomy result in preoperative planning of Bernese acetabular osteotomy. Methods Two patients with hip dysplasia were established according to different model ranges. Model 1 included the affected hip and femur, and Model 2 included the complete pelvis and affected femur. Compare and analyze the acetabular cartilage contact pressure, area and distribution of the two models under single-leg standing conditions, and simulate osteotomy. Results Compared with Model 1 before surgery, Model 2 had higher contact pressure, smaller contact area and closer distribution to the meniscus edge of acetabulum. Compared with 11 postoperative plans, the variation amplitude of contact pressure and the optimal osteotomy angle for Model 1 were all smaller than those of Model 2. Conclusions The preoperative analysis result of the model with affected hip bone and femur would underestimate the degree of stress concentration and misjudge the location of stress concentration, and the obtained optimal osteotomy rotation angle would be relatively small. The research findings provide certain theoretical basis for preoperative planning and modeling of osteotomy.