BACKGROUND:The imbalance between bone resorption and bone formation in microgravity environments leads to significant bone loss in astronauts.Current research indicates that bone loss under microgravity conditions is the result of the combined effects of various cells,tissues,and systems. OBJECTIVE:To review different biological effects of microgravity on various cells,tissues,or systems,and summarize the mechanisms by which microgravity leads to the development of osteoporosis. METHODS:Databases such as PubMed,Web of Science,and the Cochrane Database were searched for relevant literature from 2000 to 2023.The inclusion criteria were all articles related to tissue engineering studies and basic research on osteoporosis caused by microgravity.Ultimately,85 articles were included for review. RESULTS AND CONCLUSION:(1)In microgravity environment,bone marrow mesenchymal stem cells tend to differentiate more into adipocytes rather than osteoblasts,and hematopoietic stem cells in this environment are more inclined to differentiate into osteoclasts,reducing differentiation into the erythroid lineage.At the same time,microgravity inhibits the proliferation and differentiation of osteoblasts,promotes apoptosis of osteoblasts,alters cell morphology,and reduces the mineralization capacity of osteoblasts.Microgravity significantly increases the number and activity of osteoclasts.Microgravity also hinders the differentiation of osteoblasts into osteocytes and promotes the apoptosis of osteocytes.(2)In a microgravity environment,the body experiences changes such as skeletal muscle atrophy,microvascular remodeling,bone microcirculation disorders,and endocrine disruption.These changes lead to mechanical unloading in the bone microenvironment,insufficient blood perfusion,and calcium cycle disorders,which significantly impact the development of osteoporosis.(3)At present,the mechanism by which microgravity causes osteoporosis is relatively complex.A deeper study of these physiological mechanisms is crucial to ensuring the health of astronauts during long-term space missions,and provides a theoretical basis for the prevention and treatment of osteoporosis.

Cancer stem cells (CSCs) are proposed to account for the progression, metastasis, and recurrence of diverse malignancies. However, the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicines, posing a challenge in eliminating CSCs located distantly from blood vessels. Herein, a pair of twin-like small-sized nanoparticles, sunitinib (St)-loaded ROS responsive micelles (RM@St) and salinomycin (SAL)-loaded GSH responsive micelles (GM@SAL), are developed to normalize disordered tumor vessels and eradicate CSCs. RM@St releases sunitinib in response to the abundant ROS in the tumor extracellular microenvironment for tumor vessel normalization, which improved intratumor accumulation and homogeneous distribution of small-sized GM@SAL. Sequentially, GM@SAL effectively accesses CSCs and achieves reduction-responsive drug release at high GSH concentrations within CSCs. More importantly, RM@St significantly extends the window of vessel normalization and enhances vessel integrity compared to free sunitinib, thus further amplifying the anti-tumor effect of GM@SAL. The combination therapy of RM@St plus GM@SAL produces considerable depression of tumor growth, drastically reducing CSCs fractions to 5.6% and resulting in 78.4% inhibition of lung metastasis. This study offers novel insights into rational nanomedicines designed for superior therapeutic effects by vascular normalization and anti-CSCs therapy.

OBJECTIVES: To investigate the role of activating transcription factor 3 (ATF3) in atherosclerotic plaques for regulating inflammatory responses during atherosclerosis (AS) progression. METHODS: Human coronary artery specimens from autopsy cases were examined for ATF3 protein expression and localization using immunofluorescence staining and Western blotting. Apolipoprotein E-deficient (ApoE^-/-) mouse models of AS induced by high-fat diet (HFD) feeding for 12 weeks were subjected to tail vein injection of adeno-associated virus serotype 9 (AAV9) to knock down ATF3 expression. After an additional 5 weeks of HFD feeding, the mice were euthanized for analyzing structural changes of the aortic plaques, and the expression levels of ATF3, inflammatory factors (CD45, CD68, IL-1β, and TNF-α), and NF-κB pathway proteins (P-IKKα/β and P-NF-κB p65) were detected. In the cell experiment, THP-1-derived foam cells were transfected with an ATF3-overexpressing plasmid or an ATF3-specific siRNA to validate the relationship between ATF3 and NF‑κB signaling. RESULTS: In human atherosclerotic plaques, ATF3 expression was significantly elevated and partially co-localized with CD68. ATF3 knockout in ApoE^-/- mice significantly increased aortic plaque volume, upregulated the inflammatory factors, enhanced phosphorylation of the NF‑κB pathway proteins, and increased the expressions of VCAM1, MMP9, and MMP2 in the plaques. In THP-1-derived foam cells, ATF3 silencing caused activation of the NF‑κB pathway, while ATF3 overexpression suppressed the activity of the NF-κB pathway. CONCLUSIONS AS promotes ATF3 expression, and ATF3 deficiency exacerbates AS progression by enhancing plaque inflammation via activating the NF-κB pathway, suggesting the potential of ATF3 as a therapeutic target for AS.
Animals ; Activating Transcription Factor 3/metabolism* ; Signal Transduction ; NF-kappa B/metabolism* ; Humans ; Mice ; Plaque, Atherosclerotic/metabolism* ; Inflammation/metabolism* ; Apolipoproteins E ; Atherosclerosis/metabolism* ; Diet, High-Fat

Objective:To evaluate the role of mitophagy in cognitive dysfunction in rats with sepsis-associated encephalopathy (SAE).Methods:Twenty-four clean-grade healthy male Sprague-Dawley rats, aged 13-14 weeks, weighing 230-250 g, were divided into 3 groups ( n=8 each) using a random number table method: sham operation group (Sham group), SAE group and SAE+ autophagy inhibitor 3-methyladenine (3-MA) group (3-MA group).The SAE models were developed by cecal ligation and puncture in anesthetized animals.3-MA 10 mg/kg was intraperitoneally injected at 30 min after developing the model in 3-MA group.Cognitive function was assessed by Morris water maze test, and the escape latency and ratio of the time of staying at the target quadrant were recorded.After the end of Morris water maze test, the rats were sacrificed and hippocampal tissues were collected for microscopic examination of the pathological changes which were scored after hematoxylin-eosin staining and for determination of the expression of autophagy-related proteins LC3, Beclin1 and p62 (by Western blot).The ratio of LC3Ⅱ/LC3Ⅰwas calculated.The hippocampal mitochondria were isolated to measure mitochondrial membrane potential (MMP), ATP content and ATPase activity by spectrophotometry. Results:Compared with Sham group, the escape latency was significantly prolonged, the ratio of the time of staying at the target quadrant was decreased, the pathological score of hippocampus was decreased, and the contents of MMP and ATP and ATPase activity were decreased in SAE and 3-MA groups, the ratio of LC3Ⅱ/LC3Ⅰwas significantly increased, the expression of Beclin1 was up-regulated, and the expression of p62 was down-regulated in SAE group, and the ratio of LC3Ⅱ/LC3Ⅰwas significantly decreased, and the expression of Beclin1 and p62 was up-regulated in 3-MA group ( P<0.05).Compared with SAE group, the escape latency was significantly prolonged, the ratio of the time of staying at the target quadrant was decreased, the pathological score of hippocampus was decreased, the ratio of LC3/LC3Ⅰwas decreased, the expression of Beclin1 was down-regulated, the expression of p62 was up-regulated, and the contents of MMP and ATP and ATPase activity were decreased in 3-MA group ( P<0.05). Conclusions:Hippocampal mitophagy is involved in cognitive dysfunction in the rats with SAE.

Objective:To design a modified S1PR3 specific agonist, GPS-725.017, and investigate its protective effect on acute lung injury by promoting macrophage clearance of bacteria.Methods:A short peptide derived from the intracellular region of S1PR3 receptor was named GPS725.017, which was modified with norleucine (Nle) and myristicacid (myr) at its N terminus. Mice were divided into the sham operation group, solvent group and GPS-725.017 treatment group. The acute lung injury model was induced by endotracheal injection of E. coli (5×10 6 CFU), and the experimental group was treated with GPS-725.017 (10 mg/kg). The 48-h survival rate of mice was recorded. After 5 h of modeling, the bacterial load and inflammatory cytokines in peripheral blood and lung were detected, and Vps34 protein content in alveolar macrophages was determined by Western blot. After 12-h of modeling, lung tissues were collected for H&E staining and pathological scores. Results:Compared with the solvent group, the survival rate of mice in the GPS-725.017 treatment group was significantly improved ( P<0.01), the bacterial CFU in blood and alveolar lavage fluid was significantly lower than that in the solvent group ( P<0.001), and the levels of TNF-α and IL-1β in blood and alveolar lavage fluid were significantly lower than those in the solvent group ( P<0.001). Western blot showed that the expression level of Vps34 protein in alveolar macrophages was significantly higher than that in the solvent group ( P<0.01). Histopathology result showed that the pathological damage of lung in the treatment group was significantly less than that in the solvent group ( P<0.001). Conclusions:The modified synthetic S1PR3 specific agonist GPS-725.017 could specifically activate the S1PR3 receptor on the membrane of alveolar macrophages and up-regulate the expression level of intracellular Vps34 protein, which can promote the removal of bacteria in alveolar macrophages, significantly reduce the degree of lung injury and improve the survival rate in ALI mice.

Objective:To investigate the effects of different connection schemes of continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) on arterial pressure (PA), venous pressure (PV), and transmembrane pressure (TMP), and to provide a theoretical basis for choosing a suitable connection scheme.Methods:① In vitro study: the different connection schemes of CRRT and ECMO were simulated and divided into 6 schemes according to the connection between CRRT and ECMO circuits at different positions. Scheme A: connected to the front and back points of the oxygenator; scheme B: connected to the points behind and in front of the oxygenator; scheme C: connected to the points in front of the oxygenator and in front of the centrifugal pump; scheme D: connected to the points behind the oxygenator and in front of the centrifugal pump; scheme E: connected to the points in front of the oxygenator and the return catheter; scheme F: connected to the points after the oxygenator and the return catheter. Each set of ECMO circuits was measured 5 times under each connection scheme and different flow rates (2, 3, 4, 5, 5.5 L/min). Six ECMO circuits for a total of 30 measurements, and the PA, PV, and TMP of the 6 schemes were compared. ② In vivo study: the patients who were treated with ECMO combined with CRRT in the department of critical care medicine of the First Affiliated Hospital of Wannan Medical College from August 2017 to August 2021 changed the connection scheme due to high PA or PV (from scheme A or B to scheme E or F) were retrospectively analyzed. The changes of PA and PV before and after changing the scheme were compared. Results:① In vitro study results: there was no significant difference in PA between schemes A and B, C and D, E and F under different ECMO blood flow (2-5.5 L/min). The PA of schemes C and D was the lowest, followed by schemes E and F. PV of scheme B was higher than that of scheme A under different ECMO blood flow (2-5.5 L/min). There was no significant difference in PV between schemes C and D, E and F under high ECMO blood flow (3-5.5 L/min), and the absolute value of PV was lowest in schemes E and F. Compared with schemes A and B [partial PA > 300 mmHg (1 mmHg≈0.133 kPa) at high flow rate], C and D (partial PV > 350 mmHg at high flow rate), schemes E and F were more reasonable connection schemes. TMP was negative in schemes C and D at ECMO blood flow of 5 L/min and 5.5 L/min (mmHg; 5 L/min: scheme C was -29.14±11.42, scheme D was -42.45±15.70; 5.5 L/min: scheme C was -35.75±13.21, scheme D was -41.58±15.42), which indicated the presence of dialysate reverse filtration. Most of the differences in TMP among schemes A, B, E, and F under different ECMO blood flow (2-5.5 L/min) were statistically significant, and the absolute value of mean fluctuation was 9.89-49.55 mmHg, all within the normal range. ② In vivo study results: a total of 10 patients who changed the connection scheme (from scheme A or B to E or F) due to high PA or PV were enrolled, including 8 males and 2 females; 7 cases of venous-arterial ECMO (VA-ECMO) and 3 cases of venous-venous ECMO (VV-ECMO), all used continuous veno-venous hemodiafiltration (CVVHDF) mode. After changing the scheme, both PA and PV decreased significantly as compared with those before changing [PA (mmHg): 244.00±22.58 vs. 257.20±21.92, PV (mmHg): 257.20±18.43 vs. 326.40±15.41, both P < 0.01], and PV decreased more significantly than PA [difference (mmHg): 69.20±6.55 vs. 13.20±5.45, P < 0.01]. Conclusion:For patients treated with ECMO in combination with CRRT, the scheme of connecting the access line of CRRT to the pre-oxygenator or post-oxygenator and connecting the return line to the point of the return catheter can significantly reduce PA and PV and maintains normal CRRT operation even running high-flow ECMO.

Objective:To evaluate the role of p38 mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway in tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with sepsis-associated encephalopathy (SAE).Methods:Sixty healthy male C57BL6 mice, weighing 24-27 g, were divided into 4 groups ( n=15 each) using a random number table method: sham operation group (group Sham), sepsis group (group Sep), tetramethylpyrazine group (group TMP) and p38 MAPK inhibitor SB203580 group (group SB). The model of SAE was established by cecal ligation and puncture in anesthetized mice.Tetramethylpyrazine 10 mg/kg was injected intraperitoneally once a day at 3 days before the establishment of the model in TMP group, and SB203580 2.0 mg/kg was intraperitoneally injected at 30 min after the establishment of the model in SB group.The equal volume of normal saline was given intraperitoneally in Sham and Sep groups.At 1 day after operation, cognitive function was assessed by Morris water maze, and the escape latency and ratio of time spent in the target quadrant were recorded.The animals were sacrificed after the test, and hippocampal tissues were taken for determination of the contents of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 (by enzyme-linked immunosorbent assay) and for detection of the expression of phosphorylation of p38 MAPK, GSK3 and CREB and expression of brain-derived neurotrophic factor (BDNF) (by Western blot). Results:Compared with group Sham, the escape latency was significantly prolonged, the ratios of time spent in the target quadrant were decreased, the contents of IL-1β, TNF-α and IL-6 were increased, the phosphorylation of hippocampus p38 MAPK was increased, the phosphorylation of GSK3 and CREB were decreased, and the expression of BDNF was down-regulated in Sep, TMP and SB groups ( P<0.05). Compared with group Sep, the escape latency was significantly shortened, the ratios of time spent in the target quadrant were increased, the contents of IL-1β, TNF-α and IL-6 were decreased, the phosphorylation of hippocampus p38 MAPK was decreased, the phosphorylation of GSK3 and CREB were increased, and the expression of BDNF was up-regulated in TMP and SB groups ( P<0.05). Compared with group TMP, no significant change was found in the parameters mentioned above in group SB ( P>0.05). Conclusion:p38 MAPK/CREB signaling pathway is involved in the process of tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with SAE.

OBJECTIVE: To explore the safety, feasibility and short-term efficacy of intracavitary uncut Roux-en-Y (URY) anastomosis in digestive tract reconstruction following laparoscopic total gastrectomy (LTG). METHODS: From November 2015 to January 2018, 67 gastric cancer patients underwent intracavitary URY following LTG to reconstruct the digestive tract at Oncological Surgery Department of Fujian Provincial Hospital. There were 41 males and 26 females with age of 50 to 81 (61.9±7.4) years and body mass index (BMI) of (23.4±3.2) kg/m². Among 67 patients, 19 were gastric cardia carcinomas, 33 were gastric body carcinomas, and 15 were gastric fundus carcinomas; tumor size was (3.4±2.3) cm; 22 were Borrmann type I, 15 were type II, 21 were type III, and 19 were type IV; 29 were highly or moderately differentiated adenocarcinoma, 23 were lowly differentiated adenocarcinoma, and 15 were signet-ring cell carcinoma. After conventional laparoscopic D2 radical gastrectomy, the duodenum was closed and dissociated at 2 cm below the pyloric ring using the Echelon-flex endoscopic articulated linear Endo-GIA stapler, and the esophagus was dissociated above the esophagogastric junction (EGJ).URY and digestive tract reconstruction were performed under the direct vision of laparoscope: (1) Side-to-side esophagojejunostomy: An incision of 0.5 cm was made in the left lower edge of the esophageal closed end; jejunum about 25 cm distal away from the Treitz ligament was elevated to the lower end of esophagus; another incision of 0.5 cm was made in the contralateral of mesenteric side; both arms of the linear Endo-GIA stapler were inserted into the windows opened through esophagus and jejunum respectively to complete side-to-side anastomosis. The common opening of esophagus and jejunum was closed to complete esophagojejunostomy, forming the chyme outflow tract. (2) Side-to-side Braun jejunojejunostomy: Incisions of 0.5 cm were made in the proximal jejunum about 10 cm away from the esophagojejunal anastomosis and 35-40 cm away from the contralateral of mesenteric side of distal jejunum respectively for proximal-distal side-to-side jejunojejunostomy. The common opening was closed to form the biliopancreatic duodenal juice outflow tract. (3) Closure of the input loop jejunum in the esophagojejunal anastomosis: The input loop jejunum 2-3 cm away from the esophagojejunal anastomosis was closed using the non-blade linear stapler (ATS45NK), and the biliopancreatic duodenal juice reflux was blocked. Clinical data of these patients were collected for retrospective case series study. Surgical and digestive tract functional recovery, perioperative complications, as well as postoperative nutritional status were observed. Moreover, related indexes, such as anastomosis function and tumor recurrence were evaluated through endoscopic and imaging examinations during postoperative follows-up. RESULTS: All the 67 patients completed the surgery successfully. The mean operative time was (259.4±38.5) minutes, digestive tract reconstruction time was (38.2±13.2) minutes, intraoperative blood loss was (73.4±38.4) ml, and number of harvested lymph node was 36.2±14.2. The mean distance from upper resection margin to upper tumor edge was (3.3±1.2) cm, distance from upper resection margin to dentate line was (1.2±0.7) cm, and 1 case had positive upper incisal margin, which became negative after the second resection. Moreover, the average length of the auxiliary incision was (3.2±0.4) cm. The mean postoperative intestinal exhaust time was (52.8±26.4) hours, time to liquid diet was (64.8±28.8) hours, and postoperative hospital stay was (8.4±2.5) days. The morbidity of postoperative complication was 10.4%(7/67). Among these 7 cases, 4 cases were grade IIIa of Clavien-Dindo classification, including 2 with esophagojejunal anastomosis leakage, 1 with duodenal stump leakage, and 1 with abdominal infection, and all these patients were recovered after conservative treatment. All the 67 patients were followed up. The mean nutrition index 12 months after surgery was 53.4±4.2, diameter of esophagojejunal anastomosis was (3.9±0.6) cm, the incidence of Roux-en-Y stasis syndrome was 3.0% (2/67), and the incidence of reflux esophagitis was 4.5% (3/67). No patient had recanalization of the closed input loop of esophagojejunal anastomosis, anastomotic stenosis, obstruction, or tumor recurrence at anastomosis. CONCLUSION Intracavitary URY anastomosis following LTG for digestive tract reconstruction is safe and feasible, leading to fast postoperative recovery of digestive tract function and favorable short-term efficacy.
Anastomosis, Roux-en-Y ; methods ; Anastomosis, Surgical ; Female ; Gastrectomy ; methods ; Humans ; Jejunum ; Laparoscopy ; Male ; Retrospective Studies ; Stomach Neoplasms ; surgery

The German ( Kooperation für Transoarenz und Qualit?t im Gesundheitswesen, KTQ) certification system was officially launched in Germany in December 2001. Over ten years′ development proves that the KTQ certification system as a high standard medical management system. The authors introduced its background, the update of certification content and procedures, and explained its characteristics and advantages.These insights provide valuable references for establishing a professional and efficient quality certification system, suitable for China′s social and economic development level.

Objective:To develop the methods for the determination of calcined calamine and borneol in Jinniu ophthalmic remedy. Methods:The content of zinc oxide in calcined calamine was determined by an EDTA coordination titration method. A DB-WAX capillary column (30 m ×0.32 mm,0.5 μm) was used with an FID as the detector and ethylacetate as the solvent to determine the content of borneol. The column temperature was 150 ℃, the injection port temperature was 180 ℃, the detector temperature was 200 ℃, the split ratio was 5 :1,and the flow rate was 1 ml·min-1. Results:The recovery of zinc oxide was 101.5% with the RSD was 1.2%(n = 9). The linear range of borneol was 0.1-5.0 μg(r = 0.999 9). The recovery of borneol was 98.18% with the RSD was 0.8%(n = 9). The content of zinc oxide and borneol in the samples was 0.38-0.59 g·g-1and 0.13-0.21 g·g-1,respectively. Conclusion:The method is simple and accurate with high reproducibility and promising stability, which can be used for the quality control of Jinniu ophthalmic remedy.