[Therapeutic effect and mechanism of piracetam for the treatment of spinal cord injury in rats through MAPK pathway].

OBJECTIVE: To explore mechanism of piracetam for the treatment of spinal cord injury in rats through mitogen-activated protein kinase (MAPK) pathway. METHODS: Fifty-four healthy 6-week-old SD female rats with body weight of 80 to 100 g were divided into sham operation group, spinal cord injury group and piracetam group by random number table method, with 18 rats in each group. Spinal cord injury model was established in spinal cord injury group and piracetam group using percussion apparatus, while sham operation group did not damage spinal cord. Piracetam group was injected with piracetam injection through tail vein according to 5 ml·kg-1 standard, once a day for 3 days;the other two groups were injected with normal saline at the same dose, the same frequency and the same duration. The rats were sacrificed at 1, 3, and 7 days after surgery, and changes of Basso, Beattie and Bresnahan (BBB) locomotor rating scale was observed and compared. Enzyme-linked immunosorbent assay (ELISA) was used to detect spinal cord inflammatory factors, such as interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1ß (interleukin-1ß), necrosis factor-α (IL-1ß) and tumor necrosis factor-α (TNF-α);HE staining was used to observe morphological changes of rats with spinal cord injury, and immunohistochemistry was used to observe expression level of aquaporin 4 (AQP4). The activation of MAPK signaling pathway in spinal cord of rats after spinal cord injury was observed by western blotting (WB). RESULTS: BBB scores of sham operation group on 1, 3 and 7 day were 21 points. In spinal cord injury group, the scores were (1±1), (4±1) and (7±2);piracetam group was (1±1), (5±1), (9±2), respectively;the difference between spinal cord injury group and sham operation group was statistically significant (P<0.05). HE staining showed that no abnormality was found in sham operation group. In spinal cord injury group, bleeding and degeneration of spinal cord tissue appeared at 1 day after operation; flaky necrotic areas were appeared in spinal cord at 3 days after surgery, and spinal cord tissue began to slowly repair at 7 days after surgery. In piracetam group, the bleeding area was less than that of spinal cord injury group at 1 day after surgery;at 3 days after operation, the necrotic area was reduced and the range of nuclear disappearance was reduced; and the spinal cord began to recover slowly at 7 days after surgery. AQP4 staining of spinal cord of rats in sham operation group was weak at 1, 3 and 7 days after modeling, AQP4 staining was deepened and area increased in spinal cord injury group, AQP4 staining of piracetam group was lighter than that of spinal cord injury group, and the positive cells were slightly increased and the staining was slightly darker than that of sham operation group. At 1, 3 and 7 days, the level of IL-6, IL-10, IL-1ß and TNF-α in spinal cord injury group were higher than those in sham operation group and piracetam group(P<0.05). Compared with spinal cord injury group, the area of spinal cord bleeding and necrosis were decreased by HE staining in piracetam group, and AQP4 staining was decreased by immunohistochemistry. WB results showed that P-ERK, P-JNK and P-P38 levels in spinal cord injury group at 3 days were higher than those in sham operation group and piracetam group(P<0.05). CONCLUSION: Piracetam not only showed significant effect in promoting motor function recovery after spinal cord injury, but also showed positive therapeutic potential in reducing lesion area, regulating AQP4 expression to reduce edema, and reducing inflammatory response by regulating MAPK signaling pathway.

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway.

OBJECTIVE: This study aimed to investigate the impact of Dickkopf 2 (DKK2) on the progression of oral squamous cell carcinoma (OSCC) and explore its role in the PI3K/AKT signaling transduction pathway. MATERIALS AND METHODS: The study initially examined the expression of the DKK2 gene in OSCC tissues and normal tissues. Simultaneously, the expression of DKK2 in HOK cells and OSCC cells was verified, and changes in DKK2 expression under hypoxic conditions were detected. DKK2 overexpression and knockdown were performed in SCC-15 and CAL-27 cells. Subsequently, the effects of DKK2 on the proliferation, migration and invasion of OSCC were detected. Western blotting was employed to detect the expression of key proteins in the DKK2/PI3K/AKT signaling axis before and after transfection, and further explore the relevant molecular mechanisms. RESULTS: Compared to normal tissues, DKK2 expression was elevated in OSCC tissues. The expression of DKK2 in the SCC-15 and CAL-27 cell lines was higher than that in HOK cells, and hypoxic conditions could promote DKK2 expression. DKK2 overexpression promoted cell proliferation, migration, and invasion, while DKK2 knockdown inhibited these processes. DKK2 overexpression activated the PI3K/AKT pathway, while DKK2 knockdown suppressed this pathway. CONCLUSION: This study suggests that hypoxic conditions enhance the expression of DKK2 in OSCC. DKK2 regulates the proliferation, migration, and invasion of OSCC through the PI3K/AKT signaling pathway.

Network meta-analysis of invasive treatment for early-stage osteonecrosis of the femoral head.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a common disabling disease in orthopedics. Blocking the progression of ONFH in the early stage is essential for avoiding total hip replacement. PURPOSES: The purpose of this study is to evaluate the effect of invasive treatment on early-stage ONFH. METHODS: According to the PRISMA guidelines, relevant English databases were searched in August 2022 to collect published research. Extract result indicators and conduct network meta-analysis using R software. RESULTS: A total of 15 RCTs were included. All patients were diagnosed with early-stage ONFH. The surface under the cumulative ranking curve (SUCRA) showed that CD + BMMSC and CD + PRP were the most effective in improving HHS. The results of the league table showed that CD + BMMSC was superior to CD alone. Meanwhile, the SUCRA for FR showed that CD + BG + BMMSC was the most likely to be the most effective in reducing FR. The league table revealed that CD + BG, CD + BG + BMMSC, and CD + BMMSC were superior to CD alone, with statistically significant differences. CONCLUSION: Considering the HHS and FR, CD + BMMSC may be the optimal treatment option to effectively delay the progression of ONFH and restore the postoperative function of patients. REGISTRATION NUMBER: The study protocol has been registered on the PROSPERO platform (CRD42023380169).

Carbohydrate-active enzyme profiles of Lactiplantibacillus plantarum strain 84-3 contribute to flavor formation in fermented dairy and vegetable products.

Microbes are critical for flavor formation in fermented foods; however, their mechanisms of action are not fully understood. The microbial composition of 51 dairy and 47 vegetable products was functionally annotated and the carbohydrate-active enzyme (CAZyme) profiles of Lactiplantibacillus plantarum 84-3 (Lp84-3), isolated from dairy samples, can promote resistant starch (RS) degradation, were analyzed. Lactobacillus, Streptococcus, and Lactococcus were the predominant genera in dairy products, whereas the major genera in vegetables were Lactobacillus, Weissella, and Carnimonas. Phages from Siphoviridae, Myoviridae, and Herelleviridae were also present in dairy products. Additionally, the glycosyl hydrolase (GHs) family members GH1 and GH13 and the glycosyltransferase (GTs) family members GT2 and GT4 were abundant in Lp84-3. Moreover, Lp84-3 was enriched in butanoate metabolism enzymes and butanoate metabolite compounds. Therefore, fermented food microbes, especially Lp84-3, have an abundant repertoire of enzymes that promote flavor production, as starter improving the flavor of fermented dairy and vegetable products.

Potential Value of FAPI PET/CT in the Detection and Treatment of Fibrosing Mediastinitis: Preclinical and Pilot Clinical Investigation.

Fibrosing mediastinitis (FM) is a rare proliferative disease within the mediastinum that leads to pulmonary hypertension, which has been regarded as a major cause of death. This study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-PET/CT in the integration of diagnosis and treatment of FM through targeting FAPI in fibrosis rats and provide a theoretical basis for clinical management of FM patients. By performing a 18F-FAPI PET/CT scan, the presence of FAPI-avid in the fibrotic lesion was determined. Through a fibrosis rat model, 18F-FAPI-74 was used for lesion imaging and 177Lu-FAPI-46 was utilized to investigate the potential therapeutic effect on FM in vivo. In addition, biodistribution analysis and radiation dosimetry were carried out. With the 177Lu-FAPI-46 pharmacokinetic data of rats as the input, the estimated dose for female adults was computed, which can provide some useful information for the safe application of radiolabeled FAPI in the detection and treatment of FM in patients. Then, major findings on the use of FAPI PET/CT and SPECT/CT in FM were presented. 18F-FAPI-74 showed a high-level uptake in FM lesions of patients (SUVmax 7.94 ± 0.26), which was also observed in fibrosis rats (SUVmax 2.11 ± 0.23). Consistently, SPECT/CT imaging of fibrosis rats also revealed that 177Lu-FAPI-46-avid was active for up to 60 h in fibrotic lesions. In addition to this robust diagnostic performance, a possible therapeutic impact was evaluated as well. It turned out that no spontaneous healing of lesions was observed in the control group, whereas there was complete healing on day 9, day 11, and day 14 in the 30, 100, and 300 MBq groups, respectively. With a significant difference in the free of event rate in the Kaplan-Meier curve among four groups (P < 0.001), a dose of 300 MBq displayed the best therapeutic effect, and no obvious damage was observed in the kidney. Furthermore, organ-absorbed doses and an effective dose (0.4320 mSv/MBq) of 177Lu-FAPI-46 presumed for patients were assumed to give a preliminary indication of its safe use in clinical practice. In conclusion, 18F-FAPI-46 PET/CT can be a potentially valuable tool for the diagnosis of FM. Of note, 177Lu-FAPI-46 may be a novel and safe radiolabeled reagent for the integration of diagnosis and treatment of FM.

The potential of Klebsiella and Escherichia-Shigella and amino acids metabolism to monitor patients with postmenopausal osteoporosis in northwest China.

BACKGROUND: Intestinal flora has been proposed to mediate the occurrence of postmenopausal osteoporosis (PMO). However, the mechanism by which microbes and their metabolites interactively promote PMO remains unknown. METHODS: This study aimed to investigate changes in the intestinal flora and associated metabolites, and their role in PMO. 16S rRNA gene sequencing and metabolomics were performed to obtain postmenopausal women with osteopenia (lower bone mass, LBM), postmenopausal women with osteoporosis (OST), and healthy women as the control group. RESULTS: We identified taxa-specific and metabolite differences in the intestinal flora of the participants of this study. The pathogenic bacteria Klebsiella (0.59% and 0.71%, respectively) and Escherichia-Shigella (2.72% and 4.30%, respectively) were enriched in the LBM and OST groups (p < 0.05). Some short-chain fatty acid (SCFAs) producing bacteria, Lactobacillus, Akkermansia, Prevotella, Alistipes, and Butyricicoccus, were reduced in patients with LBM and OST compared to the control. Moreover, fecal metabolomic analyses suggested that the metabolites of indole-3-acetic acid and 7-ketodeoxycholic acid were altered in the LBM and OST groups compared to the control (p < 0.05). Enrichment analysis suggested that valine, leucine, and isoleucine biosynthesis; aromatic amino acid biosynthesis; and phenylalanine metabolism were significantly associated with the identified microbiota biomarkers and OST. Moreover, metabolite marker signatures distinguished patients in the OST from those in the control group with an area under the curve (AUC) of 0.978 and 1.00 in the negative and positive ion modes, respectively. Finally, we also found that the fecal level of interleukin-10 (IL-10) in the OST group was significantly lower than that in the control group and LBM group (p < 0.05), while tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly higher in the OST group than that in the control group (p < 0.05). CONCLUSIONS: This study provides robust evidence connecting the intestinal flora and fecal metabolomics with PMO. Integrated metabolite and microbiota analyses demonstrated that in addition to dysregulated bacteria, indole-3-acetic acid, 7-ketodeoxycholic acid, and other metabolites can be used for the distinguish of LBM and PMO.

Significant but Inequitable Cost-Effective Benefits of a Clean Heating Campaign in Northern China.

Residential emissions significantly contribute to air pollution. To address this issue, a clean heating campaign was implemented to replace coal with electricity or natural gas among 13.9 million rural households in northern China. Despite great success, the cost-benefits and environmental equity of this campaign have never been fully investigated. Here, we modeled the environmental and health benefits, as well as the total costs of the campaign, and analyzed the inequality and inequity. We found that even though the campaign decreased only 1.1% of the total energy consumption, PM2.5 emissions and PM2.5 exposure experienced 20% and 36% reduction, respectively, revealing the amplification effects along the causal pathway. Furthermore, the number of premature deaths attributable to residential emissions reduced by 32%, suggesting that the campaign was highly beneficial. Governments and residents shared the cost of 2,520 RMB/household. However, the benefits and the costs were unevenly distributed, as the residents in mountainous areas were not only less benefited from the campaign but also paid more because of the higher costs, resulting in a notably lower cost-effectiveness. Moreover, villages in less developed areas tended to choose natural gas with a lower initial investment but a higher total cost (2,720 RMB/household) over electricity (2,190 RMB/household). With targeted investment and subsidies in less developed areas and the promotion of electricity and other less expensive alternatives, the multidevelopment goals of improved air quality, reduced health impacts, and reduced inequity in future clean heating interventions could be achieved.

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway.

BACKGROUND AND PURPOSE: Hyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell-cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI. METHODS: Mice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy. The expression of pro-inflammatory cytokine, including IL-6, TGF-ß1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia. RESULTS: Mice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-ß1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively. CONCLUSIONS: IL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process. Video Abstract.

Oxygen inhalation has been widely used in the treatment of some diseases caused by hypoxia. This often leads people to mistakenly believe that oxygen inhalation is beneficial without harm. However, long-term high concentration oxygen inhalation will cause serious harm to the human body, sometimes even fatal. Hyperoxia causes lung cells to secrete proinflammatory factors, which promote the differentiation of infiltrated immune cells. The differentiated immune cells in turn act on lung cells and lead to their death. In short, this process is a vicious circle. Our research explores this process and is committed to finding a drug to reduce the damage of hyperoxia to the lungs when oxygen must be inhaled.

[Clinical application of adaptive minute ventilation + IntelliCycle ventilation mode in patients with mild-to-moderate acute respiratory distress syndrome].

OBJECTIVE: To verify the clinical safety and efficacy of new intelligent ventilation mode adaptive minute ventilation (AMV)+IntelliCycle ventilation in patients with mild-to-moderate acute respiratory distress syndrome (ARDS). METHODS: The patients with mild-to-moderate ARDS, admitted to intensive care unit (ICU) of the First Affiliated Hospital of Jinzhou Medical University from February 2018 to February 2019, were enrolled in the study. The patients were divided into synchronous intermittent mandatory ventilation+pressure support ventilation (SIMV+PSV) group and AMV+IntelliCycle group according to the random number table method. All patients were given mechanical ventilation, anti-infection, analgesia and sedation, nutritional support and symptomatic treatment of primary disease after admission. SV800 ventilator was used for mechanical ventilation. In the AMV+IntelliCycle group, after setting the minute ventilation volume (VE), inhaled oxygen concentration (FiO2) and positive end expiratory pressure (PEEP), the ventilator was turned on the full-automatic mode, and the preset value of VE percentage was 120%. In the SIMV+PSV group, the ventilator parameters were set as follows: the ventilation frequency was 12-20 times/min, the inspiratory expiratory ratio was 1:1-2, the peak inspiratory pressure (PIP) limit level was 35-45 cmH2O (1 cmH2O = 0.098 kPa), and the setting of FiO2 and PEEP was as the same as that of AMV+IntelliCycle group, the triggering flow was set to 2 L/min. All of the clinical parameters between the two groups were compared. The main outcomes were duration of mechanical ventilation, ventilator alarm times, manual operation times, and the mechanical power; the secondary outcomes were respiratory rate (RR), VE, tidal volume (VT), PIP, mouth occlusion pressure (P0.1), static compliance (Cst), work of breathing (WOB), and time constant at 0, 6, 12, 24, 48, 72, and 120 hours; and the blood gas analysis parameters of patients before and after ventilation were recorded. RESULTS: A total of 92 patients with mild-to-moderate ARDS were admitted during the study period, excluding those who quit the study due to death, abandonment of treatment, accidental extubation of tracheal intubation and so on. Eighty patients were finally enrolled in the analysis, with 40 patients in SIMV+PSV group and AMV+IntelliCycle group respectively. (1) Results of main outcomes: compared with the SIMV+PSV mode, AMV+IntelliCycle ventilation mode could shorten the duration of mechanical ventilation (hours: 106.35±55.03 vs. 136.50±73.78), reduce ventilator alarm times (times: 10.35±5.87 vs. 13.93±6.87) and the manual operations times (times: 4.25±2.01 vs. 6.83±3.75), and decrease the mechanical power (J/min: 12.88±4.67 vs. 16.35±5.04, all P < 0.05). But the arterial partial pressure of carbon dioxide (PaCO2) of AMV+IntelliCycle group was significantly higher than that of SIMV+PSV group [mmHg (1 mmHg = 0.133 kPa): 41.58±6.81 vs. 38.45±5.77, P < 0.05]. (2) Results of secondary outcomes: the RR of both groups was improved significantly with the prolongation of ventilation time which showed a time effect (F = 4.131, P = 0.005). Moreover, compared with SIMV+PSV mode, AMV+IntelliCycle mode could maintain a better level of RR, with intervention effect (F = 5.008, P = 0.031), but no interaction effect was found (F = 2.489, P = 0.055). There was no significant difference in VE, PIP, P0.1 or Cst between the two groups, without intervention effect (F values were 3.343, 2.047, 0.496, 1.456, respectively, all P > 0.05), but they were significantly improved with the prolongation of ventilation time in both groups, with time effect (F values were 2.923, 12.870, 23.120, 7.851, respectively, all P < 0.05), but no interaction effect was found (F values were 1.571, 1.291, 0.300, 0.354, respectively, all P > 0.05). The VT, WOB or time constant in both groups showed no significant changes with the prolongation of ventilation time, and no significant difference was found between the two groups, there was neither time effect (F values were 0.613, 1.049, 2.087, respectively, all P > 0.05) nor intervention effect (F values were 1.459, 0.514, 0.923, respectively, all P > 0.05). CONCLUSIONS: AMV+IntelliCycle ventilation mode can shorten the ventilation time of patients with mild-to-moderate ARDS, reduce mechanical power, and reduce the workload of medical care, but PaCO2 in the patients with AMV+IntelliCycle mode is higher than that in the patients with SIMV+PSV mode.

A novel organic electrochromic device with hybrid capacitor architecture towards multicolour representation.

Despite the application of electrochromic (EC) technologies in various optical modulating devices, the challenge to achieve multicolour EC behavior in a single device still remains. However, because almost all EC materials exhibit a single colour change, only a few organic materials are able to undergo multiple colour switching within a single device. The development of multicolour EC applications is therefore highly limited. In this research, we fabricated an EC device (ECD) with the simple hybrid capacitor architecture, i.e. with a flat ITO electrode as the working side and an ITO particle-modified electrode as the counter side. We also employed an electrolyte containing both anodic and cathodic EC materials consisting of small organic molecules. In this novel ECD, each EC material successfully undergoes individual colour switching from light yellow to light green and magenta. The mechanism of a multicolour system represents a significant breakthrough towards a full-colour ECD, thereby expanding the potential of EC technology.

Nonlinear optical and multi-photon absorption properties in graphene-ZnO nanocomposites.

Graphene-ZnO (GZO) nanocomposites were synthesized by a modified solvothermal method, and characterized by transmission electron microscopy, x-ray diffraction, Raman spectra, and UV-vis absorption spectra. The controllable nonlinear optical (NLO) properties of as-prepared GZO nanocomposites were tested by an open-aperture Z-scan method with 1030 nm fs laser pulses; the tested results showed that there were five-photon absorption (5PA) at 46.8 GW cm-2, 3PA at 28.1 GW cm-2, 2PA at 18.7 GW cm-2, and a vital change from saturable absorption (SA) to reverse SA (RSA) with the increase of incident intensity. This was the first time that 5PA was found in GZO nanocomposites at such a low intensity, 46.8 GW cm-2. The tunable NLO property from SA to RSA and controllable multi-photon absorption provided a facile approach for their applications in optical, optoelectronic devices, and information storage.