Objective To investigate the effects of trigonelline combined with aerobic exercise on hyperlipidemia rats and its mechanism.Methods SD rats were randomly divided into control group(normal diet),model group(hyperlipidemia rat model was established by feeding high fat diet),experimental-L,-H groups(high fat diet+15,45 mg·kg-1 trigonelline)and combine group(high fat diet+45 mg·kg-1 trigonelline+aerobic exercise).Each group had 11 rats.Serum lipid metabolism related indexes were detected by automatic biochemical analyzer.Serum levels of 6 ketone prostaglandin F1a(6-keto-PGF1a);the levels of glutamic oxaloacetic transaminase(GOT)in liver tissue were detected by enzyme-linked immunosorbent assay;the mRNA levels of interleukin-1β(IL-1β)in liver tissue were detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR);Western blot assay was used to detect the expression of proprotein convertase subtilin/kexin 9 type(PCSK9)and low density lipoprotein receptor(LDLR)protein in liver tissue.Results The serum TC levels in control group,model group,experimental-L group,experimental-H group and combine group were(1.81±0.10),(6.68±0.77),(5.10±0.44),(3.57±0.47)and(2.40±0.35)mmol·L-1;the levels of 6-keto-PGF1a were(841.47±86.74),(536.03±36.50),(664.06±52.44),(759.19±52.30)and(824.45±67.62)pg·mL-1;GOT levels were(11.95±0.88),(18.20±1.81),(15.05±1.10),(13.32±0.98)and(12.47±0.83)U·L-1;IL-1β mRNA expression levels were 1.00±0.09,2.21±0.17,1.57±0.10,1.26±0.16 and 1.14±0.09;the expression of PCSK9 protein were 0.39±0.07,0.88±0.08,0.71±0.08,0.60±0.04 and 0.52±0.07;LDLR protein levels were 1.12±0.13,0.52±0.07,0.74±0.11,0.84±0.08 and 0.96±0.11,respectively.Model group was compared with the control group,experimental-L group and experimental-H group were compared with model group respectively,combine group was compared with the experimental-H group,the differences of the above indexes were statistically significant(all P＜0.05).Conclusion Trigonelline combined with aerobic exercise may inhibit the expression of PCSK9 and up-regulate the expression of LDLR to improve lipid metabolism,so as to play a lipid-lowering role in hyperlipidemia rats.

Objective To investigate the effect and mechanism of rosuvastatin on liver injury induced by high fat diet in hyperlipidemia rats.Methods All rats were randomly divided into control group,model group and experimental group,with 10 rats in each group.Except the control group,hyperlipidiosis model rats were fed with high-fat diet combined with alcohol to construct hyperlipidiosis model rats.The experimental group was given 10 mg·kg-1 rosuvastatin by gavage,control group and model group were given gavage with 10 mL·kg-1 distilled water,once a day for 4 weeks.Serum lipids and liver function were measured by enzyme-linked immunosorbent assay(ELISA).Quantitative real-time polymerase chain reaction(qRT-PCR)was used to analyze the expression of microRNA(miR)-185-3p and mastermind like transcription coactivator 1(MAML1);the expression levels of MAML1 and inducible nitric oxide synthase(iNOS)were detected by Western blot.Results The liver tissue injury scores of control group,model group and experimental group were 0.32±0.15,4.03±1.62 and 2.36±1.14;the TG levels were(4.95±0.86),(6.75±1.42)and(5.51±0.91)mmol·L-1;the TC were(2.36±0.48),(5.11±2.05)and(3.24±1.39)mmol·L-1;the LDL-C were(0.67±0.16),(1.73±0.42)and(1.03±0.25)mmol·L-1;the HDL-C were(0.72±0.23),(0.51±0.14)and(0.64±0.11)mmol·L-1;the GOT were(158.31±32.46),(253.19±49.27)and(187.52±53.46)U·L-1;the GPT values were(53.17±6.81),(79.64±13.92)and(55.63±9.11)U·L-1.Compared with the control group,the expression of miR-185-3p in the model group was significantly down-regulated,the expression of MAML1 and iNOS was significantly increased.Compared with the model group,the expression of miR-185-3p in the liver tissue of experimental group was significantly up-regulated,while the expression of MAML1 and iNOS was significantly decreased(all P＜0.05).There were statistically significant differences in the above indexes between the control group and the model group(P＜0.05);the above data in the model group were statistically significant compared with the experimental group(P＜0.05).Conclusion Rosuvastatin inhibits the expression of MAML1 and iNOS by regulating miR-185-3p,thereby improving the liver injury induced by hyperlipidemia in rats.

Objective To investigate the effect of naringin on hyperlipidemia in mice and to elucidate its mechanism.Methods C57BL/6 mice were randomly divided into control group,hyperlipidemia group and naringin group.Mice in hyperlipidemia group and naringin group were fed high-fat diet for 4 weeks,and hyperlipidemia model was established.The control group was fed normal diet.After successful modeling,naringin group mice were intragastric with 200 mg·kg-1 naringin per day,and mice in control group and hyperlipemia group were intragastric with 0.9％NaCl per day for 5 weeks.The blood of mice was collected for lipid detection.The activities of superoxide dismutase(SOD)and catalase(CAT)and the contents of malondialdehyde(MDA)and glutathione(GSH)were detected by biochemical method.Western blot was used to detect the protein expression.Results The activity of SOD in liver tissue of mice in control group,hyperlipidemia group and naringin group were(58.43±6.27),(37.16±4.10)and(51.23±4.81)U·mg prot-1,respectively;CAT activities were(176.11±13.59),(112.65±10.02)and(158.46±14.37)U·mg prot-1,respectively;the contents of MDA were(3.15±0.74),(12.62±2.07)and(5.76±1.83)U·mg prot-1;the contents of GSH were(91.52±11.47),(34.16±4.62)and(71.64±8.79)U·mg prot-1,respectively;the relative protein expression levels of induced nitric oxide synthase(iNOS)were 0.28±0.05,4.26±1.13 and 0.94±0.19;the relative protein expression levels of adenosine 5'-monophosphate activated protein kinase(AMPK)were 1.32±0.18,0.84±0.11 and 1.49±0.16,respectively;the relative protein expression levels of cholesterol regulatory element binding protein(SREBP)were 1.76±0.24,5.78±1.21 and 2.93±0.42;the relative protein expression levels of 3-hydroxy-3-methyl glutaryl coenzyme A reductase(HMGCR)were 1.69±0.18,6.13±1.38 and 3.26±0.43,respectively.The above indexes in the control group and the naringin group were significantly different from those in the hyperlipidemia group(P＜0.05,P＜0.01,P＜0.001).Conclusion Naringin can effectively regulate the level of blood lipids,inhibit oxidative stress and apoptosis in hyperlipidemia mice,and its mechanism may be related to the regulation of AMPK/HMGCR/SREBP signaling pathway.

Ankylosing spondylitis (AS) combined with lower cervical fracture is often categorized into unstable fracture, with a high incidence of neurological injury and a high rate of disability and morbidity. As factors such as shoulder occlusion may affect the accuracy of X-ray imaging diagnosis, it is often easily misdiagnosed at the primary diagnosis. Non-operative treatment has complications such as bone nonunion and the possibility of secondary neurological damage, while the timing, access and choice of surgical treatment are still controversial. Currently, there are no clinical practice guidelines for the treatment of AS combined with lower cervical fracture with or without dislocation. To this end, the Spinal Trauma Group of Orthopedics Branch of Chinese Medical Doctor Association organized experts to formulate Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults ( version 2024) in accordance with the principles of evidence-based medicine, scientificity and practicality, in which 11 recommendations were put forward in terms of the diagnosis, imaging evaluation, typing and treatment, etc, to provide guidance for the diagnosis and treatment of AS combined with lower cervical fracture.

This paper applied gas chromatography-mass spectrometry (GC-MS), network pharmacology and nuclear magnetic resonance hydrogen spectroscopy (¹H NMR) metabolomics techniques to study the material basis and mechanism of action of Ning Shen Essential Oil in anti-insomnia. The main volatile components of Ning Shen Essential Oil were analyzed by gas chromatography-mass spectrometry (GC-MS), and the insomnia-related targets were predicted using the Traditional Chinese Medicine Systematic Pharmacology Database and Analytical Platform (TCMSP) and the databases of GeneCards, OMIM and Drugbank. The insomnia model of rats was replicated by intraperitoneal injection of 4-chloro-DL-phenylalanine (PCPA). Animal experiments were approved by the Animal Ethics Committee of Shandong University of Traditional Chinese Medicine (Ethics No.: SDUTCM20221025010). The modulating effect of Compound Ning Shen Essential Oil on anxiety behavior of rats was evaluated by behavioral related indexes. The serum levels of corticotropin-releasing hormone (CRH), adrenotropic corticotropic hormone (ACTH) and melatonin (MT) were measured by enzyme-linked immunoassay (ELISA). Rat serum and hippocampus were taken for nuclear magnetic resonance (¹H NMR) metabolomics to detect the changes of endogenous metabolites in rat serum hippocampus, to designate the differential metabolites and to construct metabolic pathways. The results showed that the exercise distance in the open field experiment and the number of times and time to enter the open arm in the elevated cross maze experiment of the rats in the model group were significantly reduced (P < 0.05, P < 0.01). The behavioral indexes of rats improved to different degrees after the administration of Ning Shen Essential Oil. The serum CRH and ACTH levels of rats in the model group increased significantly (P < 0.05, P < 0.01), and the MT level decreased significantly (P < 0.01); After the intervention, serum CRH and ACTH levels were reduced to different degrees, and MT levels could be regressed. ¹H NMR metabolomics screened 10 potential biomarkers related to insomnia, which involved in 6 potential metabolic pathways. A total of 35 components of Ning Shen Essential Oil were detected by GC-MS, the main component targets of Ning Shen Essential Oil and insomnia disease targets were intersected, a total of 172 intersecting genes were screened, and 26 core targets were identified. The study demonstrated that Ning Shen Essential Oil had protective effects against PCPA-induced insomnia in rats, which was probably correlated with regulation of the hypothalamic-pituitary-adrenal axis (HPA) related hormones and metabolism of amino acids, lipids and choline.

ObjectiveDirected differentiation of human induced pluripotent stem cells （hiPSCs） into spinal cord γ-aminobutyric acid （GABA）-ergic progenitor cells were implanted into an decellularized optical nerve （DON） bioscaffold to construct a hiPSC-derived inhibitory neural network tissue with synaptic activities. This study aimed to provide a novel stem cell-based tissue engineering product for the study and the repair of central nervous system injury. MethodsThe combination of stepwise directional induction and tissue engineering technology was applied in this study. After hiPSCs were directionally induced into human neural progenitor cells （hNPCs） in vitro， they were seeded into a DON for three-dimensional culture， allowing further differentiation into inhibitory GABAergic neurons under the specific neuronal induction environment. Transmission electron microscopy and whole cell patch clamp technique were used to detect whether the hiPSCs differentiated neurons could form synapse-like structures and whether these neurons had spontaneous inhibitory postsynaptic currents， respectively， in order to validate that the hiPSC-derived neurons would form neural networks with synaptic transmission potentials from a structural and functional perspective. ResultsThe inhibitory neurons of GABAergic phenotype were successfully induced from hiPSCs in vitro， and maintained good viability after 28 days of culture. With the transmission electron microscopy， it was observed that many cell junctions were formed between hiPSC-derived neural cells in the three-dimensional materials， some of which presented a synapse- like structure， manifested as the slight thickness of cell membrane and a small number of vesicles within one side of the cell junctions， the typical structure of a presynatic component， and focal thickness of the membrane of the other side of the cell junctions， a typical structure of a postsynaptic component. According to whole-cell patch-clamp recording， the hiPSC-derived neurons had the capability to generate action potentials and spontaneous inhibitory postsynaptic currents were recorded in this biotissue. ConclusionsThe results of this study indicated that hiPSCs can be induced to differentiate into GABAergic progenitor cells in vitro and can successfully construct iPSC-derived inhibitory neural network tissue with synaptic transmission after implanted into a DON for three-dimensional culture. This study would provide a novel neural network tissue for future research and treatment of central nervous system injury by stem cell tissue engineering technology.

Objective: To explore the application and efficacy of paclitaxel liposome in the treatment of advanced breast cancer among Chinese population in the real world. Methods: The clinical characteristics of patients with advanced breast cancer who received paclitaxel liposome as salvage treatment from January 1, 2016 to August 31, 2019 in 11 hospitals were collected and retrospectively analyzed. The primary outcome was progression free survival (PFS), and the secondary outcome included objective response rate (ORR) and safety. The survival curve was drawn by Kaplan-Meier analysis and the Cox regression model were used for the multivariate analysis. Results: Among 647 patients with advanced breast cancer who received paclitaxel liposome, the first-line treatment accounted for 43.3% (280/647), the second-line treatment accounted for 27.7% (179/647), and the third-line and above treatment accounted for 29.1% (188/647). The median dose of first-line and second-line treatment was 260 mg per cycle, and 240 mg in third line and above treatment. The median period of paclitaxel liposome alone and combined chemotherapy or targeted therapy is 4 cycles and 6 cycles, respectively. In the whole group, 167 patients (25.8%) were treated with paclitaxel liposome combined with capecitabine±trastuzumab (TX±H), 123 patients (19.0%) were treated with paclitaxel liposome alone (T), and 119 patients (18.4%) were treated with paclitaxel liposome combined with platinum ± trastuzumab (TP±H), 108 patients (16.7%) were treated with paclitaxel liposome combined with trastuzumab ± pertuzumab (TH±P). The median PFS of first-line and second-line patients (5.5 and 5.5 months, respectively) were longer than that of patients treated with third line and above (4.9 months, P<0.05); The ORR of the first line, second line, third line and above patients were 46.7%, 36.8% and 28.2%, respectively. Multivariate analysis showed that event-free survival (EFS) and the number of treatment lines were independent prognostic factors for PFS. The common adverse events were myelosuppression, gastrointestinal reactions, hand foot syndrome and abnormal liver function. Conclusion: Paclitaxel liposomes is widely used and has promising efficacy in multi-subtype advanced breast cancer.
Humans ; Female ; Breast Neoplasms/chemically induced* ; Paclitaxel/adverse effects* ; Liposomes/therapeutic use* ; Retrospective Studies ; Treatment Outcome ; Trastuzumab/therapeutic use* ; Capecitabine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/adverse effects*

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC₅₀ value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

ObjectiveTo construct a neural network-like tissue with the potential of synaptic formation in vitro by seeding human induced pluripotent stem cell-derived neural precursor cells （hiPSC-NPCs） on decellularized optic nerve （DON）， so as to provide a promising approach for repair of nerve tissue injury. MethodsThrough directional induction and tissue engineering technology， human induced pluripotent stem cells （hiPSCs） and 3D DON scaffolds were combined to construct neural network-like tissues. Then the hiPSCs were directionally induced into human neural precursor cells （hNPCs） and neurons. Immunofluorescence staining was used to identify cell differentiation efficiency. 3D DON scaffolds were prepared. Morphology and cytocompatibility of scaffolds were identified by scanning electron microscopy and Tunnel staining. Induced hiPSC-NPCs were seeded on DON scaffolds. Immunofluorescence staining， scanning electron microscopy， transmission electron microscopy and patch clamp were used to observe the morphology and functional identification of constructed neural network tissues. Results①The results of immunofluorescence staining suggested that most of hiPSC-NPCs differentiated into neurons in vitro. We had successfully constructed a neural network dominated by neurons. ② The results of scanning electron microscopy and immunohistochemistry suggested that a neural network-like tissue with predominating excitatory neurons in vitro was successfully constructed. ③The results of immunohistochemical staining， transmission electron microscopy and patch clamp indicated that the neural network-like tissue had synaptic transmission function. ConclusionA neural network-like tissue mainly composed of excitatory neurons has been constructed by the combination of natural uniform-channel DON scaffold and hiPSC-NPCs， which has the function of synaptic transmission. This neural network plays a significant role in stem cell derived replacement therapy， and offers a promising prospect for repair of spinal cord injury （SCI） and other neural tissue injuries.

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His⁶⁴) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.
Rats ; Animals ; Neuroglobin/metabolism* ; Globins/metabolism* ; Nerve Tissue Proteins/metabolism* ; Neurons/metabolism* ; Hypoxia/metabolism* ; Brain/metabolism* ; Oxygen ; Anemia/metabolism* ; Adenosine Triphosphatases/metabolism*