ObjectiveThis study sought to investigate the impact of exosomes derived from LoVo cells (LoVo-Exos) in colorectal cancer (CRC) on tumor angiogenesis, as well as to elucidate the potential molecular mechanisms underlying their pro-angiogenic effects. MethodsLoVo-Exos were isolated via ultracentrifugation, and their internalization into recipient human umbilical vein endothelial cells (HUVECs) was visualized using confocal microscopy. The influence of LoVo-Exos on angiogenesis was assessed through an in vitro tube formation assay. Additionally, the pro-angiogenic effects of LoVo-Exos were evaluated in vivo using a matrix gluing assay in mice. To investigate the molecular mechanisms through which LoVo-Exos facilitate angiogenesis, Western blot analysis was employed to examine the transfer of pEGFR by LoVo-Exos into recipient cells. Both Western blot and ELISA were utilized to assess the expression levels of key signaling proteins within the EGFR-ERK pathway, as well as the expression of downstream angiogenic core molecules. Furthermore, the impact of EGFR knockdown and ERK inhibitor treatment on angiogenesis was evaluated, with subsequent analysis of the expression of downstream angiogenic core molecules following these interventions. ResultsConfocal microscopy demonstrated the internalization of LoVo-Exos into HUVECs. In vitro angiogenesis assays further indicated that LoVo-Exos significantly enhanced the formation of tubular structures in HUVECs. Additionally, macroscopic examination of subcutaneous matrix plug formation in mice revealed a substantial increase in vascular-like structures within the matrix plugs following the administration of LoVo-Exos, compared to the PBS control group. Hematoxylin and eosin (HE) staining revealed the presence of erythrocyte-filled microvessels within the matrix plugs combined with LoVo-Exos. Furthermore, immunohistochemical analysis demonstrated the expression of the endothelial cell marker CD31 in these matrix plugs. The presence of CD31-positive cells in the LoVo-Exos-treated matrix plugs was associated with a significant enhancement in the formation of luminal structures. These findings suggest that LoVo-Exos facilitate the in vivo development of vascular-like structures. Subsequent investigations demonstrated that LoVo-Exos facilitated the delivery of pEGFR to HUVEC, thereby enhancing angiogenesis. Conversely, LoVo-Exos with EGFR knockdown exhibited a diminished capacity to promote angiogenesis, an effect that was further attenuated by the ERK phosphorylation inhibitor U0126. Western blot analysis assessing the activation of the EGFR-ERK signaling pathway in HUVEC indicated that LoVo-Exos augmented angiogenesis through the activation of this pathway. Furthermore, analysis of the impact of LoVo-Exos on the expression of downstream angiogenic core molecules revealed an increase in interleukin-8 (IL-8) secretion in HUVEC. The enhancement observed was diminished in LoVo-Exos following EGFR knockdown, and this reduction was counteracted by the ERK phosphorylation inhibitor U0126. ConclusionThe underlying mechanism may involve the delivery of pEGFR in LoVo-Exos to HUVECs, leading to increased IL-8 secretion via the EGFR-ERK signaling pathway, thereby enhancing the angiogenic potential of HUVECs. This finding may offer new insights into the mechanisms underlying cancer metastasis.

Aim To investigate whether alisol A (AA) could improve the blood brain barrier (BBB) mediated cortex cerebral ischemia-repeifusion injury (CIRI) by inhibiting matrix metalloproteinase 9 (MMP-9). Methods The global cerebral ischemia- reperfusion (GCI/R) model in mice was established, and the AA was intragastric injected subsequently for seven days. The modified neurological severity scores (mNSS), open field test and Y-maze test were applied to detect neurological function. Magnetic resonance spectroscopy (MRS) was used to detect relevant neu- rosubstance metabolism in cortex of mice. Transmission electron microscope (TEM) was employed to observe the ultrastructure of BBB in cortex. Western blot and immunohistochemistry were used to detect the MMP-9 level in cortex. The binding possibility of A A and MMP-9 was determined by molecular docking. Results Compared with Sham group, mice in GCI/R group have an increased mNSS score but decreased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01). While mice in GCI/R + AA group have a decreased mNSS score but increased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01) compared with GCI/R group. MRS results found that in cortex of GCI/R group mice, the level of GABA and NAA significantly decreased while the Cho, mI and Tau level increased (P<0.01). Whereas in GCI/R + AA group mice, the GABA and NAA level increased and the Cho, ml and Tau decreased significantly (P<0.01). By TEM we observed that the basilemma of cerebral microvessels collapsed, the lumen narrowed, the endothelial cells were active and plasma membranes ruffled, gaps between cells were enlarged and tight junctions were damaged and the end feet of astrocytes were swollen in GCI/R group mice. While in GCI/R + AA group mice, the lumen was filled, plasma membranes of endothelial cells were smooth, tight junctions were complete and end feet of astrocytes were in normal condition. Western blot and immunohistochemistry both found that the MMP-9 level increased in GCI/R group mice (P < 0.01) and decreased in GCI/R + AA group mice (P < 0.05). Molecular docking proved the binding between aliso A and MMP9 through TYR-50 and ARG-106, and the binding energy was calculated as -6.24 kcal · mol

OBJECTIVE To evaluate the cost-effectiveness of ivabradine in the treatment of chronic heart failure （CHF） in the context of “Quadruple Therapy” from the perspective of the health system. METHODS Based on real-world cohort data， the Markov model was constructed according to the natural progression of CHF， with a cycle time of 3 months， a study timeframe of 20 years， and a discount rate of 5%. Using quality-adjusted life year （QALY） and incremental cost-effectiveness ratios （ICER） as the output indexes， the cost-utility analysis was used to evaluate the cost-effectiveness of ivabradine in combination with the “Quadruple Therapy” regimen， compared with the “Quadruple Therapy” regimen for the treatment of CHF， and the robustness of the results of the base analysis was verified by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS The results of the base analysis showed that the ICER of ivabradine combined with the “Quadruple Therapy” regimen was 165 065.54 yuan/QALY， compared with the “Quadruple Therapy” regimen， which was lower than the willingness-to-pay （WTP） threshold （257 094 yuan/QALY） based on 3 times of China’s gross domestic product （GDP） per capita in 2022. The results of the univariate sensitivity analysis showed that the discount rate had the greatest impact on the robustness of the model. The probabilistic sensitivity analysis showed that the probability that the ivabradine combined with the “Quadruple Therapy” regimen was cost-effective under the WTP threshold in this study was 59.50%. CONCLUSIONS When using 3 times China’s 2022 GDP per capita （257 094 yuan/ QALY） as the WTP threshold， the combination of ivabradine and the “Quadruple Therapy” regimen for treating CHF is cost- effective.

The assessment of adverse drug events is an important basis for clinical safety evaluation and post-marketing risk control of drugs,and its causality assessment is gaining increasing attention.The existing methods for assessing the causal relationship between drugs and the occurrence of adverse reactions can be broadly classified into three categories:global introspective methods,standardized methods,and probabilistic methods.At present,there is no systematic introduction of the operational details of the various methods in the domestic literature.This paper compares representative causality assessment methods in terms of definition and concept,methodological steps,industry evaluation and advantages and disadvantages,clarifies the basic process of determining the causality of adverse drug reactions,and discusses how to further improve the adverse drug reaction monitoring and evaluation system,with a view to providing a reference for drug development and pharmacovigilance work in China.

Objective To evaluate the efficacy and safety of brexpiprazole in treating acute schizophrenia.Methods Patients with schizophrenia were randomly divided into treatment group and control group.The treatment group was given brexpiprozole 2-4 mg·d-1 orally and the control group was given aripiprazole 10-20 mg·d-1orally,both were treated for 6 weeks.Clinical efficacy of the two groups,the response rate at endpoint,the changes from baseline to endpoint of Positive and Negative Syndrome Scale(PANSS),Clinical Global Impression-Improvement(CGI-S),Personal and Social Performance scale(PSP),PANSS Positive syndrome subscale,PANSS negative syndrome subscale were compared.The incidence of treatment-related adverse events in two groups were compared.Results There were 184 patients in treatment group and 186 patients in control group.After treatment,the response rates of treatment group and control group were 79.50％(140 cases/184 cases)and 82.40％(150 cases/186 cases),the scores of CGI-I of treatment group and control group were(2.00±1.20)and(1.90±1.01),with no significant difference(all P＞0.05).From baseline to Week 6,the mean change of PANSS total score wese(-30.70±16.96)points in treatment group and(-32.20±17.00)points in control group,with no significant difference(P＞0.05).The changes of CGI-S scores in treatment group and control group were(-2.00±1.27)and(-1.90±1.22)points,PSP scores were(18.80±14.77)and(19.20±14.55)points,PANSS positive syndrome scores were(-10.30±5.93)and(-10.80±5.81)points,PANSS negative syndrome scores were(-6.80±5.98)and(-7.30±5.15)points,with no significant difference(P＞0.05).There was no significant difference in the incidence of treatment-related adverse events between the two group(69.00％vs.64.50％,P＞0.05).Conclusion The non-inferiority of Brexpiprazole to aripiprazole was established,with comparable efficacy and acceptability.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

Objective To explore the effect of propranolol on femoral fracture healing in mice through regulation of microRNA-92a-3p(miR-92a-3p)and its mechanism.Methods C57BL/6J male mice were randomly divided into sham group(equal amount of 0.9％NaCl),model group(equal amount of 0.9％NaCl),experimental group(50 mg·kg-1 propranolol administration),inhibitor group(mice were injected with 100 mg·kg-1 miR-92a-3p inhibitor via tail vein on the basis of the experimental group).Femur was severed and molded in all mice except sham operation group.X-ray was used to observe bone healing.Quantitative real time polymerase chain reaction was used to detect the expression of miR-92a-3p in femur tissues.The expression level of bone formation and bone metabolism markers was detected by enzyme linked immunosorbent assay.Western blot was used to detect the expression of pathway-related proteins.Results The X-ray scores of femur in sham group,model group and experimental group were 11.20±2.60,4.70±1.50 and 9.60±2.40,respectively;the relative expression levels of miR-92a-3p in sham operation group,model group,experimental group and inhibitor group were 1.00±0.09,0.73±0.06,0.90±0.07 and 0.78±0.06;alkaline phosphatase levels were(35.21±2.63),(43.16±3.29),(67.58±5.37)and(49.62±4.05)U·L-1,respectively;crosslaps levels were(4.57±0.52),(8.41±0.91),(4.26±0.67)and(5.73±0.84)ng·mL-1,respectively;the relative expression levels of brain derived neurotrophic factor were 1.00±0.14,0.58±0.05,0.83±0.09 and 0.71±0.06,respectively;the relative expression levels of phospho-tyrosine kinase receptor B were 1.00±0.12,0.62±0.05,0.89±0.08 and 0.76±0.07,respectively;the relative expression levels of phospho-extracellular regulated protein kinases were 1.00±0.11,0.54±0.04,0.78±0.07 and 0.65±0.05,respectively.The above indexes in the model group were compared with those in the sham group,those in the experimental group were compared with those in the model group,and those in the inhibitor group were compared with those in the experimental group,and the differences were statistically significant(P＜0.05,P＜0.001).Conclusion Propranolol can promote femoral fracture healing in mice,which may be achieved by up-regulating miR-92a-3p activation of brain derived neurotrophic factor/tyrosine kinase receptor B/extracellular regulated protein kinases signaling pathway.

Objective To explore the effect of behavioral vision training on post-stroke ocular motility disorders(PSOMD). Methods From August to Octobor,2023,a total of 21 PSOMD patients in Beijing Bo'ai Hospital were selected.They re-ceived behavioral vision training,including brain-based visual training and visual fusion training,for four weeks.Visual function was assessed with Snellen eye chart,strabismus prism and Titmus near stereopia. Results The vision of both right and left eyes improved after training(Z right eye=-3.601,Z left eye=3.012,P<0.01),while the strabismus prism reduced significantly(t=8.930,P<0.001).But Titmus near stereopia showed no difference(P>0.05). Conclusion Behavioral vision training could improve vision and strabismus after stroke.

Objective To explore the efficacy and safety of recombinant human anti-severe acute respiratory syn-drome coronavirus 2(anti-SARS-CoV-2)monoclonal antibody injection(F61 injection)in the treatment of patients with coronavirus disease 2019(COVID-19)combined with renal damage.Methods Patients with COVID-19 and renal damage who visited the PLA General Hospital from January to February 2023 were selected.Subjects were randomly divided into two groups.Control group was treated with conventional anti-COVID-19 therapy,while trial group was treated with conventional anti-COVID-19 therapy combined with F61 injection.A 15-day follow-up was conducted after drug administration.Clinical symptoms,laboratory tests,electrocardiogram,and chest CT of pa-tients were performed to analyze the efficacy and safety of F61 injection.Results Twelve subjects(7 in trial group and 5 in control group)were included in study.Neither group had any clinical progression or death cases.The ave-rage time for negative conversion of nucleic acid of SARS-CoV-2 in control group and trial group were 3.2 days and 1.57 days(P=0.046),respectively.The scores of COVID-19 related target symptom in the trial group on the 3rd and 5th day after medication were both lower than those of the control group(both P＜0.05).According to the clinical staging and World Health Organization 10-point graded disease progression scale,both groups of subjects improved but didn't show statistical differences(P＞0.05).For safety,trial group didn't present any infusion-re-lated adverse event.Subjects in both groups demonstrated varying degrees of elevated blood glucose,elevated urine glucose,elevated urobilinogen,positive urine casts,and cardiac arrhythmia,but the differences were not statistica-lly significant(all P＞0.05).Conclusion F61 injection has initially demonstrated safety and clinical benefit in trea-ting patients with COVID-19 combined with renal damage.As the domestically produced drug,it has good clinical accessibility and may provide more options for clinical practice.

italic>Artemisia argyi is a traditional Chinese medicine in China, which is used as medicine with its leaves. The leaves of A. argyi mainly contain flavonoids, phenolic acids, volatile oils and other compounds, and have a variety of pharmacological activities. AP2/ERF transcription factors are abundant in plants and are mainly involved in plant growth and development, abiotic stress response and secondary metabolite biosynthesis regulation. However, there are few reports on the AP2/ERF gene family and its functions in A. argyi. In this study, we systematically identified the AP2/ERF gene family in A. argyi genome, and analyzed its phylogenetic tree, protein physicochemical properties, subcellular localization, conserved motifs, promoter elements, and expression patterns. The results showed that a total of 204 AP2/ERF transcription factors were identified in A. argyi genome, encoding proteins consisting of 88-483 amino acids with a relative molecular mass of 10-52.94 kDa and a theoretical isoelectric point of 4.62-9.88. Subcellular prediction showed that the majority of AP2/ERFs were located in the nucleus, cytoplasm, and the minority of them is located in the membrane and chloroplasts. According to the Arabidopsis AP2/ERF family classification, A. argyi AP2/ERF proteins were divided into four subfamilies: Soloist, AP2, ERF (B3, B4, B5, B6), and DREB (A1, A2, A4, A5, A6), among which DREB family accounted for the largest proportion, and the same subfamily had similar conserved motifs. cis-Acting element analysis showed that AP2/ERF promoters have a large number of elements responding to light and abiotic stress. Expression pattern analysis showed that most of the genes of the AP2/ERF family were dominantly expressed mainly in roots and stems, of which 19 were dominantly expressed in leaves, 77 would be induced to be expressed by methyl jasmonate, of which 16 genes were both dominantly expressed in leaves and induced to be expressed by methyl jasmonate, and these AP2/ERF genes may be the key regulatory genes for the synthesis of active ingredients in A. argyi leaves.This study lays the foundation for the functional study of AP2/ERF family genes and their regulating roles in the active components biosynthesis in A. argyi leaves.