AIM To investigate the repair effects of tauroursodeoxycholic acid(TUDCA)combined with bone marrow mesenchymal stem cells(BMSCs)transplantation on spinal cord injury(SCI)in rats.METHODS The rats were randomly divided into the sham operation group,the model group,the TUDCA group,the BMSCs transplantation group and the combination therapy of TUDCA and BMSCs transplantation group,with the SCI rat model established by Allen's method.The next day after modeling,the rats of TUDCA and combination therapy groups were given 200 mg/kg TUDCA by gavage.On the 3rd day after modeling,rats in BMSCs transplantation group and combination therapy group were injected with 1 mL tuned bone marrow BMSCs(the 3rd generation,1× 106/mL)via tail vein.Rats in the sham operation group and the model group were given gastric perfusion of normal saline and injection of 1 mL PBS through tail vein.On the 3rd,7th and 14th day after modeling,the rats had their motor function of hind limbs observed and BBB score determined.After the corresponding drug administration,the rats had their movement track of hind limbs recorded by footprint experiment;their the protein expressions of IL-6,IL-10,Arg-1,PI3K and Akt in spinal cord tissue detected by Western blot;their pathological changes of spinal cord tissue observed by HE staining and Nissl staining;and their expressions of MAP2,GAP43 and GFAP detected by immunofluorescence staining.RESULTS Compared with the model group,the groups intervened with TUDCA,or BMSCs transplantation,or combination therapy shared improved hind limb function and spinal cord histomorphology(P＜0.05);increased fluorescence intensity of MAP2 and GAP43,and protein expressions of IL-10,Arg-1,p-PI3K and p-Akt(P＜0.05);decreased fluorescence intensity of GFAP and IL-6 protein expressions(P＜0.05);among which the combination therapy group took the lead(P＜0.05).CONCLUSION The combination therapy of TUDCA and BMSCs transplantation may restore the function of the rat model of SCI by reducing inflammatory reaction,alleviating secondary injury,and promoting axon and myelin regeneration via PI3K/Akt signaling pathway.

AIM To investigate the promotional effects of esculin combined with bone marrow mesenchymal stem cells(BM-MSCs)transplantation on the repair of spinal cord injury(SCI)in rats.METHODS The rats were randomly divided into the sham operation group,the model group,the esculin group for gavage of 20 mg/kg esculin,the BM-MSCs group for tail vein injection of 1 mL of 1×106/mL BM-MSCs,and the combinaiton treatment group.The SCI rat model was established using Allen's method,followed by the 14 days consecutive corresponding drug administration starting from the 2nd day after modeling.On days 3,7 and 14 of drug administration,the rats had their hind limbs motor function evaluated by the BBB scoring;and their footprint experiment conducted on the 14th day after modeling.After 14 days of administration,the rats had their morphological changes of spinal cord tissue observed with HE staining and Nissl staining;their activities of SOD and GSH,and level of MDA in spinal cord tissue detected by kits;their expressions of MAP2,GAP43 and GFAP in spinal cord tissue detected by immunofluorescence;and their expressions of NQO-1,Nrf-2,Bcl-2 and Bax proteins in spinal cord tissue detected by Western blot.RESULTS Compared with the model group,the groups interved with esculin,or BM-MSCs,or the combination treatment showed improvements in hind limb function and spinal cord tissue morphology(P＜0.05);decreased MDA levels(P＜0.05);increased SOD and GSH activities(P＜0.05);increased MAP2 and GAP43 fluorescence intensity(P＜0.05);decreased GFAP fluorescence intensity(P＜0.05);increased NQO-1,Nrf-2 and Bcl-2 protein expressions(P＜0.05);and decreased Bax protein expression(P＜0.05).And the combination treatment group was observed with an even better effects(P＜0.05).CONCLUSION The combination of esculin and BM-MSCs transplantation can effectively improve the spinal cord tissue damage and hind limb function in SCI rats.This effect may be achieved by activating the Nrf-2/NQO-1 signaling pathway to inhibit oxidative stress response,thereby reducing neuronal apoptosis,blocking glial scar formation,and promoting stem cell differentiation to rebuild neurons.

Objective:This study aims to analyze the disease burden trends of schizophrenia and bipolar disorder from 1990 to 2021 in China, and to predict the trends of these two disorders over the next 20 years.Methods:This study was conducted between September and October 2024. The data on incidence, prevalence, and disease burden of schizophrenia and bipolar disorder in China were retrieved from the database of the Global Burden of Disease Study 2021 (GBD2021). Temporal trends were quantified via the annual percentage change, average annual percentage change (AAPC), and their corresponding P-values, which were calculated using the empirical quantile method with the Joinpoint software. The autoregressive integrated moving average (ARIMA) model was constructed using data on the incidence, prevalence, and disease burden of schizophrenia and bipolar disorder from 1990 to 2021 to predict the trends in prevalence and disease burden of these two diseases from 2022 to 2041. Results:In China, during the period from 1990 to 2021, the age-standardized incidence rate (ASIR), age-standardized prevalence rates (ASPR), and age-standardized disability-adjusted life year (DALY) rate (ASDR) of schizophrenia all showed a fluctuating upward trend. By 2021, the AAPC of these rates was 3.83% ( P<0.001), 12.99% ( P<0.001), and 14.11% ( P<0.001), respectively, indicating a significant increase. Regarding bipolar disorder, the annual average ASIR in China significantly increased (AAPC=1.25%, P<0.001), while the annual average ASPR significantly decreased (AAPC=-1.03%, P<0.001), and the annual average ASDR showed no significant change (AAPC=-0.08%, P=0.342). The incidence of schizophrenia was mainly concentrated in the 15-34 age group. The prevalence and DALY rates of schizophrenia were on the rise across all age groups. For bipolar disorder, the peak incidence occurred between the ages of 10 and 19, with higher incidence, prevalence, and DALY rates in females compared to males. Looking ahead from 2022 to 2041, the overall ASIR, ASIR for both females and males, and ASPR for males with schizophrenia are projected to gradually increase, while the ASPR and ASDR of bipolar disorder are expected to remain stable, with females continuing to bear a higher disease burden than males. Conclusion:In China, the disease burden of schizophrenia and bipolar disorder substantially changed from 1990 to 2021, with distinct differences across gender and age-groups. The disease burden of schizophrenia is projected to keep rising in the next 20 years. It is imperative to develop targeted and precise prevention and control strategies for different populations.

AIM To investigate the repair effects of tauroursodeoxycholic acid(TUDCA)combined with bone marrow mesenchymal stem cells(BMSCs)transplantation on spinal cord injury(SCI)in rats.METHODS The rats were randomly divided into the sham operation group,the model group,the TUDCA group,the BMSCs transplantation group and the combination therapy of TUDCA and BMSCs transplantation group,with the SCI rat model established by Allen's method.The next day after modeling,the rats of TUDCA and combination therapy groups were given 200 mg/kg TUDCA by gavage.On the 3rd day after modeling,rats in BMSCs transplantation group and combination therapy group were injected with 1 mL tuned bone marrow BMSCs(the 3rd generation,1× 106/mL)via tail vein.Rats in the sham operation group and the model group were given gastric perfusion of normal saline and injection of 1 mL PBS through tail vein.On the 3rd,7th and 14th day after modeling,the rats had their motor function of hind limbs observed and BBB score determined.After the corresponding drug administration,the rats had their movement track of hind limbs recorded by footprint experiment;their the protein expressions of IL-6,IL-10,Arg-1,PI3K and Akt in spinal cord tissue detected by Western blot;their pathological changes of spinal cord tissue observed by HE staining and Nissl staining;and their expressions of MAP2,GAP43 and GFAP detected by immunofluorescence staining.RESULTS Compared with the model group,the groups intervened with TUDCA,or BMSCs transplantation,or combination therapy shared improved hind limb function and spinal cord histomorphology(P＜0.05);increased fluorescence intensity of MAP2 and GAP43,and protein expressions of IL-10,Arg-1,p-PI3K and p-Akt(P＜0.05);decreased fluorescence intensity of GFAP and IL-6 protein expressions(P＜0.05);among which the combination therapy group took the lead(P＜0.05).CONCLUSION The combination therapy of TUDCA and BMSCs transplantation may restore the function of the rat model of SCI by reducing inflammatory reaction,alleviating secondary injury,and promoting axon and myelin regeneration via PI3K/Akt signaling pathway.

AIM To investigate the promotional effects of esculin combined with bone marrow mesenchymal stem cells(BM-MSCs)transplantation on the repair of spinal cord injury(SCI)in rats.METHODS The rats were randomly divided into the sham operation group,the model group,the esculin group for gavage of 20 mg/kg esculin,the BM-MSCs group for tail vein injection of 1 mL of 1×106/mL BM-MSCs,and the combinaiton treatment group.The SCI rat model was established using Allen's method,followed by the 14 days consecutive corresponding drug administration starting from the 2nd day after modeling.On days 3,7 and 14 of drug administration,the rats had their hind limbs motor function evaluated by the BBB scoring;and their footprint experiment conducted on the 14th day after modeling.After 14 days of administration,the rats had their morphological changes of spinal cord tissue observed with HE staining and Nissl staining;their activities of SOD and GSH,and level of MDA in spinal cord tissue detected by kits;their expressions of MAP2,GAP43 and GFAP in spinal cord tissue detected by immunofluorescence;and their expressions of NQO-1,Nrf-2,Bcl-2 and Bax proteins in spinal cord tissue detected by Western blot.RESULTS Compared with the model group,the groups interved with esculin,or BM-MSCs,or the combination treatment showed improvements in hind limb function and spinal cord tissue morphology(P＜0.05);decreased MDA levels(P＜0.05);increased SOD and GSH activities(P＜0.05);increased MAP2 and GAP43 fluorescence intensity(P＜0.05);decreased GFAP fluorescence intensity(P＜0.05);increased NQO-1,Nrf-2 and Bcl-2 protein expressions(P＜0.05);and decreased Bax protein expression(P＜0.05).And the combination treatment group was observed with an even better effects(P＜0.05).CONCLUSION The combination of esculin and BM-MSCs transplantation can effectively improve the spinal cord tissue damage and hind limb function in SCI rats.This effect may be achieved by activating the Nrf-2/NQO-1 signaling pathway to inhibit oxidative stress response,thereby reducing neuronal apoptosis,blocking glial scar formation,and promoting stem cell differentiation to rebuild neurons.

Objective:This study aims to analyze the disease burden trends of schizophrenia and bipolar disorder from 1990 to 2021 in China, and to predict the trends of these two disorders over the next 20 years.Methods:This study was conducted between September and October 2024. The data on incidence, prevalence, and disease burden of schizophrenia and bipolar disorder in China were retrieved from the database of the Global Burden of Disease Study 2021 (GBD2021). Temporal trends were quantified via the annual percentage change, average annual percentage change (AAPC), and their corresponding P-values, which were calculated using the empirical quantile method with the Joinpoint software. The autoregressive integrated moving average (ARIMA) model was constructed using data on the incidence, prevalence, and disease burden of schizophrenia and bipolar disorder from 1990 to 2021 to predict the trends in prevalence and disease burden of these two diseases from 2022 to 2041. Results:In China, during the period from 1990 to 2021, the age-standardized incidence rate (ASIR), age-standardized prevalence rates (ASPR), and age-standardized disability-adjusted life year (DALY) rate (ASDR) of schizophrenia all showed a fluctuating upward trend. By 2021, the AAPC of these rates was 3.83% ( P<0.001), 12.99% ( P<0.001), and 14.11% ( P<0.001), respectively, indicating a significant increase. Regarding bipolar disorder, the annual average ASIR in China significantly increased (AAPC=1.25%, P<0.001), while the annual average ASPR significantly decreased (AAPC=-1.03%, P<0.001), and the annual average ASDR showed no significant change (AAPC=-0.08%, P=0.342). The incidence of schizophrenia was mainly concentrated in the 15-34 age group. The prevalence and DALY rates of schizophrenia were on the rise across all age groups. For bipolar disorder, the peak incidence occurred between the ages of 10 and 19, with higher incidence, prevalence, and DALY rates in females compared to males. Looking ahead from 2022 to 2041, the overall ASIR, ASIR for both females and males, and ASPR for males with schizophrenia are projected to gradually increase, while the ASPR and ASDR of bipolar disorder are expected to remain stable, with females continuing to bear a higher disease burden than males. Conclusion:In China, the disease burden of schizophrenia and bipolar disorder substantially changed from 1990 to 2021, with distinct differences across gender and age-groups. The disease burden of schizophrenia is projected to keep rising in the next 20 years. It is imperative to develop targeted and precise prevention and control strategies for different populations.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Objective:To evaluate the efficacy of acute T-cell lymphoblastic leukemia(T-ALL)in children and explore the prognostic risk factors.Methods:The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed,and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia(B-ALL)in the same period.Kaplan-Meier analysis was used to evaluate the overall survival(OS)and event-free survival(EFS),and COX proportional hazard regression model was used to evaluate the prognostic factors.Among 116 children with T-ALL who received standard treatment,78 cases received the Chinese Childhood Leukemia Collaborative Group(CCLG)-ALL 2008 protocol(CCLG-ALL 2008 group),and 38 cases received the China Childhood Cancer Collaborative Group(CCCG)-ALL 2015 protocol(CCCG-ALL 2015 group).The efficacy and serious adverse event(SAE)incidence of the two groups were compared.Results:Proportion of male,age ≥ 10 years old,white blood cell count(WBC)≥ 50 × 109/L,central nervous system leukemia,minimal residual disease(MRD)≥ 1％during induction therapy,and MRD ≥ 0.01％at the end of induction in T-ALL children were significantly higher than those in B-ALL children(P＜0.05).The expected 10-year EFS and OS of T-ALL were 59.7％and 66.0％,respectively,which were significantly lower than those of B-ALL(P＜0.001).COX analysis showed that WBC ≥ 100 x 109/L at initial diagnosis and failure to achieve complete remission(CR)after induction were independent risk factors for poor prognosis.Compared with CCLG-ALL 2008 group,CCCG-ALL 2015 group had lower incidence of infection-related SAE(15.8％vs 34.6％,P=0.042),but higher EFS and OS(73.9％vs 57.2％,PEFS=0.090;86.5％vs 62.3％,PoS=0.023).Conclusions:The prognosis of children with T-ALL is worse than children with B-ALL.WBC ≥ 100 × 109/L at initial diagnosis and non-CR after induction(especially mediastinal mass has not disappeared)are the risk factors for poor prognosis.CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

Objective:To analyze the clinical characteristics and prognosis of children with hypodiploid B-cell precursor acute lymphoblastic leukemia(BCP-ALL).Methods:The clinical data of 1 287 children with BCP-ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.According to the results of chromosome karyotype,all the patients were grouped into hypodiploid subgroup and non-hypodiploid subgroup.The clinical characteristics,early treatment response[minimal residual disease(MRD)on middle stage of induction chemotherapy and end of induction chemotherapy]and long-term efficacy[overall survival(OS)and event-free survival(EFS)]were compared.The prognostic factors of hypodiploid BCP-ALL were further explored.Results:Among 1 287 BCP-ALL patients,28 patients(2.2％)were hypodiploid BCP-ALL.The proportion of patients with white blood cell count(WBC)≥50 x 109/L in the hypodiploid subgroup was significantly higher than that in the non-hypodiploid subgroup(P=0.004),while there was no statistically significant difference in gender ratio,age group at initial diagnosis,and early treatment response between the two groups(all P＞0.05).The 5-year EFS and OS rate of the hypodiploid subgroup were 75.0％(95％CI:66.8％-83.2％)and 77.8％(95％CI:69.8％-85.8％),respectively,which were lower than those of non-hypodiploid subgroup[EFS:79.6％(95％CI:78.4％-80.8％);OS:86.4％(95％CI:85.4％-87.5％)],but the difference was not statistically significant(all P＞0.05).Further subgroup analysis by risk stratification showed that the 5-year EFS and OS rates of the hypodiploid subgroup were significantly lower than those in the low-risk(LR)group[LR group EFS:91.4％(95％CI:88.4％-93.6％),P＜0.001;OS:94.7％(95％CI:92.1％-96.4％),P＜0.001];it was similar to that of BCP-ALL children stratified into intermediate-risk(IR)excluding hypodiploid[IR group EFS:79.4％(95％CI:74.9％-83.2％),P=0.343;OS:87.3％(95％CI:83.6％-90.2％),P=0.111];while was higher than that of EFS in HR group,but the difference was not statistically significant[HR group EFS:58.7％(95％CI:52.6％-64.8％),P=0.178.OS:69.9％(95％CI:63.5％-75.4％),P=0.417].Univariate analysis showed that gender,age,white blood cell count,and MRD on middle stage of induction chemotherapy had no significant impact on OS and EFS;chromosome count＜40 was a risk factor for lower OS(P=0.026),but has no significant effect on EFS;MRD≥0.01％after induction therapy was a risk factor for lower OS and EFS(P=0.002,and 0.001,respectively).Conclusion:Children with hypodiploid BCP-ALL have an intermediate prognosis,and MRD ≥0.01％after induction chemotherapy may be a risk factors for poor prognosis.

Objective:To analyze the related factors of treatment failure in children with acute lymphoblastic leukemia (ALL)in real-world.Methods:The clinical data of 1414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.Treatment failure was defined as relapse,non-relapse death,and secondary tumor.Results:Following-up for median time 49.7 (0.1-136. 9)months,there were 269 cases (19.0％)treatment failure,including 140 cases (52.0％)relapse,and 129 cases (48.0％)non-relapse death.Cox univariate and multivariate analysis showed that white WBC≥50 ×109/L at newly diagnosis,acute T-cell lymphoblastic leukemia (T-ALL),BCR-ABL1,KMT2A-rearrangement and poor early treatment response were independent risk factor for treatment failure (all HR>1.000,P<0.05).The 5-year OS of 140 relapsed ALL patients was only 23.8％,with a significantly worse prognosis for very early relapse (relapse time within 18 months of diagnosis).Among 129 patients died from non-relapse death,71 cases (26.4％)were died from treatment-related complications,56 cases (20.8％)died from treatment abandonment,and 2 cases (0.7％)died from disease progression.Among them,treatment-related death were significantly correlated with chemotherapy intensity,while treatment abandonment were mainly related to economic factors.Conclusion:The treatment failure of children with ALL in our province is still relatively high,with relapse being the main cause of treatment failure,while treatment related death and treatment abandonment caused by economic factors are the main causes of non-relapse related death.