Efficacy and safety of immunosuppressive therapy combined with eltrombopag for severe aplastic anemia: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Immunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA. METHODS: We conducted a systematic review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis. RESULTS: A total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics. CONCLUSION: EPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.

Fisetin alleviates cerebral ischemia/reperfusion injury by regulating Sirt1/Foxc1/Ubqln1 pathway-mediated proteostasis.

BACKGROUND: Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with protein damage. The flavonoid fisetin has good therapeutic effects on cerebral IRI. However, the role of fisetin in regulating protein damage during cerebral IRI development remains unclear. This study investigated the pharmacological effects of fisetin on protein damage during cerebral IRI progression and defined the underlying mechanism of action. METHODS: In vivo and in vitro models of cerebral IRI were established by middle cerebral artery occlusion/reperfusion (MACO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) treatment, respectively. Triphenyl tetrazolium chloride staining was performed to detect cerebral infarct size, and the modified neurologic severity score was used to examine neurological deficits. LDH activity and protein damage were assessed using kits. HT22 cell vitality and apoptosis were examined using CCK-8 assay and TUNEL staining, respectively. Interactions between Foxc1, Ubqln1, Sirt1, and Ezh2 were analyzed using CoIP, ChIP and/or dual-luciferase reporter gene assays. RESULTS: Fisetin alleviated protein damage and ubiquitinated protein aggregation and neuronal death caused by MCAO/R and OGD/R. Ubqln1 knockdown abrogated the inhibitory effect of fisetin on OGD/R-induced protein damage, ubiquitinated protein aggregation, and neuronal death in HT22 cells. Further experiments demonstrated that Foxc1 functions as a transcriptional activator of Ubqln1 and that Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its activity. Furthermore, Sirt1 knockdown abrogated fisetin-mediated biological effects on OGD/R-treated HT22 cells. CONCLUSION: Fisetin improved proteostasis during cerebral IRI by regulating the Sirt1/Foxc1/Ubqln1 signaling axis. Our findings strongly suggest that fisetin-mediated inhibition of protein damage after ischemic stroke is a part of the mechanism through which fisetin is neuroprotective in cerebral IRI.

Meta­analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia.

The present study aimed to compare the efficacy of combination therapy with venetoclax and azacitidine with that of azacytidine monotherapy in the treatment of acute myeloid leukemia (AML). The Web of Science, PubMed, Embase, The Cochrane Library, Weipu Database, Wanfang Digital Periodicals, Sinomed, China National Knowledge Infrastructure, ProQuest Dissertations and Theses and Cumulative Index to Nursing and Allied Health Literature were searched for publications on the treatment of AML with venetoclax combined with azacitidine or with azacitidine monotherapy. A total of 5,271 relevant studies were retrieved, of which 10 were included. Literature quality was evaluated according to the Cochrane systematic review methodology, and data were extracted for meta-analysis using Review Manager 5.4. The combination of venetoclax and azacitidine demonstrated greater overall efficacy than azacitidine monotherapy for AML treatment. Notably, combination therapy resulted in a higher frequency of complete remission. By contrast, combined treatment and monotherapy showed no significant differences in partial remission, whereas there was a statistically significant decrease in the frequency of no remission in the combination therapy group compared with in the monotherapy group. The results also revealed a significantly higher incidence of adverse reactions when venetoclax and azacitidine were combined in the treatment of AML compared with the observed rates in response to azacitidine monotherapy. Moreover, subgroup analyses showed that no statistically significant differences were observed between the two groups regarding adverse events, including hypokalemia and liver insufficiency. In conclusion, the combination of venetoclax and azacitidine was more effective than azacitidine alone, and had a good clinical application value in the treatment of AML. Although some adverse reactions occurred in response to the combination therapy, they did not significantly affect the prognosis of AML. To better evaluate the efficacy and safety of this treatment regimen, multicenter clinical studies with larger sample sizes are required.

Caspase-1/IL-1ß represses membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1 in Alzheimer's disease.

BACKGROUND: Alzheimer's disease is a neurodegenerative disease. Previous study has reported that caspase-1/IL-1ß is closely associated with Alzheimer's disease. However, the biological role of caspase-1/IL-1ß in Alzheimer's disease has not been fully elucidated. This study aimed to explore the mechanism of action of caspase-1/IL-1ß in Alzheimer's disease. METHODS: Mouse hippocampal neurones were treated with Aß1-42 to induce Alzheimer's disease cell model. APP/PS1 mice and Aß1-42-induced hippocampal neurones were treated with AC-YVAD-CMK (caspase-1 inhibitor). Spatial learning and memory ability of mice were detected by morris water maze. Flow cytometry, TUNEL staining, Thioflavin S staining and immunohistochemistry were performed to examine apoptosis and senile plaque deposition. Enzyme linked immunosorbent assay and western blot were performed to assess the levels of protein or cytokines. Co-Immunoprecipitation was performed to verify the interaction between Stargazin and GluA1. RESULTS: AC-YVAD-CMK treatment improved spatial learning and memory ability and reduced senile plaque deposition of APP/PS1 mice. Moreover, AC-YVAD-CMK promoted membrane transport of GluA1 in APP/PS1 mice. In vitro, Aß1-42-induced hippocampal neurones exhibited an increase in apoptosis and a decrease in the membrane transport of GluA1, which was abolished by AC-YVAD-CMK treatment. In addition, Stargazin interacted with GluA1, which was repressed by caspase-1. Caspase-1/IL-1ß inhibited membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1. CONCLUSIONS: Our data demonstrate that caspase-1/IL-1ß represses membrane transport of GluA1 by inhibiting the interaction between Stargazin in Alzheimer's disease. Thus, caspase-1/IL-1ß may be a target for Alzheimer's disease treatment.

Claudin18 associated with corticosteroid-induced expression of surfactant proteins in pulmonary epithelial cells.

OBJECTIVE: The present study was undertaken to test the hypothesis that if Cldn18 is associated with lung maturation and play a key role in the corticosteroid-induced expression of surfactant proteins. METHODS: Mouse embryonic lung tissue at different developmental stages (E14.5, E16.5 and E18.5) was collected to detect the temporal-spatial expression of Cldn18 by Western blot and immunofluorescence staining. Dexamethasone + cAMP + isobutylmethylxanthine (DCI), a commonly used agent for inducing maturation of alveolar epithelial cell in vitro, was used to mimic the roles of corticosteroid. Mouse alveolar epithelial cell line MLE12 treated with or without DCI were harvested, expression of Cldn18 and surfactant proteins were assessed by real-time RT-PCR. For Si-RNA experiments, MLE-12 was transfected with control siRNA or Cldn18 siRNA for 24 h before DCI treatment. Expression of Cldn18 and surfactant proteins was assessed by real-time RT-PCR. RESULTS: Expression of Cldn18 was detected in peripheral lung epithelial cells, and increased expression was detected from E14.5 to E18.5 during lung development. Expression of Cldn18 and surfactants (SPA, SPB and SPC) were significantly induced in MLE12 after DCI treatment. Silencing of Cldn18 effectively suppressed the DCI-induced expression of SPB and SPC but not SPA. CONCLUSION: Our results demonstrated that expression of Cldn18 is associated with peripheral lung epithelial cell maturation and play a key role in the corticosteroid-induced expression of surfactant proteins.

Heparanase Is a Critical Regulator of Mitotic Spindles Required for Maintaining Chromosome Stability.

The mitotic spindle, assembled by microtubule organization center (MTOC), is a critical structure required for proper chromosome segregation during mitosis. Studies demonstrated that defects of mitotic spindle assembling would result in chromosome instability, associating with oncogenesis. In this study, we identified that heparanase (HPSE) was localized on MTOC in mitotic cells. Induced expression of HPSE in human airway epithelial cells promoted mitotic spindle formation, and silencing of HPSE expression disrupted the mitotic spindle formation, resulting in chromosome instability, including chromosome mis-segregation and increased micronuclei formation. In conclusion, HPSE is an important protein in regulation of mitotic spindle and loss of HPSE function on MTOC associates with chromosome instability, indicating that loss of HPSE on MTOC may play critical roles in oncogenesis.

[Expression of B7 Family Co-inhibitory Molecules in the Establishment of Pulmonary Regional Immunity].

OBJECTIVE: To identify the temporal-spatial expression of B7 family co-inhibitory molecules during lung development, and to explore the roles of B7 family co-inhibitory molecules in the developmental process of pulmonary regional immunity. METHODS: The expression of B7 family co-inhibitory molecules (B7-1, B7-2, B7-H1, B7-DC) in different developmental stages of Rhesus monkey lungs were normalized and calculated by the reads per kilo-base of transcript per million mapped reads (RPKM) method. Immunohistochemical staining was performed to identify the localization and the protein of B7 family co-inhibitory molecules in different developmental phase (canalicular stage, cystic stage, alveolar stage) in mouse. RESULTS: The expression of B7 family co-inhibitory molecules in rhesus monkey were increased during the prenatal period (cystic stage, alveolar stage), the expressions of B7-2 and B7-H1 mRNA were significantly increased in alveolar stage (P<0.05). The results of immuno-histochemistry indicated that B7 family co-inhibitory molecules were mainly expressed in airway epithelial cells, and their protein levels were increased during the prenatal period. The expressions of B7-2, B7-H1 and B7-DC were significantly increased from canalicular stage (P<0.05). The protein of B7-2 was higher in airway than that in bronchus (P<0.05). CONCLUSIONS: B7 family co-inhibitory molecules are mainly expressed in airway epithelial cells, and the expressions are increased during the prenatal period, which suggests that B7 family co-inhibitory molecules are involved possibly in the development of pulmonary regional immunity.