Ticlopidine protects hepatic ischemia-reperfusion injury via suppressing ferroptosis.

Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during hepatic resection, transplantation, and other surgical procedures, often leading to graft failure and liver dysfunction. Recent studies have identified ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, as a key contributor to IRI. In this study, we investigated the protective effects of Ticlopidine, a thienopyridine compound and platelet aggregation inhibitor, on hepatic IRI. Using a C57BL/6J mouse model, we demonstrated that prophylactic Ticlopidine treatment significantly reduced necrotic and fibrotic areas in liver tissues, as well as serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Prussian Blue staining revealed that Ticlopidine pretreatment decreased iron accumulation in hepatic tissues, whereas markers of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and ferroptosis (PTGS2) were significantly downregulated. Additionally, Ticlopidine ameliorated inflammatory infiltration as indicated by reduced Gr-1 staining. In vitro, Ticlopidine dose-dependently inhibited ferroptosis induced by various inducers in liver cancer cell lines HUH7 and fibrosarcoma cells HT1080. The protective effects involved partial rescue of lipid peroxidation, significant reduction of ferrous iron levels, and strong protection against mitochondrial damage. These findings suggested that Ticlopidine acts as a broad-spectrum ferroptosis inhibitor, offering a promising therapeutic approach for protecting the liver against IRI.

Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation.

Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent. Also, more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among acute myeloid leukemia and colorectal carcinoma cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases. The study supports the suggestion that the level of DNA methylation changes in AML progression.

SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression.

OBJECTIVE: SUMO-specific protease 3 (SENP3), a member of the SUMO-specific protease family, reverses the SUMOylation of SUMO-2/3 conjugates. Dysregulation of SENP3 has been proven to be involved in the development of various tumors. However, its role in mantle cell lymphoma (MCL), a highly aggressive lymphoma, remains unclear. This study was aimed to elucidate the effect of SENP3 in MCL. METHODS: The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR, Western blotting or immunohistochemistry. MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs. Cell proliferation was assessed by CCK-8 assay, and cell apoptosis was determined by flow cytometry. mRNA sequencing (mRNA-seq) was used to investigate the underlying mechanism of SENP3 knockdown on MCL development. A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo. RESULTS: SENP3 was upregulated in MCL patient samples and cells. Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis. Meanwhile, the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown. Furthermore, the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model. CONCLUSION: SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

Interspecific competitive effects and annual differences in predation of Empoasca onukii (Hemiptera: Cicadellidae) by wandering spiders.

Empoasca onukii Matsuda is an important pest widely distributed in tea areas in China, which greatly affects tea production and quality. The long-term use of chemical control measures will cause environmental pollution. To better utilize wandering spiders that have strong competitive effects on the predation of E. onukii, we conducted a path analysis between the populations of E. onukii and wandering spiders in 3 tea plantations in 2020 and 2021. The wandering spider species that had the greatest direct and indirect effects on the population of E. onukii were analyzed by the magnitude of the path coefficient. Then, a gray system analysis was conducted to determine the closeness of the populations of different wandering spiders to E. onukii by the magnitude of gray correlation coefficient. Finally, the competition coefficients were calculated to determine the competitiveness of wandering spiders. In addition, considering the influence of the number of E. onukii on the interspecific competition of wandering spiders, the gray correlation coefficient and competition coefficient were combined to derive the competition intensity index, which was used to analyze the competitiveness of wandering spiders in a comprehensive manner. The highest competition coefficients in 2020 and 2021 were found for Ebrechtella tricuspidata Fabricius (Araneae: Thomisidae) (X2, 0.5329) and Clubiona reichlini Fabricius (Araneae: Clubionidae) (X4, 0.8475), respectively. The magnitude of the competition intensity index showed that the most competitive wandering spider in 2020 and 2021 was E. tricuspidata (X2, 0.5692) and C. reichlini (X4, 0.8892), respectively. The least competitive spider in both years was Plexippus setipes Karsch (Araneae: Salticidae) (X7). The more competitive the wandering spider is, the closer it is to E. onukii in terms of numbers, and the more dominant it is in feeding on E. onukii. By reasonably protecting and utilizing the competitive E. tricuspidata (X2) and C. reichlini (X4), we can achieve sustainable and effective control of E. onukii.

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials.

Objective: Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Methods: Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Results: Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Conclusions: Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1.

Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer's disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1. Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety. Results: Of the 13 patients with NP-C1 (12-33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium. Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding. Clinical Trial Registration: ClinicalTrials.gov, NCT03201627.

From astrocytoma to glioblastoma: a clonal evolution study.

Astrocytomas often recur after surgical resection, but the underlying mechanism remains enigmatic. Elucidation of clonal evolution in primary and relapse tumors may provide important information on tumor progression. Here, we examined genetic factors underlying recurrence in a patient with astrocytoma initially diagnosed with World Health Organization (WHO) grade II astrocytoma, who then relapsed with glioblastoma (WHO grade IV) complicated with local anaplastic astrocytoma (WHO grade III). We performed genomic DNA sequencing and data analysis of paired tumor tissue specimens and a peripheral blood sample (control), and used expands software for subclone analysis. A germline NOTCH1 missense mutation was identified in the peripheral blood sample, the primary tumor and the relapse tumor; in addition, we identified a tumor protein p53 (TP53) heterozygous nonsense mutation in the primary tumor and a TP53 homozygous nonsense mutation and an IDH1 heterozygous missense mutation in the relapse tumor. Clonal evolution trees indicated higher heterogeneity in the relapse tumor. Although germline mutations might contribute to the driving force of the primary tumor, aggressive chemotherapy and radiation may apply selective pressure for tumor clonal evolution; furthermore, a total loss of function of gatekeeping genes (TP53) may result in impaired DNA repair and catastrophic chromosomal aberrations.

Genetic polymorphisms of NAT2 and risk of acute myeloid leukemia: A case-control study.

Our purpose was to investigate the possible associations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of acute myeloid leukemia (AML) in Chinese Han population.A case-control study was conducted including 98 AML cases and 112 healthy controls. NAT2 gene 2 polymorphisms rs1799930 and rs1799931 were genotyped using direct sequencing. Chi-square test was performed to compare the genotype and allele distribution differences between groups. Odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between NAT2 gene polymorphisms and AML onset.A remarkable decrease trend of rs1799931 GA genotype was detected in AML patients compared with controls, whereas the ancestral GG genotype frequency increased in cases (P < .05). And the mutant A allele of rs1799931 significantly reduced the risk of AML by 0.585-fold versus the ancestral G allele carriers (OR = 0.585, 95% CI = 0.361-0.950). But the distributions of rs1799930 genotype and allele were similar between groups (P > .05).Our findings suggested that NAT2 gene polymorphism rs1799931 was associated with decreased risk of AML and was likely to be a protective factor against AML development.

Proinsulin Promotes Self-Renewal of a Hematopoietic Progenitor Cell Line In Vitro.

The objective of this study was to assess the effects of exogenously expressed proinsulin on the biological characters of a hematopoietic stem cell line (HSC) and erythroid myeloid lymphoid (EML) cells and explore new strategies for cell therapy for type I diabetes. EML cells were transduced with lentivirus particles carrying the human proinsulin (proINS) gene. The positive transduced cells were selected based on green fluorescence protein (GFP) positivity and puromycin resistance. Overexpression of proINS was confirmed via real-time PCR and Western blotting. The functional activity of the human proINS secreted by EML cells was elucidated by analyzing the activation of insulin receptor and its downstream signaling. Pro-INS + EML cells were able to prime the phosphorylation of insulin receptor as well as induce the expression of downstream genes of insulin receptor. Furthermore, Wnt3a can significantly promote self-renewal of Pro-INS + EML cells. However, we did not observe significant changes in the proliferation and differentiation of INS + EML cells, compared to the control EML cells. Our results might be useful for developing a new therapy for diabetes mellitus.

High Doses of Daunorubicin during Induction Therapy of Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Prospective Clinical Trials.

The right dose of daunorubicin (DNR) for the treatment of newly diagnosed acute myeloid leukemia (AML) is uncertain. Previous trials have shown conflicting results concerning the efficacy of high or low doses of daunorubicin to induction chemotherapy for newly diagnosed AML. A systematic review and meta-analysis was conducted to resolve this controversial issue. We compared the efficacy and safety of high doses of daunorubicin (HD-DNR) and traditional low doses of daunorubicin (LD-DNR) or idarubicin (IDA) during induction therapy of newly diagnosed AML. Data of 3,824 patients from 1,796 articles in the literature were retrieved and six randomized controlled trials were analyzed. The primary outcomes were overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The secondary outcomes included complete remission (CR), relapse, and toxicity. The meta-analysis results suggest that comparing HD-DNR with LD-DNR, there were significant differences in CR (RR = 1.19, 95%CI[1.12,1.18], p<0.00001), OS(HR = 0.88, 95%CI[0.79,0.99], p = 0.002), and EFS (HR = 0.86, 95%CI [0.74, 1.00], p = 0.008), but not in DFS, relapse, and toxicity. There were no statistically significant differences in any other outcomes between HD-DNR and IDA. The analysis indicates that compared with LD-DNR, HD-DNR can significantly improve CR, OS and EFS but not DFS, and did not increase occurrence of relapse and toxicity.

[Species diversity and seasonal change of entomogenous fungi in Langya Mountains Nature Reserve].

672 specimens of entomogenous fungi belonging to 20 species, 8 genera and 4 families were collected from 20 sampling quadrates in the Langya Mountains Nature Reserve of East Anhui. The dominant species were Beauveria bassiana, Paecilomyces farinosus, P. cateinannulatus, B. brongniartii and P. fumosoroseus, and B. bassiana was most dominant, with the relative abundance of 73.8%. The entomogenous fungi in the Reserve were high in amount but low in diversity. The amount of isolates and the abundance of each species were the highest in summer and decreased with decreasing air temperature and rainfall, while the Pielou evenness changed from relatively low to relatively high. Paecilomyces spp. had a less seasonal fluctuation of quantity than Beauveria spp.

[Effects of insecticides on insect pest-natural enemy community in early rice fields].

This paper studied the effects of triazophos, shachongshuang, abamectin, and Bt + imidacloprid on the insect pest-natural enemy community in early rice fields in the Yangtze-Huaihe region of Anhui Province. The results showed that all of the test insecticides had significant effects in controlling the growth of major insect pest populations. The average value of insect pest-natural enemy community diversity under effects of triazophos, shachongshuang, abamectin, and Bt + imidacloprid was 1.545, 1.562, 1.691 and 1.915, respectively, while that in control plot was 1.897. After two weeks of applying insecticides, the plots applied with shachongshuang and abamectin had a similar composition of insect pest-natural enemy community, but the community composition was significantly different between the plots applied with triazophos and Bt + imidacloprid. From the viewpoints of community stability and pest control, Bt + imidacloprid had the best effect, and shachongshuang and abamectin were better than triazophos.

[Relationships of bee population fluctuation and distribution with natural environment in Anhui province].

In 2002 to approximately 2004, an investigation was made on the bee population dynamics and its relationships with the ecological environment in four ecological regions of Anhui Province. The results indicated that in the mountainous areas of south and west Anhui, there were 46 and 37 species of nectariferous plants, and the distribution density of Apis cerena cerena population was 2.01 and 1.95 colony x km(-2), respectively. In Jianghuai area and Huaibei plain, there were 17 and 12 species of nectariferous plants, which had concentrated and short flowering period and fitted for Apis mellifera Ligustica oysterring and producing, and the distribution density of Apis cerena cerena population was 0. 06 and 0. 02 colony x km(-2), respectively. Bee population fluctuation and distribution was affected by wasp predation. The breeding proportion of Apis cerena cerena to local apis population was 41.5%, 36.8%, 3.1% and 1.1%, and that of Apis mellifera Ligustica was 58.5%, 63.2%, 96.9% and 98.9% in the mountainous areas of south and west Anhui, Jianghuai area, and Huaibei plain, respectively.

[Effects of rare earth elements on soil fauna community structure and their ecotoxicity to Holotrichia parallela].

By the method of OECD filter paper contact, this paper studied the effects of applied rare earth elements on soil fauna community structure and their ecological toxicity to Holotrichia parallela in bean field. The results showed that there were no significant differences between the treatments and the control in soil fauna species, quantity of main species, and diversity index. Urgent and chronic toxic test showed that the differences between the treatments and the control were not significant. It was suggested that within the range of test dosages, rare earth elements had little ecological toxicity to Holotrichia parallela, and did not change the soil fauna community structure.

[Three-dimensional spatial distribution patterns of Monochamus alternatus and its natural enemy Dastarcus helophoroides].

In 2003 to approximately 2005, the Monochamus alternatus-infected Pinus thunbergii, P. massoniana and P. elliotii in pure and mixed forests were selected as attractants and dissected with one meter section manner, and five aggregation indices were used to analyze the spatial distribution patterns of M. alternatus and its natural enemy Dastarcus helophoroides. The results showed that M. alternatus and D. helophoroides had the horizontal distribution indices of diffused coefficient C > 1, diffused index I delta > 1, Kuno index C(A) > 0, clump intensity index I > 1, and swarm index Iw > 1 in the two stands, suggesting their aggregated horizontal distribution patterns, and except D. helophoroides on the P. massoniana in mixed forest appeared assemble vertical distribution, these two insects all had an even vertical distribution, with their C < 1, I delta < 1, C(A) < 0, Iw < 1, and I < 0. The spatial distribution patterns of M. alternatus and D. helophoroides were consistent, and the latter was spatially following the former.

[Structural characteristics of arthropod community in grapery].

By the method of principal component analysis, this paper analyzed the characteristic parameters of arthropod community and its phytophagous and predacious sub-communities in grapery. The results showed that in the first principal component, the contribution of arthropod community, phytophagous sub-community and predacious sub-community was 66.70%, 73.39% and 54.17%, respectively. For arthropod community, the absolute values of normalized regressive coefficients of individuals' number N, Hill diversity index N1, Hill diversity index N2 and McIntosh index D(mc) were larger, indicating their greater contribution on the community. For phytophagous sub-community, N, N1, N2, N and S (total species) had greater contribution; while for predacious sub-community, the greater contribution was made by N1, N2, Shannon-Wiener diversity index H' and abundance R. Synthetically, N2 and N1 had greater contribution on the arthropod community and its phytophagous and predacious sub-communities in grapery, comparing with other characteristic parameters.

[Community structure and its dynamics of predatory arthropod in different tobacco varieties fields].

With principal component analysis and using community structural characteristic indices, this paper studied the community structure and its dynamics of predatory arthropod in fields planted with tobacco varieties Nc89, Nc82 and K326. The results showed that in all test fields, spiders and predatory insects were the predominant components of the predatory arthropod community, and their relative abundances were 83.25%-86.87% and 13.13%-16.38%, respectively. There was a significant difference in the mean density (individuals per 8 plants) of the most common predatory arthropod groups between different tobacco varieties fields, which was the highest in K326 field, followed by Nc82, and Nc89 field. The individuals of both Linyphiidae and Coccinellidae played the dominant role in the community. There was a significant difference in the richness of predatory arthropod community between Nc89 and Nc82 fields, but the differences of other structural characteristic indices were not significant. The temporal dynamics of the richness and dominancy in all test fields had a trend of low-high-low, and those of the diversity and evenness index were high-low-high.

[Effects of herbicides on diversity indices of cotton field arthropod community].

This paper studied the differences of the diversity, abundance and evenness of arthropod community and sub-community in cotton field among treatments haloxyfor-k (A), paraquat (B) and contrast (CK). The results showed that in the diversity of phytophagous sub-community, tA-CK = 3.099 and tB-CK = 2.449 (t > t0.05 = 2.228), the difference being significant, and in the diversity of predatory sub-community, tA-B = 2.260 and tA-CK = 2.377 (t > t0.05 = 2.228), the difference being also significant. In the arthropod community and sub-community, no significant difference was found for A-CK, B-CK and A-B. The abundance of arthropod community tA- CK = 4.359, and that of phytophagous sub-community tA-CK = 2.963, the effect being all significant (t > t0.05 = 2.228). No significant difference was found in the evenness of arthropod community and sub-community for A-B, A-CK and B-CK. The biodiversity had the same change trend for treatments haloxyfor-R (A) paraquat (B) and contrast (CK).

[Characteristics, dynamics and niche of insect community in plum orchard].

The insect community in plum orchard was investigated on organization level and temporal-spatial niche. The results showed that the insect community was abundant, which included 6 orders, 23 families. The individuals of species, diversity indices, and evenness increased with time. Myzus persicae and Asiaarposina sasokii had the widest spatial niche breadth, while Didesmococcus koreauus borchs had the widest temporal niche breadth. Among the natural enemies, Chilocorus rubidus had the widest both temporal and spatial niche breadth. The niche of Chicocorus rubidus and Didesmococcus koreauus overlapped larger than that of the others, which indicated their synchrony in temporal dimension and their similarity in spatial dimension. As the dominant natural enemies, the two populations should be protected and utilized to control plum pest.