A novel iheyamine A derivative L42 suppresses acute myeloid leukemia via dual regulation of the PI3K/AKT/FOXO3a axis and TNF signaling pathway.

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and the development of new drugs is crucial for the treatment of this lethal disease. Iheyamine A is a nonmonoterpenoid azepinoindole alkaloid from the ascidian Polycitorella sp., and its anticancer mechanism has not been investigated in leukemias. Herein, we showed the significant antileukemic activity of L42 in AML cell lines HEL, HL-60 and THP-1. The IC50 values were 0.466±0.099 µM, 0.356±0.023 µM, 0.475±0.084 µM in the HEL, HL-60 and THP-1 cell lines, respectively, which were lower than the IC50 (2.594±0.271 µM) in the normal liver cell line HL-7702. Furthermore, L42 significantly inhibited the growth of peripheral blood mononuclear cells (PBMCs) from an AML patient. In vivo, L42 effectively suppressed leukemia progression in a mouse model induced by Friend murine leukemia virus (F-MuLV). Mechanistically, we showed that L42 induced cell cycle arrest and apoptosis in leukemia cell lines. RNA sequencing analysis of L42-treated THP-1 cells revealed that the differentially expressed genes (DEGs) were enriched in the cell cycle and apoptosis and predominantly enriched in the PI3K/AKT pathway. Accordingly, L42 decreased the expression of the phospho-PI3K (p85), phospho-AKT and phospho-FOXO3a. Docking and CETSA analysis indicated that L42 bound to the PI3K isoform p110α (PIK3CA), which was implicated in the suppression of the PI3K/AKT pathway. L42 was also shown to initiate the TNF signaling-mediated apoptosis. Moreover, L42 exhibited stronger anti-leukemia activity and sensitivity in IDH2-mutant HEL cells than in IDH2-wild-type control. In conclusion, L42 effectively suppresses cell proliferation and triggers apoptosis in AML cell lines in part through inhibition of the PI3K/AKT signaling pathway to restore FOXO3a expression and activation of the TNF signaling pathway. Thus, the iheyamine A derivative L42 represents a novel candidate for AML therapy.

Urea regulates soil nematode population by enhancing the nematode-trapping ability of nematode-trapping fungi.

As the most abundant animal in the soil, nematodes are directly or indirectly involved in almost all soil ecological processes. Studying soil nematode population regulation is essential to understanding soil ecological processes. This study found urea combines nematode-trapping fungi to regulate the population of soil nematodes. In soil, compared with no urea, adding 0.2 mg/mL urea after applying Arthrobotrys oligospora and Dactylellina ellipsospora reduced the number of nematodes by 34.7% and 31.7%. Further, the mechanism of urea couple nematode-trapping fungi to regulate the nematode population was explored in the medium environment. The results showed that the addition of 0.2 mg/ml urea accelerated the trap formation of A. oligospora and D. ellipsosporas by 50% and 46.5%, and increased the yield of traps of A. oligospora and D. ellipsosporas by 39.5% and 40.6%, thus, the predatory efficiency of A. oligospora and D. ellipsospora on nematodes was increased by 34.2% and 32.7%. In conclusion, urea regulates the predation ability of A. oligospora and D. ellipsosporas to regulate the soil nematode population. This study deepens the understanding of the regulatory pathways of the soil nematodes but also provides a potential new strategy for harmful nematode bio-control.

Ozone therapy for high-grade glioma: an overview.

High-grade gliomas (grades III and IV) are highly malignant and aggressive brain tumors that present significant treatment challenges. Despite advances in surgery, chemotherapy, and radiation therapy, the prognosis for patients with glioma remains poor, with a median overall survival (mOS) range of 9-12 months. Therefore, exploring new and effective therapeutic strategies to improve glioma prognosis is of utmost importance and ozone therapy is a viable option. Ozone therapy has been used in various cancers, such as colon, breast, and lung, yielding significant results in preclinical studies and clinical trials. Only a few studies have been conducted on gliomas. Furthermore, since the metabolism of brain cells involves aerobic glycolysis, ozone therapy may improve the oxygen condition and enhance glioma radiation treatment. However, understanding the correct ozone dosage and optimal time of administration remains challenging. Herein, we hypothesize that ozone therapy should be more effective in gliomas compared with other tumors. This study provides an overview of the use of ozone therapy in high-grade glioma, including mechanisms of action, preclinical data, and clinical evidence.

Chest wall muscle mass depletion is related to certain pulmonary functions and diseases in patients with bronchiectasis.

BACKGROUND AND OBJECTIVE: Many bronchiectasis patients suffer dyspnea, decreased exercise tolerance, and low body mass index. Chest wall muscles play a special role in respiratory movement and make up parts of skeletal muscles. This study aimed to examine the chest wall muscle thickness and their relationship with disease severity in bronchiectasis. METHODS: We retrospectively included 166 patients with bronchiectasis and 62 patients with pneumonia as comparators. The thickness of chest wall muscle as determined in chest CT, pulmonary function, and Bronchiectasis Severity Index (BSI) score were recorded. We compared the thickness of the chest wall muscle in two groups and assessed the relationships among chest wall muscle thickness, pulmonary function, and BSI score. RESULTS: Chest wall muscle thickness of the anterior midclavicular line and posterior exterior scapula were thinner in bronchiectasis patients than comparators both above the aortic arch level and at the aortic arch window level. Muscle thickness of the posterior interior scapula above the aortic arch level was significantly thinner in bronchiectasis patients. Chest wall muscle thickness at the anterior midclavicular line both the above aortic arch level and at the level of the aortic arch window were related to diffuse capacity in bronchiectasis patients. Anterior chest wall muscle thickness above the aortic arch was found to be a risk factor of disease severity. CONCLUSION: Anterior chest wall muscles in the upper and middle chest were thinner in bronchiectasis patients than in comparators, and had relationship with spirometry and diffuse compacity factors. We provide another method to conveniently assess bronchiectasis severity.

The pathogenesis of duck virus enteritis in experimentally infected ducks: a quantitative time-course study using TaqMan polymerase chain reaction.

Duck virus enteritis is an acute and contagious herpesvirus infection of duck, geese and swans with high morbidity and mortality. The kinetics of viral DNA loads and immunohistochemical localization of virulent duck enteritis virus, as well as histopathological examination in various tissues of ducks following oral infection, were investigated. The time course for the appearance of viral antigen and tissue lesions in various tissues was coincident with the levels of duck enteritis virus at the various sites, suggesting that the levels of duck enteritis virus in systemic organs have a close correlation with the progression of disease. The abundance of target epithelial and lymphoid cells may contribute to the high levels of virus infection and replication in lymphoid and intestinal tissues.

Opposite effects of MK-801 on the expression of food and morphine-induced conditioned place preference in rats.

Behavioural studies have provided strong evidence for common substrates in the rewards of natural and addictive substances, but it is still unclear whether there is a common glutamatergic NMDA receptor mechanism involved in the processing of reward for both. The present study was designed to investigate the effects of MK-801 (0.1mg/kg) on the expression of place preference conditioned with food and morphine (5.0mg/kg) in rats. The data indicates that MK-801 potentiates the expression of food-induced conditioned place preference (CPP) but retards that of morphine CPP. It also demonstrates that the opposite effects of MK-801 on food and morphine CPP expression were caused neither by hyperactivity nor by the impairment of memory retrieval. These results suggest that MK-801 enhances food craving and inhibits morphine craving in rats, and that the roles of glutamatergic NMDA receptor mechanisms in the reward processing of natural reinforcers and addictive drugs may be dissociable.

Social crowding sensitizes high-responding rats to psychomotor-stimulant effects of morphine.

Large individual differences have been identified toward varied addictive effects as evidenced in self-administration, place conditioning, and psychomotor stimulation paradigms, which have been primarily attributed to the role of congenital factors. However, it remains unknown whether environmental factors, like extraneous social stress events, could distinctively modulate animals with differentiated biobehavioral traits, such as rats with higher motor activity (high responder, HR) developed in a novel environment and their counterparts, LR (low responder) rats. In the present study, the influence of social crowding procedure upon morphine psychomotor effect was investigated. Moreover, the roles social stress played, respectively, on HRs and LRs were explored based on previous observation that HRs not only responded more to drugs but also to stress. Our results revealed that social crowding procedure could sensitize morphine psychomotor effect as a whole, and this effect was only evident for HR but not LR rats. The individual differences toward morphine psychomotor effects was indiscernible in rats housed in normal social conditions and only turned out to be significant under stress conditions. Given the fact that the occurrence of human addictive behavior usually happens within social environment permeated with various stress factors, the genetic and environmental elements may collaboratively contribute to the ultimate susceptibility of drug-prone individuals.