The effects of Wharton's jelly MSCs secretomes for restoring busulfan-induced reproductive toxicity in male mice.

Several studies investigated the application of Mesenchymal stem cells (MSCs) for treating spermatogenic disorders. Considering the limitation of MSC application, the present study aimed to compare Wharton's jelly MSCs secretomes, including condition medium (CM) 10-fold concentrated (CM10), 20-fold concentrated CM (CM20), and extracellular vesicles (EVs) to restore busulfan-induced damage on male mice reproduction. So, Wharton's jelly MSCs were cultured, CM was collected, and EVs were isolated. Seventy-two mice were randomly assigned to nine groups, including Control, Busulfan 1 month (1M), Busulfan 2 months (2M), CM10, Busulfan + CM10, CM20, Busulfan + CM20, EVs, and Busulfan + EVs groups. Sperm characteristics, DNA maturity, DNA fragmentation index (DFI), and testicular gene expression were evaluated. Data analysis revealed that CM10 significantly improved sperm plasma membrane integrity, sperm DNA maturity, and DFI in the Busulfan + CM10 group compared to the Busulfan 2M group. Although CM20 and EVs showed a non-significant improvement. Gene expression analysis showed busulfan administration significantly decreased the expression of AR, CREB1, and PLCζ genes, while CM10 significantly restored CREB1 gene expression. The present study demonstrated that CM10 is more effective than CM20 or EVs in reducing busulfan-induced reproductive toxicity.

Arginine Biosynthesis Mediates Wulingzhi Extract Resistance to Busulfan-Induced Male Reproductive Toxicity.

Busulfan, an indispensable medicine in cancer treatment, can cause serious reproductive system damage to males as a side effect of its otherwise excellent therapeutic results. Its widespread use has also caused its accumulation in the environment and subsequent ecotoxicology effects. As a Chinese medicine, Wulingzhi (WLZ) has the effects of promoting blood circulation and improving female reproductive function. However, the potential effects of WLZ in male reproduction and in counteracting busulfan-induced testis damage, as well as its probable mechanisms, are still ambiguous. In this study, busulfan was introduced in a mouse model to evaluate its production of the testicular damage. The components of different WLZ extracts were compared using an untargeted metabolome to select extracts with greater efficacy, which were further confirmed in vivo. Here, we demonstrate abnormal spermatogenesis and low sperm quality in busulfan-injured testes. The WLZ extracts showed a strong potential to rehabilitate the male reproductive system; this effect was more prominent in room-temperature extracts. Additionally, both water and ethanol WLZ extracts at room temperature alleviated various busulfan-induced adverse effects. In particular, WLZ recovered spermatogenesis, re-activated arginine biosynthesis, and alleviated the increased oxidative stress and inflammation in the testis, ultimately reversing the busulfan-induced testicular injury. Collectively, these results suggest a promising approach to protecting the male reproductive system from busulfan-induced adverse side effects, as well as those of other similar anti-cancer drugs.

Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times.

Purpose: Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Patients and methods: Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Results: Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. Conclusion: While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

Histological differences between the central and peripheral areas of the testes of busulfan-administered mice.

Busulfan is an anticancer drug known to cause serious damage to seminiferous tubules in the testes and deplete germ cells in human and animal models. The testicular artery is anastomosed with deferential and cremasteric arteries and is divided into capsular arteries, which give rise to the centripetal arteries and then recurrent arteries. The arterial blood in the testicular tissue is supplied by such a consequent system of arterial vessels, in order from the peripheral to the central area. As anticancer drugs are generally distributed throughout the whole body via the bloodstream and the running and distribution of arteries differ among the testicular areas, we hypothesized that the efficacy of busulfan differs in different testicular areas, particularly between the central and peripheral areas. In this study, busulfan was intraperitoneally injected at 40 mg/kg body weight into C57BL/6J male mice. After 28 days, in busulfan-treated mice, the diameters of seminiferous tubules were significantly higher in the central than in the peripheral area of the testes. The seminiferous tubular areas also significantly decreased in the peripheral areas compared with the central areas. The number of germ cells per seminiferous tubule was significantly higher in the central than in the peripheral area. Sertoli cell nuclei were detached into the lumen in the peripheral area. The number of Leydig cells was significantly lower in the peripheral areas. These data suggest that the effects of busulfan differ between the central and peripheral areas of the testis at 4 weeks after busulfan administration.

Exosomes derived from umbilical cord mesenchymal stem cells ameliorate male infertility caused by busulfan in vivo and in vitro.

Environmental pollution has emerged as a global concern due to its detrimental effects on human health. One of the critical aspects of this concern is the impact of environmental pollution on sperm quality in males. Male factor infertility accounts for approximately 40%- 50% of all infertility cases. Nonobstructive azoospermia (NOA) is the most severe type of male infertility. Human umbilical cord mesenchymal stem cell (hUCMSC) exosomes enhance proliferation and migration, playing crucial roles in tissue and organ injury repair. However, whether hUCMSC exosomes impacting on NOA caused by chemotherapeutic agents remains unknown. This study aimed to explore the functional restoration and mechanism of hUCMSC exosomes on busulfan-induced injury in GC-1 spg cells and ICR mouse testes. Our results revealed that hUCMSC exosomes effectively promoted the proliferation and migration of busulfan-treated GC-1 spg cells. Additionally, oxidative stress and apoptosis were significantly reduced when hUCMSC exosomes were treated. Furthermore, the injection of hUCMSC exosomes into the testes of ICR mice treated with busulfan upregulated the expression of mouse germ cell-specific genes, such as vasa, miwi, Stra8 and Dazl. Moreover, the expression of cellular junction- and cytoskeleton-related genes, including connexin 43, ICAM-1, ß-catenin and androgen receptor (AR), was increased in the testicular tissues treated with exosomes. Western blot analysis demonstrated significant downregulation of apoptosis-associated proteins, such as bax and caspase-3, and upregulation of bcl-2 in the mouse testicular tissues injected with hUCMSC exosomes. Further, the spermatogenesis in the experimental group of mice injected with exosomes showed partial restoration of spermatogenesis compared to the busulfan-treated group. Collectively, these findings provide evidence for the potential clinical applications of hUCMSC exosomes in cell repair and open up new avenues for the clinical treatment of NOA.

Investigaçäo de neuropatia periférica durante o período recente do transplante de medula óssea / Peripheral neuropathy investigation in the early stage of bone marrow transplantation

Investigamos prospectivamente a incidência de neuropatia periférica em 43 pacientes através do estudo da velocidade de conduçao nervosa e do teste de limiar de sensibilidade vibratória (palestesiômetro) realizados antes e após o transplante de medula óssea. Nesse período as principais drogas utilizadas para o condicionamento e imunossupressao foram o bussulfan, ciclofosfamida, ciclosporina A, methotrexate e corticoesteróides. Foram estudadas as velocidades de conduçao nervosa nos nervos mediano motor, fibular, tibial, mediano sensitivo e sural. Obtivemos alteraçoes estatisticamente significativas na duraçao do potencial composto proximal do nervo mediano motor, na amplitude distal do nervo tibial posterior e na amplitude proximal do nervo sural. As diferenças observadas nao se correlacionaram com alteraçoes clínicas, e nao foram suficientes para o diagnóstico de neuropatia periférica. Acreditamos que o esquema terapêutico utilizado nao provoca toxicidade neurológica periférica no período recente do transplante de medula óssea.