Single Dose Of Cyclophosphamide Research Articles

Coenzyme Q10 ameliorates cyclophosphamide-induced chemobrain by repressing neuronal apoptosis and preserving hippocampal neurogenesis: Mechanistic roles of Wnt/ β-catenin signaling pathway

Deterioration in the neurocognitive function of cancer patients referred to as “Chemobrain” is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/β-catenin pathway as evidenced by the elevated expressions of Wnt-3a, β-catenin, and Phoshpo-glycogen synthase kinase-3 β (p-GSK-3β). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/β-catenin pathway.

Ameliorative Effect of Chitosan/Spirulina platensis Ethanolic Extract Nanoformulation against Cyclophosphamide-Induced Ovarian Toxicity: Role of PPAR-γ/Nrf-2/HO-1 and NF-kB/TNF-α Signaling Pathways.

Cyclophosphamide (CP) is an anticancer drug that causes infertility disorders. This study was designed to evaluate a nanoformulation of chitosan with an ethanolic extract from Spirulina platensis in terms of its protection against cyclophosphamide-induced ovarian toxicity. Nine groups of female Wistar rats were randomly assigned as follows: 1: control vehicle, 2: chitosan polymer, 3: telmisartan, 4: Spirulina platensis extract, 5: nanoformulation of the Spirulina platensis, and 6: single injection of CP; groups 7, 8, and 9 received the same treatments as those used in groups 3, 4, and 5, respectively, with a single dose of CP (200 mg/kg, I.P). The results displayed that the CP treatment decreased estradiol, progesterone, anti-mullerian hormone, and GSH content, and it downregulated PPAR-γ, Nrf-2, and HO-1 gene expression. In addition, the CP treatment caused an increase in the FSH, LH, and MDA levels. In the same manner, the protein expression of caspase-3, NF-kB, and TNF-α was upregulated in response to the CP treatment, while PPAR-γ was downregulated in comparison with the control. The rats treated with SPNPs exhibited a substantial reduction in the detrimental effects of oxidative stress and inflammation of the ovarian tissue. This study's conclusions showed that SPNPs counteracted the effects of CP, preventing the death of ovarian follicles and restoring the gonadotropin hormone balance and normal ovarian histological appearance.

Efecto del Consumo del Extracto del Fruto “Camu Camu” en la Integridad del ADN Espermático de Ratones Pretratados con Dosis Única de Ciclofosfamida

Introduction: Myrciaria dubia known as “camu camu” is a fruit that grows in the Amazon and its main characteristic is its high content of vitamin C. Ascorbic acid has a protective role in spermatogenesis as it is a compound that has excellent reducing action. The purpose of this research was to evaluate in vivo the cytoprotective capacity of the aqueous extract of the fruit of Myrciaria dubia (Kunth) McVaugh “camu-camu” against the mutagenic damage produced by the antineoplastic drug cyclophosphamide (CP) on the male germ line. Methodology: Mice (n= 60) were divided into five treatment groups: T1= negative control (without treatment); T2 ingested the aqueous extract (10mgkg-1), T3 ingested the aqueous extract (50mgkg-1), T4 ingested the aqueous extract (100mgkg-1); T5 is the positive control. All of them were injected with a single dose of CP (50 mgkg-1) intraperitoneally. Treatment with camu-camu continued for 45 days, then the mice were euthanized to determine sperm quality and the frequency of DNA damage using the Index protocol. Sperm DNA fragmentation – Halomax protocol. Results: The effect of camu-camu extract was observed in all trials (p< 0.05) compared to the negative control. Group T4, which was administered the highest concentration of the aqueous extract of the fruit, evidenced the cytoprotective effect of camu-camu (p< 0.05). Conclusion: The damaging effect on DNA due to the oxidative action of CP could be inhibited by the aqueous extract of the “camu camu” fruit.

Protective Role of Doxofylline against Cyclophosphamide-induced Testicular Toxicity in Rats

Background: Cyclophosphamide (CP) is a widely used anticancer and immunosuppressant drug. However, CP's significant toxicities and adverse effects restrict its clinical use. Doxofylline (DF) is a phosphodiesterase inhibitor that has antioxidant and anti-inflammatory properties. Objective: To determine the protective effect of doxofylline on rats exposed to a single dose of CP. Methods: We randomly assigned thirty Sprague-Dawley male rats to three groups. On the sixth day, the apparently healthy control group (AH) received normal saline; the induction group (IN) received normal saline and a single dose of CP (100 mg/kg); and the DF group received DF (50 mg/kg) and a single dose of CP (100 mg/kg). Treatment in all groups was given once daily and intraperitoneally. At the end of treatment, caudal fluid is used to determine sperm parameters. A blood sample was taken to determine the testosterone levels. We determined the levels of testicular glutathione peroxidase and malondialdehyde. The testes were harvested, allowing for histological examination. Results: Sperm parameters, testosterone and oxidative stress markers were notably declining in testicular tissue among the IN compared with AH, although these measures can be markedly improved with DF. Histopathological analysis revealed a substantial change in the testicular tissue structure in the CP group, although doxofylline co-treatment significantly attenuated and even reversed these changes. Conclusions: Doxofylline may function as a protective agent, mitigating the testicular damage caused by CP therapy in rats. The proposed process may be attributed to its phosphodiesterase inhibitory and antioxidant properties.

Ranferon-12 tonic mitigates haematological abnormalities in cyclophosphamide-treated rats

Cyclophosphamide (CPA) has anticancer property with many side-effects including haematotoxicity while ranferon-12 tonic (RFT) possesses haematinic effect. This study investigated the mitigating effects of RFT on haematotoxicity in CPA-treated rats. Twenty-four animals were grouped into four (n=6) and treated orally as indicated: Group A: (Control) received 0.4 mL of physiological saline (PS) for 7 consecutive days; Group B: (CPA) received 0.4 mL of PS for 7 days followed by a single intraperitoneal dose of CPA (200 mg/kg) on the 7th day; Group C: (RFT) received RFT at 0.029 mL/kg for 7 days; Group D: (RFT+CPA) received RFT at 0.029 mL/kg for 7 days followed by a single intraperitoneal dose of CPA on the 7th day. Twenty-four hours after the final treatment, the animals were weighed, anaesthetised and sacrificed. Blood was obtained via cardiac puncture and transferred to EDTA and plain tubes for further analysis. Result showed that a single dose of CPA (200 mg/kg) significantly (p < 0.05) reduced the level of white blood cells, haemoglobin, red blood cells, packed cell volume, and platelet (values >36%). Additionally, the body temperature was significantly (p<0.05) elevated by 5.1 %. Furthermore, decreased levels of superoxide dismutase and catalase with a concomitant rise in MDA content were observed. All these alterations were mitigated; to some extent, in animals pre-treated with RFT prior to CPA-administration. The study suggests that RFT could mitigate haematotoxicity in CPA-administered rats by suppressing oxidative stress via modulation of haematopoietic factors, which in turn promotes haematopoiesis.

Impact of scutellarin on cyclophosphamide-induced testicular damage in Sprague Dawley male rats

Cyclophosphamide is one of the most invasive chemotherapeutic drugs, which is commonly used despite its adverse effects and toxicities. Scutellarin is an herbal flavonoid with multiple pharmacological activities and clinical applications. The goal of the current study was to investigate whether scutellarin protected the gonads of male rats exposed to a single dose of cyclophosphamide. In the experiment, 21 male Sprague-Dawley male rats were divided into three groups (n=7/group). Control group; received normal saline for 12 days by mouth; Induction group; received normal saline for 12 days by mouth and a single dose of cyclophosphamide (100 mg/kg) intraperitoneally on day 6; and Scutellarin group; received intragastric scutellarin (100mg/kg) for 12 days and a single dose of cyclophosphamide (100mg/kg) intraperitoneally on day 6. At the end of treatment, the samples were collected, the gonadosomatic index (GSI) was calculated, sperm parameters, serum testosterone, testicular malondialdehyde (MDA), and glutathione peroxidase (GPx) levels were measured, and histopathological alternation was evaluated. The results showed that GSI, sperm parameters, testosterone, and GPx levels were notably declined, while the level of MDA was significantly higher in the induction group compared to the control group. Interestingly, these measures markedly improved in scutellarin treated group. Additionally, histopathological analysis revealed a substantial change in the testicular tissue structure and a decrease in Jonson’s score in the induction group, although scutellarin co-treatment considerably attenuated and even reversed these changes. In conclusion, the outcomes demonstrated that scutellarin may act as a protective agent that alleviates rats’ testicular toxicity caused by cyclophosphamide therapy. Further, the proposed process may be attributed to its potent antioxidant properties.

Melatonin prevents overproduction of reactive oxygen species and vascular dysfunction induced by cyclophosphamide

AimsOverproduction of reactive oxygen species (ROS) is a pathologic hallmark of cyclophosphamide toxicity. For this reason, antioxidant compounds emerge as promising tools for preventing tissue damage induced by cyclophosphamide. We hypothesized that melatonin would display cytoprotective action in the vasculature by preventing cyclophosphamide-induced oxidative stress. Materials and methodsMale C57BL/6 mice (22–25 g) were injected with a single dose of cyclophosphamide (300 mg/kg; i.p.). Mice were pretreated or not with melatonin (10 mg/kg/day, i.p.), given during 4 days before cyclophosphamide injection. Functional (vascular reactivity) and oxidative/inflammatory patterns were evaluated at 24 h in resistance arteries. The antioxidant action of melatonin was assessed in vitro in cultured vascular smooth muscle cells (VSMCs) of mesenteric arteries. Key findingsCyclophosphamide induced ROS generation in both mesenteric arterial bed (MAB) and cultured VSMCs, and this was normalized by melatonin. Cyclophosphamide-induced ROS generation and lipoperoxidation in the bladder and kidney was also prevented by melatonin. Increased levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were detected in the MAB of cyclophosphamide-treated mice, all of which were prevented by melatonin. Functional assays using second-order mesenteric arteries of cyclophosphamide-treated mice revealed a decrease in vascular contractility. Melatonin prevented vascular hypocontractility in the cyclophosphamide group. Melatonin partially prevented the decrease in myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities in the MAB of the cyclophosphamide group. SignificanceMelatonin may constitute a novel and promising therapeutic approach for management of the toxic effects induced by cyclophosphamide in the vasculature.

#3436 EFFICACY OF ADJUNCT HEMOPERFUSION VERSUS STANDARD MEDICAL THERAPY ON 28-DAY MORTALITY IN LEPTOSPIROSIS PATIENTS WITH RENAL FAILURE AND SHOCK

Abstract Background and Aims Leptospirosis, a ubiquitous zoonotic infection in the Philippines, is a classic representation of sepsis-induced multi-organ dysfunction with its life-threatening complications: pulmonary hemorrhage, renal and liver failure. Despite pre-established treatment guidelines, leptospirosis- induced morbidity and mortality continue to rise. Hemoperfusion with HA 330 is a promising adjunct therapy as it removes rogue cytokines responsible for the dysregulated inflammatory response in severe sepsis. However, studies on its survival benefit have yielded conflicting results, so far. This study was designed to assess the efficacy and safety of hemoperfusion among leptospirosis patients in septic shock and renal failure, in terms of improvement in 28-day mortality, SOFA score, level of inflammatory markers, hemodynamics, renal and pulmonary function. Method This is an open-label randomized controlled trial which enrolled a total of 37 adult presumptive leptospirosis patients with early signs of septic shock and acute renal failure. The study participants were randomized into either of the two treatment arms: 1. standard medical therapy (SMT) alone or 2. SMT + HA330 Hemoperfusion (HP). All patients were managed based on the NKTI Leptospirosis treatment protocol (hydration, antibiotics, three-day steroid pulsing, single cyclophosphamide dose and respective organ support) and were placed on daily intermittent hemodialysis. Subjects randomized to the HP group received three hemoperfusion sessions (on top of SMT). Vital signs, urine output, vasopressor dose, P/F ratio and biochemical parameters (including level of inflammatory markers) of patients from each treatment arm were measured at baseline, day 3 and day 7 and compared subsequently. Monitoring of participants continued until 28 days post-randomization. Descriptive statistics was used to summarize the general and clinical characteristics of the participants. Independent Sample T-test, Mann-Whitney U test, and Fisher's Exact/Chi-square test was used to determine the difference of mean, median and frequency between hemoperfusion group and control group, respectively. Mean, median, or risk difference and their corresponding 95% confidence intervals were calculated. Friedman test or Wilcoxon's signed-rank test were used to determine whether differences between groups were significant over time. Intention to treat and per protocol analyses were performed. Null hypothesis was rejected at 0.05α-level of significance. Stata 15.0 (StataCorp LLC, TX) was used for data analysis. Results Hemoperfusion conferred a 36.84% (p = 0.017) risk reduction in 28-day mortality. Serial monitoring of inflammatory markers and SOFA score of patients showed significant improvement in sepsis score (p = 0.018 HP, 0.002 SMT) and levels of procalcitonin (p = 0.013 HP, 0.003 SMT), IL6 (p = 0.033 HP, 0.020 SMT) and lactate (p< 0.001 HP, 0.021 SMT) in both treatment arms, from baseline to Day 7. There is, however, no statistically significant difference in the change in SOFA (p = 0.965) and inflammatory marker levels if we compare HP versus SMT (p = 0.997, 0.451, 0.858, 0.052 for hsCRP, procalcitonin, IL6 and lactate, respectively). Statistically significant improvement in serum creatinine (p = 0.04) and PF ratio (p = 0.045) were observed in the hemoperfusion cohort as early as Day 3. Vasopressor dose did not differ significantly between two groups (p = 0.792). No adverse events were observed in both treatment arms. Conclusion Hemoperfusion is a safe and effective adjunct therapy in managing severe sepsis. It promotes earlier renal and pulmonary function recovery and, in doing so, improves survival of septic shock patients.

Uro-protective role of chrysin against cyclophosphamide-induced hemorrhagic cystitis in rats involving the turning-off NF-κB/P38-MAPK, NO/PARP-1 and STAT-3 signaling cascades

BackgroundChemotherapeutic agents are used to treat a wide range of cancer types, but they cause serious side effects which must be managed after treatment. Cyclophosphamide (CYP) is one of chemotherapeutic drugs that causes hemorrhagic cystitis (HC) induced by acrolein. ObjectiveThe current investigation intended to uncover the role of chrysin (CHR) in CYP-induced HC in rats and explore the signaling pathway beyond this effect. Analysisprocess: A single dose of CYP (200 mg/kg/IP) was injected, meanwhile CHR (25, 50 and 100 mg/kg, P.O) was administered respectively for 7 days prior to CYP administration and resume for 7 days afterwards. Urinary bladder tissue was then isolated from all rats to assess oxidative stress and inflammatory biomarkers. Moreover, histopathological examinations were performed. ResultsTreatment with CHR showed a marked alleviation in oxidative stress biomarkers induced by CYP. Furthermore, CHR treatment presented a dose-dependent boost in the anti-inflammatory; IL-10 levels and a drop in the pro-inflammatory biomarkers; IL-1β, IL-6, and TNF–α. Additionally, stabilization of the PARP-1 protein expression was also detected thus preventing DNA damage. Similarly, CHR restored the urinary bladder cGMP levels. Notably, CHR treatment was accompanied with inhibition in NF-κB/p38-MAPK, NO/PARP-1 and STAT-3 signaling pathways inflammatory cascades. All these findings conformed with the histopathological examinations as well as iNOS immunostaining in the urinary bladder tissue. ConclusionCo-administration of CHR and CYP attained uro-protective therapeutic potential to guard against HC as well as spot the tangled mechanism of CHR in attenuating the HC induced by CYP.

PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE

You have accessJournal of UrologyCME1 Apr 2023PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE Garth Whiteside, Stamford, CT, Celine Auge, and Philippe Lluel Garth WhitesideGarth Whiteside More articles by this author , Stamford Stamford More articles by this author , CT CT More articles by this author , Celine AugeCeline Auge More articles by this author , and Philippe LluelPhilippe Lluel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003229.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial Cystitis (IC) is a chronic urological disorder characterized by pain urinary urgency, frequency and nocturia. Not all patients are responsive to existing treatments which are also limited by side-effects. As such new treatments with novel mechanisms of action are needed. Sunobinop (V117957) is a selective partial agonist of the nociceptin/orphanin-FQ (N/OFQ) peptide receptor which is excreted unchanged by the kidneys. The objective of these studies was to examine the effect of sunobinop on visceral pain in a model of interstitial cystitis in female rats. METHODS: Female Sprague-Dawley rats (10/group) were administered sunobinop (30 mg/kg, p.o.), ibuprofen (300 mg/kg, p.o.) or vehicle and 5 minutes later a single dose of cyclophosphamide (CYP; 150 mg/kg i.p). Tactile sensitivity (von Frey fibers) was measured at baseline, 2, 3, 4 and 24 hr after CYP. Parameters analyzed were nociceptive threshold (g), nociceptive scores (%) and area under the nociception curve (AUC) across two fiber ranges (1-6 g and 6-26 g) all of which were expressed as mean±standard error of the mean (SEM) with significance set at p≤0.05. RESULTS: At all evaluated time points CYP induced a significant decrease of nociception measures as compared to saline (p<0.0001) indicating successful model development. Ibuprofen-treated rats displayed a significant overall increase in nociceptive thresholds and significantly decreased nociceptive scores and AUC measures as compared to vehicle (p<0.0001). Post hoc statistical analysis showed a slight and gradual decrease of ibuprofen effect was observed over time. Sunobinop produced an overall inhibitory effect on nociceptive thresholds (significant at 3 hr), a significant decrease in nociceptive scores and a significant decrease in AUCs starting from 2h and up to 24h after CYP injection (p<0.01). After 3h, efficacy of sunobinop decreased slightly and gradually over time. CONCLUSIONS: The positive control, ibuprofen, significantly decreased pain responses, as compared to vehicle in an acute model of CYP induced IC. Likewise, sunobinop was significantly anti-nociceptive. As such this data suggests sunobinop has potential utility in treatment of pain associated with IC. Source of Funding: Imbrium Therapeutics L.P. a subsidiary of Purdue Pharmaceuticals L.P. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e152 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Garth Whiteside More articles by this author Stamford More articles by this author CT More articles by this author Celine Auge More articles by this author Philippe Lluel More articles by this author Expand All Advertisement PDF downloadLoading ...

Severe Hyponatremia Manifesting as Status Epilepticus Caused by a Single Dose of Cyclophosphamide.

1 Department of Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH; and 2 Department of Hematology and Oncology, Cleveland Clinic Fairview Hospital, Cleveland, OH. The authors have no conflicts of interest to declare.

Combination of Curcumin and Quercetin: Reclaiming the Lost Ground Against Nephrotoxicity

Background: An alkylating agent named cyclophosphamide (CP) is an immunosuppressant used in the therapy of rheumatoid arthritis and various cancers. The combination of curcumin and quercetin was evaluated for antioxidant activity against CP-induced renal oxidative stress in Wistar rats. Methods: A prophylactic treatment using a combination of curcumin and quercetin is given to the rats at 80 mg/kg and 200 mg/kg (b.w.) of the oral dose administered before single injection of CP at 200 mg/kg intra-peritoneally (i.p.). The effects of curcumin and quercetin combination on CP-induced nephrotoxicity were investigated using the assay of oxidative stress biomarkers, serum kidney toxicity markers, and histopathology of kidney tissue. Result: A single dose of CP were enhanced the malondialdehyde (MDA), creatinine, blood urea nitrogen (BUN) level and reduced the body weight indices (OBWI), haematological parameter, glutathione (GSH) content. The oral administration of curcumin and quercetin were caused a substantial reduction of the MDA, creatinine, BUN level and increased the OBWI, haematological parameter, GSH content. Conclusion: The present findings suggest that curcumin and quercetin combination has a prominent role against CP-induced renal injury.

Integrative proteomics and metabolomics approach to identify the key roles of icariin-mediated protective effects against cyclophosphamide-induced spermatogenesis dysfunction in mice.

The alkylating antineoplastic agent cyclophosphamide (CP) is known to be toxic to the male reproductive system, but there are no effective prevention or treatment options. The flavonoid icariin (ICA), which is used in Chinese medicine, has been shown to have a number of biological functions, including testicular protection. The current study looked into the protective effects of ICA in preventing CP-induced spermatogenesis dysfunction. The current study looked into the role of ICA in preventing testicular dysfunction caused by CP. For 5days, healthy adult mice were given saline or a single dose of CP (50mg/kg) intraperitoneally (i.p). For the next 30days, mice were given ICA (80mg/kg) by gavage. Animals were euthanized 12h after receiving ICA, and testes were removed for biochemical, histopathological, sperm evaluation, and transmission electron microscope analysis (TEM). We also investigated the potential biological effects of ICA on CP-induced spermatogenesis dysfunction in mice using an integrated proteomic and metabolomic approach. The levels of 8309 proteins and 600 metabolites were measured. The majority of the differential proteins and metabolites were found to be enriched in a variety of metabolic pathways, including the PI3K-Akt signaling pathway, necroptosis, the mTOR signaling pathway, glycerophospholipid metabolism, and ABC transporters, implying that ICA may have molecular mechanisms that contribute to CP-induced spermatogenesis dysfunction in the testis. Taken together, these findings show that ICA effectively reduces testis injury, implying that ICA may have a role in male infertility preservation.

Overcoming Barriers to T Cell Therapy Against AML with Dual Costimulatory Receptors

Acute myeloid leukemia (AML) is a rapidly progressing and highly fatal disease, with only 27% of patients surviving 5 years after diagnosis. Adoptive cell therapy (ACT) provides the opportunity to genetically modify T cells to generate a "living drug" that can recognize and destroy tumor, and subsequently generate a memory population to protect against future recurrence. ACT is particularly attractive as a potential AML therapy, as T cells naturally home to the sites of disease, and ACT has proven effective and is now an FDA-approved therapy for other hematological malignancies. However, several obstacles in the AML bone marrow (AML-BM) can impede T cell therapeutic efficacy, including T cell exhaustion, limited metabolic substrates, and lack of costimulation. Additionally, engineering strategies to improve ACT have mainly been T cell-intrinsic, with little or no support of endogenous anticancer immunity. Costimulatory signals transmitted through cell surface receptors can initiate gene expression programs that address multiple issues in the AML-BM by mechanisms such as lowering the threshold of activation, metabolic reprogramming, and reducing exhaustion. In particular, tumor necrosis family receptor (TNFR) members have been targeted in the clinic with drug-based approaches, with the aim of activating antigen presenting cells (APCs), such as dendritic cells (DCs), macrophages, and B cells, both to boost their own antitumor functions and enhance costimulatory signals leading to enhanced antitumor activity of T and NK cells. Dual costimulatory receptors as a new cell engineering platform. We innovate synthetic transmembrane fusion proteins (FPs) that combine a receptor ectodomain with a costimulatory signaling endodomain. We have shown that engineered fusion proteins, such as immunomodulatory fusion proteins (IFPs) that utilize an inhibitory decoy ectodomain, can empower T cells to overcome several hurdles faced in the tumor microenvironment and significantly improve therapeutic efficacy in cancer models. Here we report our next generation of FP, called Dual Costimulatory Receptors (DCRs), that pair a costimulatory ligand ectodomain with a costimulatory endodomain. This approach addresses two critical objectives: to enable engineered T cells to attack cancer more powerfully and durably AND to support the activation of endogenous immune cells in the AML-BM. To build on insights from agonist antibody research, we developed DCRs with TNFR ectodomains and created a flexible platform with a variety of pre-selected costimulatory endodomains. We hypothesized that this approach would result in greater efficacy over traditional T cell engineering strategies that aim only to enhance cell-intrinsic function and tested this using murine and human models of AML. Primary human DCR-engineered T cells exhibited high surface expression of the DCR ectodomain, and increased DCR-T cell activation and ability to lyse tumor in in vitro studies. DCR-T cells co-cultured with immature DCs induced maturation similar to positive control conditions (LPS-maturation), demonstrating cell-extrinsic DCR activity. To determine if promising DCR candidates could enhance in vivo ACT efficacy, AML-bearing B6 mice were treated with1e6 engineered T cells after a single dose of cyclophosphamide (Cy) conditioning therapy, modeling human ACT protocols. Whereas the native full-length costimulatory ligand only modestly improved survival (P=ns), several DCR candidates showed significantly improved therapeutic efficacy (P<0.01-0.05). Here we describe a first-of-kind engineering strategy for the treatment of AML to expand our basic understanding of how different cell-intrinsic and -extrinsic costimulatory signals might achieve enhanced antitumor function and provide a dataset to support clinical translation for AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Protective Effects of Sesamin against Cyclophosphamide-Induced Nephrotoxicity through Modulation of Oxidative Stress, Inflammatory-Cytokines and Apoptosis in Rats.

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1β and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.

Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed-Effects Analysis.

Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed-effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first-order elimination, representing renal clearance (ClR ) of PM. For a 70-kg patient, ClR was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration-time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity.

Neuroprotective potential of ferulic acid against cyclophosphamide-induced neuroinflammation and behavioral changes.

In the present study, ferulic acid (FRA) has been explored for possible neuroprotective effects against cyclophosphamide (CP)-induced neurotoxicity in the Swiss Albino mice. Animals were divided into five groups and treated with FRA for fourteen days and a single dose of CP was administered on the seventh day. Animals were subjected to neurobehavioral tests such as the forced swim test and Morris Water Maze test. On day fifteenth, the brain was removed and used for biochemical analysis. The outcome of the study showed that CP administration induced significant neurotoxicity in the form of depression, anxiety, and cognitive dysfunction. Cyclophosphamide administration also reduced the activity of antioxidant enzymes, reduced the level of neurotransmitters (i.e., dopamine, 5-HT, and BDNF), anti-inflammatory cytokines (IL-10), and increased lipid peroxidation and proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Additionally, CP administration increased the level of acetylcholine esterase. Treatment with FRA significantly reversed these behavioral, and biochemical markers towards normal and mitigated CP-induced neurotoxic manifestation. PRACTICAL APPLICATIONS: Ferulic acid has a variety of pharmacological activities viz. anti-inflammatory, antioxidant, antimicrobial activity, anti-cancer, and anti-diabetic effects. The results of the present study showed that FRA mitigates the neurotoxicity (i.e., alteration of neurotransmitters, inflammation, and oxidative stress) induced by CP in mice. Treatment with FRA knowingly overturned the behavioral and biochemical markers in the direction of the moderated CP-influenced neurotoxic demonstration. Thus, FRA can be useful in the prevention of anticancer drugs induced neurotoxicity. Contrariwise, supplementary in-depth studies are obligatory to bring FRA from bench to bedside that it be used as an adjuvant among chemotherapeutically treated patients.

Epigallocatechin-3-gallate attenuates cyclophosphamide-induced damage in mouse ovarian tissue via suppressing inflammation, apoptosis, and expression of phosphorylated Akt, FOXO3a and rpS6

This study was conducted to evaluate the protective effects of epigallocatechin-3-gallate (EGCG) against ovarian toxicity in cyclophosphamide-treated mice and to verify the possible involvement of phosphorylated Akt, FOXO3a and rpS6 in the EGCG actions. Mice received saline solution (i.p.; control) or a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) or mice were pretreated with N-acetylcysteine (150 mg/kg body weight, i.p.; positive control) or with EGCG (5, 25 or 50 mg/kg body weight, i.p.) once daily for three days followed by injection with single dose of cyclophosphamide (200 mg/kg body weight, i.p.). Thereafter, the mice were euthanized, and the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemistry (cleaved caspase-3 and TNF-α) and fluorescence (mitochondrial activity and GSH concentrations) analyses. Furthermore, we examined the participation of p-Akt, p-FOXO3a and p-rpS6 in the protective effects of EGCG in cyclophosphamide-induced ovarian damage by immunohistochemical staining. The results showed that pretreatment with N-acetylcysteine or EGCG at 25 and 50 mg/kg before cyclophosphamide administration preserved the normal follicular morphology, prevented primordial follicle loss, reduced atresia, inflammation, and mitochondrial damage, and increased GSH concentrations compared to the only cyclophosphamide treatment. Additionally, pretreatment with 25 mg/kg EGCG regulated phosphorylated Akt, FOXO3a and rpS6 after cyclophosphamide treatment. In conclusion, short-time pretreatment with 25 mg/kg EGCG can prevent follicle loss in cyclophosphamide-treated mice by reducing oxidative damage, inflammation, and apoptosis, and regulating of p-Akt, p-FOXO3a and p-rpS6.

Evaluation of the protective effect of coenzyme Q10 on the growth process of embryos from in vitro fertilization in laboratory mice treated with cyclophosphamide

"Cyclophosphamide is an anticancer drug that acts as an alkylating agent after metabolism in the liver. Despite its many clinical applications in cancer treatment, this drug has toxic effects on the body's organs, especially the genitals. One of the most critical side effects is a change in the function of the female reproductive system, which can lead to infertility. This study aimed to investigate the antioxidant effects of coenzyme Q10 on cyclophosphamide-induced toxicity in vitro fertilized embryos in mice. In this experimental study, 24 female mice weighing 25 g 4 groups of 6 were divided and treated for 21 days. The first group (control group), solvent (cyclophosphamide) including DMSO and PBS (0.1 ml intraperitoneally), the second group (sham group), cyclophosphamide at a dose of 10 mg/kg was injected as a single dose, and the third group (experimental group), along with single-dose cyclophosphamide, coenzyme Q10 at a dose of 200 mg/kg/day was injected intraperitoneally and the fourth group (positive control group), only coenzyme Q10 at a dose of 200 mg/kg/day was injected intraperitoneally. At the end of the treatment period, ovulation stimulation was performed using PMSG and HCG hormones. Six adult male mice were used to prepare normal sperm. The animals were facilitated after anesthesia. After extraction of regular eggs and sperm and fertilization in HTF + 4 mg BSA medium, the fertilized eggs were incubated for 120 hours, and the embryonic developmental stages were examined during this period. Were analyzed by ANOVA and comparison of ratios. Cyclophosphamide significantly reduced oocyte quality, fertilization rate, pre-implantation embryonic development, and embryo quality. Coenzyme Q10 (Co Q10) significantly reduced the adverse effects of cyclophosphamide. The present study showed that crocin could protect the fertility of the female sex against damage caused by cyclophosphamide. "

Icariin attenuates cyclophosphamide-induced cystitis via down-regulation of NF-кB and up-regulation of Nrf-2/HO-1 signaling pathways in mice model

Cystitis is a chronic bladder pain associated with frequency and nocturia. In the present study, Icariin a prenylated flavonoid extracted from Epimedium koreanum, was investigated against cyclophosphamide (CYP)-induced cystitis pain in mice model. Preliminarily in an acute model, single dose of CYP (150 mg/kg; i.p) was administered followed by Icariin (5, 25 and 50 mg/kg, i.p.). The visceral sensitivity and nociceptive behaviors were significantly ameliorated by pretreatment with Icariin (25, 50 mg/kg) that were assessed by spontaneous pain scoring, von Frey test and clinical scoring. Further, in chronic model Icariin (25 mg/kg, i.p.) was administered for 10 consecutive days prior to CYP (75 mg/kg; i.p) challenged every 3rd day for the duration of 10 days. Icariin not only had a protective effect on edema including bladder wet weight and hemorrhage but also had a potential to reduce vascular permeability, mast cells infiltration and tissue fibrosis. Evidently, Icariin prevented the neutrophilia/lymphopenia caused by CYP, and markedly improved the antioxidant enzymes level including superoxide dismutase, glutathione sulfo-transferase, catalase, glutathione level and reduced Malondialdehyde level, myeloperoxidase activity and nitric oxide, and also decreased the production of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) in bladder. Icariin markedly enhanced the Nrf-2, heme oxygenase (HO-1) and IкB-α expression, while attenuated the expression level of Keap1, TLR-4, NF-кB, i-NOS, COX-2 and TRPV1 as compared to negative group. This research illustrated the anti-inflammatory properties of Icariin and effectively improved CYP-induced cystitis pain.