Potential Usefulness of Leukotriene B4 (LTB4) on Mobilization of Hematopoietic Progenitor Cells (HPC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5271-5271
Author(s):  
Yeung-Chul Mun ◽  
Seung-Eun Lee ◽  
Kyung-Eun Lee ◽  
Eun-Sun Yoo ◽  
Eun Suk Kang ◽  
...  
Keyword(s):  
Side Effects ◽  
Synergistic Effects ◽  
Leukotriene B4 ◽  
Lipid Mediator ◽  
Control Group ◽  
Optimal Timing ◽  
Dependent Manner ◽  
Dose Dependent

Abstract The mechanisms on HPC mobilization seem to be multifactorial processes. Many cell adhesion molecules (VLA-4, ICAM-1, VCAM-1 etc), SDF-1/CXCR4, and proteases (ie, MMP-9) may be important players for this mobilization processes. However, finding more mechanisms on HPC mobilization is under intense scrutiny. So far, G-CSF is the best known cytokine for this purpose. Meanwhile, its limitation on using G-CSF is to take 4–6 days for the optimal mobilization at clinic and its side effects (ie; bone pain, high WBC counts) are not negligible. LTB4 is lipid mediator during the process of inflammation, having many roles (ie; inducer of chemotaxis, the production of nitric oxide, transepithelial migration of neutrophil). In present study, we focused on the roles of LTB4 on HPC mobilization and its feasibility on mobilization in vivo. Samples were collected from the peripheral blood via heart puncture and the bone marrow on time dependent manner (1hr, 4hr, 6hr, 12hr, 24hr, 48hr) after LTB4 injection which was given via intravenously and the dose dependent manner of LTB4 (0.5μg, 1μg, 2μg, 3μg). These data were compared with two other groups after G-CSF injection and normal saline injection. Collected total nucleated cells were analyzed for Sca-1+/Lin- using flow cytometry and CFU studies. There were definite increase of Sca-1+/Lin- cells after 1μg of LTB4 injection group (TNC: 29.55(±0.92)×105/ml and HPC: 3.72(±0.09) %). Its control group showed as follows: TNC: 14.55(±0.21)×105/ml, HPC: 0.41(±0.04) %, (p<0.05). Mobilization was optimal only after 4hours of LTB4 injection (TNC: 36.25(±2.90)×105/ml & HPC: 3.50(±0.37) %). After 4hours of LTB4 injection, there was a obvious down pattern. In terms of quantity, more than 20 fold of HPC mobilization after one LTB4 injection was observed. There were no immediate toxicity in the cohort, though long term potential side effects are under investigations. In conclusion, we showed the rapid mobilization of HPC with LTB4 at only 4 hours post-injection. This finding with LTB4 could be significant in terms of shortening the optimal period of mobilization comparing to that by G-CSF, which takes at least 4–6 days by repetitive injection to reach the optimal timing for collection. The possible synergistic effects of G-CSF with LTB4 for larger quantity of HPC and the cellular and molecular mechanism(s) of mobilization by LTB4 are being investigated in our lab.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Vitamin D as a Regulator of Adipocyte Differentiation Effects in vivo and in vitro

2018 ◽  
Vol 69 (3) ◽  
pp. 731-734
Author(s):  
Alin Constantin Pinzariu ◽  
Teodor Oboroceanu ◽  
Florin Zugun Eloae ◽  
Ioana Hristov ◽  
Victor Vlad Costan ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipocyte Differentiation ◽  
Dependent Manner ◽  
Omental Adipose Tissue ◽  
In Vivo Experiments ◽  
Dose Dependent ◽  
Stromal Stem Cells

The age-associated adiposity and the effect of long-term vitamin D was studied in vitamin D deficient rats. In in vivo experiments, the influence of a 9 months of vitamin D treatment (weekly oral gavage with 0.125 mg vitamin D3 (5000 IU)/100g body weight) on the adipocyte precursors from the omental adipose tissue was examinated. In in vitro experiment, rat adipose-derived mesenchymal stromal/stem cells (ASCs) were induced to differentiate into adipocytes in the presence or absence of 25(OH)D3 (0.25, 25, and 2500 nmol/L). ASCs derived from vitamin D-treated animals showed an increase adipogenic potential as compared to vitamin D-deficient rats. The addition of 25(OH)D3 inhibits the adipocyte differentiation and lipid deposition in a dose dependent manner.

scholarly journals Oxidative stress is reduced in Wistar rats exposed to smoke from tobacco and treated with specific broad-band pulse electromagnetic fields

2009 ◽  
Vol 61 (3) ◽  
pp. 353-366 ◽  
Author(s):  
V. Bajic ◽  
B. Bajic ◽  
Zorana Milicevic ◽  
Slavica Ristic ◽  
A. Nokolau
Keyword(s):  
Oxidative Stress ◽  
Wistar Rats ◽  
Broad Band ◽  
Control Group ◽  
Dependent Manner ◽  
Sod Activity ◽  
Rat Lungs ◽  
Pulse Electromagnetic Fields ◽  
Dose Dependent

There have been a number of attempts to reduce the oxidative radical burden of tobacco. A recently patented technology, pulse electromagnetic technology, has been shown to induce differential action of treated tobacco products versus untreated products on the production of reactive oxygen species (ROS) in vivo. In a 90-day respiratory toxicity study, Wistar rats were exposed to cigarette smoke from processed and unprocessed tobacco and biomarkers of oxidative stress were compared with pathohistological analysis of rat lungs. Superoxide dismutase (SOD) activity was decreased in a dose-dependent manner to 81% in rats exposed to smoke from normal cigarettes compared to rats exposed to treated smoke or the control group. These results correspond to pathohistological analysis of rat lungs, in which those rats exposed to untreated smoke developed initial signs of emphysema, while rats exposed to treated smoke showed no pathology, as in the control group. The promise of inducing an improved health status in humans exposed to smoke from treated cigarettes merits further investigation.

scholarly journals 745 Oncolytic adenovirus expressing 4-1BBL demonstrates a significant increase of survival in Diffuse Midline Glioma models

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A776-A776
Author(s):  
Virginia Laspidea ◽  
Sara Labiano ◽  
Iker Ausejo-Mauleon ◽  
Daniel de la Nava ◽  
Marc García-Moure ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Dependent Manner ◽  
Pontine Glioma ◽  
Long Term Survivors ◽  
Dose Dependent ◽  
Oncolytic Effect

BackgroundDiffuse Midline Gliomas (DMG) are aggressive pediatric brain tumors that arise in the brainstem of children between 5–10 years old. DMGs are the leading cause of pediatric death caused by a brain tumor, with a median survival of only 9 months.1 2 We have previously shown that the administration of the oncolytic adenovirus Delta-24-RGD is safe and lead to an increase in long-term survivors in murine models.3 4 In order to further increase the antitumor effect of Delta-24-RGD by boosting the immune response, we have constructed a new adenovirus, Delta-24-ACT, which incorporates the 4-1BBL (CD137L) into its backbone. 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells and NK cells and the generation and maintenance of memory CD8+ T cells, among other functions.5 6MethodsMurine and human DMG cell lines were used. 4-1BBL expression was assessed in infected cells by flow cytometry and immunofluorescence. Viral protein expression was measured by western blot, viral replication was analyzed using a method based on hexon detection and the oncolytic effect by MTS assay. For in vivo experiments, cells were injected in the pons of mice using a screw-guided system.7 A single administration of the adenovirus was injected intratumorally using the same procedure. The tumor immune populations were analyzed by flow cytometry.ResultsWe first confirmed by flow cytometry that DMG cells infected with Delta-24-ACT expressed 4-1BBL in their membrane in a dose-dependent manner. Afterwards, we analyzed the oncolytic effect of Delta-24-ACT in vitro. Delta-24-ACT was able to express viral early and late proteins in murine and human DMG cell lines and to replicate efficiently in human cells. In addition, the virus caused cell death in a dose-dependent manner. In vivo, Delta-24-ACT administration demonstrated to be safe and to produce a significant survival benefit in murine DMG models, obtaining 30–50% of long-term survivors depending on the model. More importantly, Delta-24-ACT generated immune memory, as long-term survivors were disease-free after cell rechallenge. On the other hand, we analyzed immune infiltration 7 or 10 days after the viral administration into the tumor and observed a significant increase of tumor infiltration in treated mice, which showed an activated state.ConclusionsDelta-24-ACT administration into DMG murine tumor models significantly increases the recruitment and activation of immune cells, which leads to long term survivors and immunological memory.ReferencesCooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary S, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih C, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International diffuse Intrinsic pontine glioma registry study. Neuro Oncol 2017;19(9):1279–1280.Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo PJ, Ponnuswami A, Chen S, Johung TB, Sun W, Kogiso M, Du Y, Qi L, Huang Y, Hütt-Cabezas M, Warren KE, Le Dret L, Meltzer PS, Mao H, Quezado M, van Vuurden DG, Abraham J, Fouladi M, Svalina MN, Wang N, Hawkins C, Nazarian J, Alonso MM, Raabe EH, Hulleman E, Spellman PT, Li XN, Keller C, Pal R, Grill J, Monje M. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 2015;21(6):555–9.Martínez-Vélez N, Garcia-Moure M, Marigil M, González-Huarriz M, Puigdelloses M, Gallego Pérez-Larraya J, Zalacaín M, Marrodán L, Varela-Guruceaga M, Laspidea V, Aristu JJ, Ramos LI, Tejada-Solís S, Díez-Valle R, Jones C, Mackay A, Martínez-Climent JA, García-Barchino MJ, Raabe E, Monje M, Becher OJ, Junier MP, El-Habr EA, Chneiweiss H, Aldave G, Jiang H, Fueyo J, Patiño-García A, Gomez-Manzano C, Alonso MM. The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nat Commun 2019;10(1):2235.Garcia-Moure M, Gonzalez-Huarriz M, Labiano S, Guruceaga E, Bandres E, Zalacain M, Marrodan L, de Andrea C, Villalba M, Martinez-Velez N, Laspidea V, Puigdelloses M, Gallego Perez-Larraya J, Iñigo-Marco I, Stripecke R, Chan JA, Raabe EH, Kool M, Gomez-Manzano C, Fueyo J, Patiño-García A, Alonso MM. Delta-24-RGD, an oncolytic adenovirus, increases survival and promotes proinflamatory immune landscape remodeling in models of AT/RT and CNS-PNET. Clin Cancer Res 2021;27(6):1807–1820.Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018;131(1):49–57.Yonezawa A, Dutt S, Chester C, Kim J, Kohrt HE. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res 2015;21(14):3113–20.Marigil M, Martinez-Velez N, Domínguez PD, Idoate MA, Xipell E, Patiño-García A, Gonzalez-Huarriz M, García-Moure M, Junier MP, Chneiweiss H, El-Habr E, Diez-Valle R, Tejada-Solís S, Alonso MM. Development of a DIPG orthotopic model in mice using an implantable guide-screw system. PLoS One 2017;12(1):e0170501.

scholarly journals Purified Astaxanthin from Haematococcus pluvialis Promotes Tissue Regeneration by Reducing Oxidative Stress and the Secretion of Collagen In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Hsin-Yu Chou ◽  
Dik-Lung Ma ◽  
Chung-Hang Leung ◽  
Chien-Chih Chiu ◽  
Tzyh-Chyuan Hour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Haematococcus Pluvialis ◽  
Tissue Injury ◽  
Fluorescein Isothiocyanate ◽  
Normal Fibroblast ◽  
Control Group ◽  
Dependent Manner ◽  
Dose Dependent

Intracellular reactive apoptosis and reactive oxygen species (ROS) play a crucial role in ultraviolet- (UV-) induced inflammation and aging reaction in human dermal tissues. This study determines the mechanism by which Haematococcus pluvialis extracts (HPE) and purified astaxanthin (HPA) to promote skin regeneration in the injured tissue in vitro and in vivo. The results show that HPE and HPA decrease the DNA damage and promote the secretion of collagen from the human normal fibroblast cell line (Hs68) in a dose-dependent manner. UV irradiation and HPA reduce oxidative stress damage due to phorbol-12-myristate-13-acetate (PMA). When skin cells are injured by free radicals, cells undergo a programmed cellular death. Cellular apoptotic death is determined using annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining to verify that there is no cell membrane asymmetry and that the nuclear membrane is broken. Inflammatory symptoms and apoptotic injuries to experimental rats in a group that is treated with HPA treated are decreased in a dose-dependent manner after UVB exposure (300 mJ/cm2) for 15 min in vivo, compared to the vehicle control group. These positive results show that HPA repairs UVB-triggered skin tissue injury and aging by conducting electrons out of cells to maintain a low level of oxidative stress so that collagen is synthesized in vitro and in vivo.

scholarly journals Deciphering the Formulation Secret Underlying Chinese Huo-Clearing Herbal Drink

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianan Wang ◽  
Bo Zhou ◽  
Xiangdong Hu ◽  
Shuang Dong ◽  
Ming Hong ◽  
...  
Keyword(s):  
Lower Percentage ◽  
Dependent Manner ◽  
Prunella Vulgaris ◽  
Cellular Inflammation ◽  
Optimal Health ◽  
Dose Dependent ◽  
Body Heat

Herbal teas or herbal drinks are traditional beverages that are prevalent in many cultures around the world. In Traditional Chinese Medicine, an herbal drink infused with different types of medicinal plants is believed to reduce the ‘Shang Huo’, or excessive body heat, a status of sub-optimal health. Although it is widely accepted and has a very large market, the underlying science for herbal drinks remains elusive. By studying a group of herbs for drinks, including ‘Gan’ (Glycyrrhiza uralensis Fisch. Ex DC.), ‘Ju’ (Dendranthema morifolium (Ramat.) Tzvelev), ‘Bu’ (Microcos paniculata L.), ‘Jin’ (Lonicera japonica Thunb.), ‘Xia’ (Prunella vulgaris L.), and ‘Ji’ (Plumeria rubra L.), the long-term jargon is connected with the inflammation of modern immunology through a few pro-inflammatory markers. In vitro studies have indicated that cellular inflammation is lowered by Ju and Jin either individually or synergistically with Gan. Among all herbs, only Gan detoxicated cellular toxicity of Bu in a dose dependent manner. The synergistic formulation of Ju and Gan, or Jin and Gan, in a reduction of Shang Huo, was tested in vivo. Both combinations exhibited a lower percentage of neutrophils, monocytes, and CD4+/CD8+ ratio in the blood, as well as inflammatory cytokines. Furthermore, body weight in the combinatory groups was more stable than treatments using single herbs. The combination of old traditional oriental methods with Western science logistics, has resulted in the formulation of different herbs into one concoction for the use of detoxification and synergism.

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Red Cell ◽  
Cell Velocity ◽  
Red Cell Velocity ◽  
The Mean ◽  
Wall Shear ◽  
Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

Ethanol Extract of Achillea fragrantissima Enhances Angiogenesis through Stimulation of VEGF Production

2020 ◽  
Vol 21 ◽  
Author(s):  
Hana M. Hammad ◽  
Amer Imraish ◽  
Maysa Al-Hussaini ◽  
Malek Zihlif ◽  
Amani A. Harb ◽  
...  
Keyword(s):  
Wound Healing ◽  
Rural Communities ◽  
Ex Vivo ◽  
Ethanol Extract ◽  
Aortic Ring ◽  
Treated Group ◽  
Control Group ◽  
Dependent Manner ◽  
Achillea Fragrantissima

Objective: Achillea fragrantissima L. (Asteraceae) is a traditionally used medicinal herb in the rural communities of Jordan. Methods: The present study evaluated the efficacy of the ethanol extract of this species on angiogenesis in both, ex vivo using rat aortic ring assay and in vivo using rat excision wound model. Results: In concentrations of 50 and 100 µg/ml, the ethanol extract showed angiogenic stimulatory effect and significantly increased length of capillary protrusions around aorta rings of about 60% in comparison to those of untreated aorta rings. In MCF-7 cells, the ethanol extract of A. fragrantissima stimulates the production of VEGF in a dose-dependent manner. 1% and 5% of ethanol extract of A. fragrantissima containing vaseline based ointment was applied on rat excision wounds for six days and was found to be effective in wound healing and maturation of the scar. Both preparations resulted in better wound healing when compared to the untreated control group and vaseline-treated group. This effect was comparable to that induced by MEBO, the positive control. Conclusion: The results indicate that A. fragrantissima has a pro-angiogenic effect, which may act through the VEGF signaling pathway.

Long-Term Follow-Up of Early Cochlear Implant Device Activation

2021 ◽  
pp. 1-11
Author(s):  
Stefanie Bruschke ◽  
Uwe Baumann ◽  
Timo Stöver
Keyword(s):  
Speech Recognition ◽  
Side Effects ◽  
Cochlear Implant ◽  
Surgical Techniques ◽  
Control Group ◽  
First Year ◽  
Safe Procedure ◽  
Sound Processor

Background: The cochlear implant (CI) is a standard procedure for the treatment of patients with severe to profound hearing loss. In the past, a standard healing period of 3–6 weeks occurred after CI surgery before the sound processor was initially activated. Advancements of surgical techniques and instruments allow an earlier initial activation of the processor within 14 days after surgery. Objective: Evaluation of the early CI device activation after CI surgery within 14 days, comparison to the first activation after 4–6 weeks, and assessment of the feasibility and safety of the early fitting over a 12 month observation period were the objectives of this study. Method: In a prospective study, 127 patients scheduled for CI surgery were divided into early fitting group (EF, n = 67) and control group (CG, n = 60). Individual questionnaires were used to evaluate medical and technical outcomes of the EF. Medical side effects, speech recognition, and follow-up effort were compared with the CG within the first year after CI surgery. Results: The early fitting was feasible in 97% of the EF patients. In the EF, the processor was activated 25 days earlier than in the CG. No major complications were observed in either group. At the follow-up appointments, side effects such as pain and balance problems occurred with comparable frequency in both groups. At initial fitting, the EF showed a significantly higher incidence of medical minor complications (p < 0.05). When developing speech recognition within the first year of CI use, no difference was observed. Furthermore, the follow-up effort within the first year after CI surgery was comparable in both groups. Conclusions: Early fitting of the sound processor is a feasible and safe procedure with comparable follow-up effort. Although more early minor complications were observed in the EF, there were no long-term wound healing problems caused by the early fitting. Regular inspection of the magnet strength is recommended as part of the CI follow-up since postoperative wound swelling must be expected. The early fitting procedure enabled a clear reduction in the waiting time between CI surgery and initial sound processor activation.

scholarly journals Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuxing Shen ◽  
Chao Wu ◽  
Meng Lei ◽  
Qing Yan ◽  
Haoyang Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Serum Enzyme ◽  
Herg Channels ◽  
Anti Tumor Activity ◽  
Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

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