Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with...Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury.Bexarotene,a type of retinoid,exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease.Bexarotene has been proven to promote autophagy,but it has not been used in the treatment of spinal cord injury.To investigate the effects of bexarotene on spinal cord injury,we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days.We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord,increased the number of synapses of nerve cells,reduced oxidative stress,inhibited pyroptosis,promoted the recovery of motor function,and reduced death.Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury.Bexarotene enhanced the nuclear translocation of transcription factor E3,which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways.Intravenous injection of transcription factor E3 sh RNA or intraperitoneal injection of compound C,an AMP-activated protein kinase blocker,inhibited the effects of bexarotene.These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-Sphase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways,promotes autophagy,decreases reactive oxygen species level,inhibits pyroptosis,and improves motor function after spinal cord injury.展开更多
Breast cancer cell growth can be inhibited in vivo by retinoid X receptor (RXR) specific retinoids. In both animal and cell culture studies, omega-3 fatty acids share growth regulatory effects similar to those of RXR ...Breast cancer cell growth can be inhibited in vivo by retinoid X receptor (RXR) specific retinoids. In both animal and cell culture studies, omega-3 fatty acids share growth regulatory effects similar to those of RXR specific retinoids (rexinoids). One synthetic rexinoid, bexarotene (LCD 1069, Targretin), is used clinically to treat cancer patients. Of concern is that some patients are unable to tolerate high doses of such treatment drugs. We hypothesized that n-3 fatty acids and bexarotene may work synergistically to slow breast cancer cell growth. To test our hypothesis, we used MCF-7 human mammary carcinoma cells and an in vitro cell culture model. We investigated the relationship between the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alone and in conjunction with bexarotene in slowing MCF-7 cell growth. Following a 72 hr incubation with the respective treatments, bexarotene enhanced cell growth (p < 0.05) while DHA showed a strong growth inhibitory effect which was not enhanced by the addition of bexarotene (p < 0.05). EPA alone was not effective in altering cell growth (p < 0.05). Interestingly, when combined with bexarotene, EPA was more effective at slowing cell growth than when cells received EPA alone. Thus, select omega-3 fatty acids alone are more effective than bexarotene in slowing MCF-7 cell progression. However, the use of the RXR-selective retinoids may enhance the growth regulatory mechanisms of the fatty acid EPA.展开更多
Background. A 63-year-old man with therapy-resistant Se′ zary syndrome was enrolled in a multicenter trial of oral bexarotene for advanced-stage cutaneous T-cell lymphoma(CTCL). Methods. Monthly evaluations for effic...Background. A 63-year-old man with therapy-resistant Se′ zary syndrome was enrolled in a multicenter trial of oral bexarotene for advanced-stage cutaneous T-cell lymphoma(CTCL). Methods. Monthly evaluations for efficacy and side-effects were conducted and documented. Results. Gradual improvement in erythema, pruritus, and scale was noted during the initial 16week trial period and treatment was extended to 40 weeks. From week 20 to week 40, the erythroderma continued to improve and the lymph node burden decreased, but the absolute Se′ zary cell count inversely increased. By week 40, intractable pruritus and erythroderma abruptly recurred, and bexarotene was discontinued. Conclusions. Bexarotene is well tolerated and can be efficacious in patients with Se′ zary syndrome. Shifting of Se′ zary cells between different compartments was noted. Further studies on the interaction between the skin, lymph nodes, and peripheral blood compartments during bexarotene treatment in this subset of patients with CTCL are needed.展开更多
Objective: To investigate the protective effect of bexarotene in radiation-induced skin injury and elucidate underlying mechanism.Methods: Irradiated cellular and animal models were established using an X-ray linear a...Objective: To investigate the protective effect of bexarotene in radiation-induced skin injury and elucidate underlying mechanism.Methods: Irradiated cellular and animal models were established using an X-ray linear accelerator. Cell viabilityand apoptosis were evaluated by CCK8 and flow cytometry. In vivo protective effect of bexarotene was measuredin irradiated SD rats. The antioxidant capacity of bexarotene was validated by DCF-DA method. The signalingpathways involved in bexarotene-mediated skin repair were enriched by RNA sequencing.Results: Bexarotene could significantly restore the proliferation and inhibit the apoptosis of WS1 cells with radiation damage (P < 0.05). Moreover, bexarotene could effectively shorten the process of skin damage andpromote skin repair in a rat model of radiation-induced skin injury (P < 0.05). Mechanistically, bexaroteneeffectively reduced the expression of RXRα (P < 0.05), thus leading to an early decrease in reactive oxygen species(ROS) after radiation exposure. Furthermore, a transcriptome analysis indicated that bexarotene-mediated recovery of radiation damage involves redox signaling, immune regulation, lipid metabolism and autophagy.Conclusion: Bexarotene is a promising therapeutic agent in the treatment of radiation-induced skin injury.展开更多
基金grants from Zhejiang Provincial Medicine and Health Technology Project,No.2021KY214(to SS)Zhejiang Provincial Science and Technology Project of Traditional Chinese Medicine,No.2021ZB183(to HX)。
文摘Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury.Bexarotene,a type of retinoid,exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease.Bexarotene has been proven to promote autophagy,but it has not been used in the treatment of spinal cord injury.To investigate the effects of bexarotene on spinal cord injury,we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days.We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord,increased the number of synapses of nerve cells,reduced oxidative stress,inhibited pyroptosis,promoted the recovery of motor function,and reduced death.Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury.Bexarotene enhanced the nuclear translocation of transcription factor E3,which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways.Intravenous injection of transcription factor E3 sh RNA or intraperitoneal injection of compound C,an AMP-activated protein kinase blocker,inhibited the effects of bexarotene.These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-Sphase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways,promotes autophagy,decreases reactive oxygen species level,inhibits pyroptosis,and improves motor function after spinal cord injury.
文摘Breast cancer cell growth can be inhibited in vivo by retinoid X receptor (RXR) specific retinoids. In both animal and cell culture studies, omega-3 fatty acids share growth regulatory effects similar to those of RXR specific retinoids (rexinoids). One synthetic rexinoid, bexarotene (LCD 1069, Targretin), is used clinically to treat cancer patients. Of concern is that some patients are unable to tolerate high doses of such treatment drugs. We hypothesized that n-3 fatty acids and bexarotene may work synergistically to slow breast cancer cell growth. To test our hypothesis, we used MCF-7 human mammary carcinoma cells and an in vitro cell culture model. We investigated the relationship between the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alone and in conjunction with bexarotene in slowing MCF-7 cell growth. Following a 72 hr incubation with the respective treatments, bexarotene enhanced cell growth (p < 0.05) while DHA showed a strong growth inhibitory effect which was not enhanced by the addition of bexarotene (p < 0.05). EPA alone was not effective in altering cell growth (p < 0.05). Interestingly, when combined with bexarotene, EPA was more effective at slowing cell growth than when cells received EPA alone. Thus, select omega-3 fatty acids alone are more effective than bexarotene in slowing MCF-7 cell progression. However, the use of the RXR-selective retinoids may enhance the growth regulatory mechanisms of the fatty acid EPA.
文摘Background. A 63-year-old man with therapy-resistant Se′ zary syndrome was enrolled in a multicenter trial of oral bexarotene for advanced-stage cutaneous T-cell lymphoma(CTCL). Methods. Monthly evaluations for efficacy and side-effects were conducted and documented. Results. Gradual improvement in erythema, pruritus, and scale was noted during the initial 16week trial period and treatment was extended to 40 weeks. From week 20 to week 40, the erythroderma continued to improve and the lymph node burden decreased, but the absolute Se′ zary cell count inversely increased. By week 40, intractable pruritus and erythroderma abruptly recurred, and bexarotene was discontinued. Conclusions. Bexarotene is well tolerated and can be efficacious in patients with Se′ zary syndrome. Shifting of Se′ zary cells between different compartments was noted. Further studies on the interaction between the skin, lymph nodes, and peripheral blood compartments during bexarotene treatment in this subset of patients with CTCL are needed.
文摘Objective: To investigate the protective effect of bexarotene in radiation-induced skin injury and elucidate underlying mechanism.Methods: Irradiated cellular and animal models were established using an X-ray linear accelerator. Cell viabilityand apoptosis were evaluated by CCK8 and flow cytometry. In vivo protective effect of bexarotene was measuredin irradiated SD rats. The antioxidant capacity of bexarotene was validated by DCF-DA method. The signalingpathways involved in bexarotene-mediated skin repair were enriched by RNA sequencing.Results: Bexarotene could significantly restore the proliferation and inhibit the apoptosis of WS1 cells with radiation damage (P < 0.05). Moreover, bexarotene could effectively shorten the process of skin damage andpromote skin repair in a rat model of radiation-induced skin injury (P < 0.05). Mechanistically, bexaroteneeffectively reduced the expression of RXRα (P < 0.05), thus leading to an early decrease in reactive oxygen species(ROS) after radiation exposure. Furthermore, a transcriptome analysis indicated that bexarotene-mediated recovery of radiation damage involves redox signaling, immune regulation, lipid metabolism and autophagy.Conclusion: Bexarotene is a promising therapeutic agent in the treatment of radiation-induced skin injury.
