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Objective(s): Rhabdomyolysis (RM) is a serious fatal syndrome. The RM leads to acute kidney injury (AKI) as a fatal complication. The belief is that RM-induced AKI is triggered by myoglobin (MB). MB activates oxidative and apoptotic pathways. Trans-sodium crocetinate (TSC) is obtained from saffron. It has anti-oxidant and renoprotective effects. This research was designed to assess the mechanisms of MB-induced cytotoxicity in HEK-293 cells (human embryonic kidney cells) as well as the possible effects of TSC against MB-induced cytotoxicity. Materials and Methods: HEK-293 cells were exposed to diverse concentrations of TSC (2.5, 5, 10, 20, 40, 80, and 100 µM) for 24 hr. Then, MB (9 mg/ml) was added to the cells. After 24 hr, cell viability was measured through MTT, and the values of ROS generation were calculated using DCFH-DA assay. Also, autophagy and apoptosis markers in cells were assessed by western blot analysis.Results: MB decreased viability and increased ROS levels in HEK-293 cells. However, pretreatment of HEK-293 cells with TSC for 24 hr reduced the cytotoxicity and ROS production caused by MB. Furthermore, MB enhanced both the apoptosis (cleaved caspase-3 and Bax/Bcl-2 ratio) and autophagy markers (LC3II/I ratio and Beclin-1) in HEK-293 cells. On the other hand, TSC pretreatment condensed the levels of autophagy and apoptosis criteria in response to MB cytotoxicity. Conclusion: TSC has a positive effect in preventing MB-induced cytotoxicity in HEK-293 cells by increasing anti-oxidant activity and regulation of apoptotic and autophagy signaling pathways.

Objective(s): Rhabdomyolysis (RM) is a serious fatal syndrome. The RM leads to acute kidney injury (AKI) as a fatal complication. The belief is that RM-induced AKI is triggered by myoglobin (MB). MB activates oxidative and apoptotic pathways. Trans-sodium crocetinate (TSC) is obtained from saffron. It has anti-oxidant and renoprotective effects. This research was designed to assess the mechanisms of MB-induced cytotoxicity in HEK-293 cells (human embryonic kidney cells) as well as the possible effects of TSC against MB-induced cytotoxicity. Materials and Methods: HEK-293 cells were exposed to diverse concentrations of TSC (2.5, 5, 10, 20, 40, 80, and 100 μM) for 24 hr. Then, MB (9 mg/ml) was added to the cells. After 24 hr, cell viability was measured through MTT, and the values of ROS generation were calculated using DCFH-DA assay. Also, autophagy and apoptosis markers in cells were assessed by western blot analysis. Results: MB decreased viability and increased ROS levels in HEK-293 cells. However, pretreatment of HEK-293 cells with TSC for 24 hr reduced the cytotoxicity and ROS production caused by MB. Furthermore, MB enhanced both the apoptosis (cleaved caspase-3 and Bax/Bcl-2 ratio) and autophagy markers (LC3II/I ratio and Beclin-1) in HEK-293 cells. On the other hand, TSC pretreatment condensed the levels of autophagy and apoptosis criteria in response to MB cytotoxicity. Conclusion: TSC has a positive effect in preventing MB-induced cytotoxicity in HEK-293 cells by increasing anti-oxidant activity and regulation of apoptotic and autophagy signaling pathways. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disorder characterized by the degeneration of myelin and inflammation in the central nervous system. Trans sodium crocetinate (TSC), a novel synthetic carotenoid compound, possesses antioxidant, anti-inflammatory and neuroprotective effects. This study aimed to evaluate the protective effects of TSC against the development of experimental autoimmune encephalomyelitis (EAE), a well-established model for MS. Female BALB/C57 mice were divided into different groups, including control, EAE, vehicle, TSC-treated (25, 50, and 100 mg/kg, administered via gavage) + EAE, methyl prednisone acetate + EAE, and TSC-treated (100 mg/kg, administered via gavage for 28 days) groups. EAE was induced using MOG35-55, complete Freund's adjuvant, and pertussis toxin. In the mice spinal cord tissues, the oxidative markers (GSH and MDA) were measured using spectrophotometry and histological evaluation was performed. Mitophagic pathway proteins (PINK1and PARKIN) and inflammatory factors (IL-1β and TNF-α) were evaluated by western blot. Following 21 days post-induction, EAE mice exhibited weight loss, and the paralysis scores increased on day 13 but recovered after TSC (100 mg/kg) administration on day 16. Furthermore, TSC (50 and 100 mg/kg) reversed the altered levels of MDA and GSH in the spinal cord tissue of EAE mice. TSC (100 mg/kg) also decreased microgliosis, demyelination, and the levels of inflammatory markers IL-1β and TNF-α. Notably, TSC (100 mg/kg) modulated the mitophagy pathway by reducing PINK1 and Parkin protein levels. These findings demonstrate that TSC protects spinal cord tissue against EAE-induced MS through anti-inflammatory, antioxidant, and anti-mitophagy mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Acrylamide (ACR) is a neurotoxic agent whose damage could be attenuated by antioxidants administration. Crocetin is a saffron-derived antioxidant that has neuroprotective effects. This study evaluates the protective effects of trans-sodium crocetinate (TSC) and its water-soluble derivative, Bis-N-(N-methylpyprazinyl) crocetinate (BMPC) against ACR neurotoxicity.Materials and Methods: PC12 cells were treated with TSC and BMPC (1.95, 3.9, 7.81, 15.62, 31.25, 62.5, 125, 250, 500, and 1000 μM) for 24 hr. ACR was then added at a concentration of 6.5 mM (IC50), and cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In the in vivo study, male Wistar rats were treated with ACR (50 mg/kg, intraperitoneal (i.p.)) for 11 days alone or in combination with TSC and BMPC (2.5, 5, and 10 mg/kg, i.p.) or vitamin E (200 IU/kg, i.p.). Motor impairments were then evaluated. The cerebral cortex of sacrificed rats was taken for the malondialdehyde (MDA) and glutathione (GSH) levels measurement. Results: In vitro studies showed that TSC at a concentration of 7.81 μM and BMPC at concentrations of 3.9, 7.81, and 15.62 μM exhibited the lowest toxicity in acrylamide administration. In the in vivo study, pretreatment with 2.5, 5, and 10 mg/kg of TSC ameliorated behavioral impairments, but BMPC could not attenuate them. GSH and MDA were improved by 2.5, 5, and 10 mg/kg TSC and 2.5 mg/kg BMPC.Conclusion: TSC and BMPC administration improved behavioral index and oxidative stress injuries in Wistar rats exposed to ACR through MDA reduction and GSH content enhancement in the cerebral cortex.

Objective: Acrylamide (ACR) is a neurotoxic agent whose damage could be attenuated by antioxidants administration. Crocetin is a saffron-derived antioxidant that has neuroprotective effects. This study evaluates the protective effects of trans-sodium crocetinate (TSC) and its water-soluble derivative, Bis-N-(Nmethylpyprazinyl) crocetinate (BMPC) against ACR neurotoxicity. Materials and Methods: PC12 cells were treated with TSC and BMPC (1.95, 3.9, 7.81, 15.62, 31.25, 62.5, 125, 250, 500, and 1000 μM) for 24 hr. ACR was then added at a concentration of 6.5 mM (IC50), and cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide. In the in vivo study, male Wistar rats were treated with ACR (50 mg/kg, intraperitoneal (i.p.)) for 11 days alone or in combination with TSC and BMPC (2.5, 5, and 10 mg/kg, i.p.) or vitamin E (200 IU/kg, i.p.). Motor impairments were then evaluated. The cerebral cortex of sacrificed rats was taken for the malondialdehyde (MDA) and glutathione (GSH) levels measurement. Results: In vitro studies showed that TSC at a concentration of 7.81 μM and BMPC at concentrations of 3.9, 7.81, and 15.62 µM exhibited the lowest toxicity in acrylamide administration. In the in vivo study, pretreatment with 2.5, 5, and 10 mg/kg of TSC ameliorated behavioral impairments, but BMPC could not attenuate them. GSH and MDA were improved by 2.5, 5, and 10 mg/kg TSC and 2.5 mg/kg BMPC. Conclusion: TSC and BMPC administration improved behavioral index and oxidative stress injuries in Wistar rats exposed to ACR through MDA reduction and GSH content enhancement in the cerebral cortex. [ABSTRACT FROM AUTHOR]

Objective(s): Contrast media (CM) are used for diagnostic or therapeutic intervention purposes in medicine. The main adverse reaction after the administration of CM is contrast-induced nephropathy (CIN). This complication is the third cause of renal failure after hospital treatment. The current study is designed to investigate the possible protective effect of trans-sodium crocetinate (TSC), derived from carotenoid crocetin, against sodium amidotrizoate/meglumine amidotrizoate (SAMA) induced cytotoxicity in HEK-293 cells.Materials and Methods: HEK-293 cells were incubated with different concentrations of TSC (1, 2.5, 5, 10, 25, and 50 µM, for 48 hr) and then SAMA (7 mgI/ml, for 24 hr) was added. The cell viability, intracellular ROS, and phosphatidyl serine exposure were detected by MTT assay, DCFH-DA, and annexin V-FITC/PI method, respectively. The P-ERK/ERK ratio, apoptosis (Bax/Bcl-2 ratio and cleaved caspase-3), and autophagy (LC3 II/I ratio and beclin-1) markers in cells were evaluated by the western blot method.Results: The exposure of HEK-293 cells to SAMA reduced viability, increased apoptotic cells, enhanced ROS production, and subsequently decreased P-ERK/ERK ratio. Similarly, SAMA enhanced apoptosis (Bax/Bcl-2 ratio and cleaved caspase-3) and autophagy (LC3 II/I ratio and beclin-1) markers in HEK-293 cells. The pretreatment of cells with TSC before exposure to SAMA significantly attenuated contrast-induced cytotoxicity. TSC reduced intracellular ROS production and activated the phosphorylation of ERK. In addition, TSC decreased the levels of apoptosis and autophagy proteins. Conclusion: The pretreatment of HEK-293 cells with TSC can decrease contrast-induced cytotoxicity through antioxidant effect and modulate ERK, apoptosis, and autophagy pathways.

Objective(s): Contrast media (CM) are used for diagnostic or therapeutic intervention purposes in medicine. The main adverse reaction after the administration of CM is contrast-induced nephropathy (CIN). This complication is the third cause of renal failure after hospital treatment. The current study is designed to investigate the possible protective effect of trans-sodium crocetinate (TSC), derived from carotenoid crocetin, against sodium amidotrizoate/meglumine amidotrizoate (SAMA) induced cytotoxicity in HEK-293 cells. Materials and Methods: HEK-293 cells were incubated with different concentrations of TSC (1, 2.5, 5, 10, 25, and 50 µM, for 48 hr) and then SAMA (7 mgI/ml, for 24 hr) was added. The cell viability, intracellular ROS, and phosphatidyl serine exposure were detected by MTT assay, DCFH-DA, and annexin V-FITC/PI method, respectively. The P-ERK/ERK ratio, apoptosis (Bax/Bcl-2 ratio and cleaved caspase-3), and autophagy (LC3 II/I ratio and beclin-1) markers in cells were evaluated by the western blot method. Results: The exposure of HEK-293 cells to SAMA reduced viability, increased apoptotic cells, enhanced ROS production, and subsequently decreased P-ERK/ERK ratio. Similarly, SAMA enhanced apoptosis (Bax/Bcl-2 ratio and cleaved caspase-3) and autophagy (LC3 II/I ratio and beclin-1) markers in HEK-293 cells. The pretreatment of cells with TSC before exposure to SAMA significantly attenuated contrast-induced cytotoxicity. TSC reduced intracellular ROS production and activated the phosphorylation of ERK. In addition, TSC decreased the levels of apoptosis and autophagy proteins. Conclusion: The pretreatment of HEK-293 cells with TSC can decrease contrast-induced cytotoxicity through antioxidant effect and modulate ERK, apoptosis, and autophagy pathways. [ABSTRACT FROM AUTHOR]

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life‐saving in emergency situations. Oxygen diffusion‐enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first‐in‐class molecule, trans‐sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID‐19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first‐in‐class agent, small‐ and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders. [ABSTRACT FROM AUTHOR]

Trans-sodium crocetinate (TSC) is a vitamin A-analog that increases diffusivity of oxygen in aqueous solutions, including plasma. The current study is the initial investigation of the effects of TSC on oxygen delivery to brain. Adult male rats were intubated and ventilated with 21%, 60%, or 100% oxygen. A craniotomy was performed and a Licox rat brain tissue PO2 probe inserted into parietal cortex. Rats were then administered intravenous infusions of either TSC or saline and brain tissue PO2 values were recorded. TSC significantly increased brain tissue oxygen delivery. This effect was minimal in rats ventilated with normal air and substantial in rats on oxygen supplementation. Arterial blood gas parameters did not differ within groups. These results provide clear indication to study the utility of TSC in ameliorating hypoxic/ischemic insults in neurological disorders. [Copyright &y& Elsevier]

Trans-sodium crocetinate (TSC) is a novel synthetic carotenoid compound that improves diffusion of small molecules, including oxygen, in solutions. TSC provides neuroprotection in healthy rats and rabbits. This study seeks to determine whether TSC is neuroprotective in obese mice. Sixteen-week-old CD-1 male mice that had been fed a high-fat diet for 10 weeks were subjected to a 90-min middle cerebral arterial occlusion (MCAO). They received TSC by two boluses through a tail vein 10 min after the onset of MCAO and reperfusion, respectively, with doses of 0.14, 0.28, and 0.7 mg/kg or by a bolus-infusion-bolus strategy with a dose of 0.14 mg/kg during MCAO. The neurological outcome was evaluated 72 hr after MCAO. Brain tissues were harvested 24 hr after MCAO to measure nitrotyrosine-containing proteins, 4-hydroxy-2-nonenal, matrix metalloproteinase (MMP)-2 and -9 activity and expression, and inflammatory cytokines. TSC given in the two-bolus strategy did not improve the neurological outcome. The bolus-infusion-bolus strategy significantly reduced brain edema, infarct volume, and hemorrhagic transformation and improved neurological functions. TSC reduced nitrotyrosine-containing proteins, MMP-9 activity and expression, and inflammatory cytokines in ischemic brain tissues. Our results indicate that TSC delivered by the bolus-infusion-bolus strategy provides neuroprotection in obese mice. This protection may occur through reduction of oxidative stress, MMP-9 activity, or inflammatory cytokines in the ischemic brain tissues., (© 2014 Wiley Periodicals, Inc.)