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Burns are the fourth most common type of civilian trauma worldwide, and the management of severe irregular scald wounds remains a significant challenge. Herein, crocin-1 laden hydroxybutyl chitosan (CRO-HBC) thermosensitive hydrogel with smart anti-inflammatory performance was developed for accelerating full-thickness burn healing. The injectable and shape adaptability of the CRO-HBC gel make it a promising candidate for effectively filling scald wounds with irregular shapes, while simultaneously providing protection against external pathogens. The CRO-HBC gel network formed by hydrophobic interactions exhibited an initial burst release of crocin-1, followed by a gradual and sustained release over time. The excessive release of ROS and pro-inflammatory cytokines should be effectively regulated in the early stage of wound healing. The controlled release of crocin-1 from the CRO-HBC gel adequately addresses this requirement for wound healing. The CRO-HBC hydrogel also exhibited an excellent biocompatibility, an appropriate biodegradability, keratinocyte migration facilitation properties, and a reactive oxygen species scavenging capability. The composite CRO-HBC hydrogel intelligently mitigated inflammatory responses, promoted angiogenesis, and exhibited a commendable efficacy for tissue regeneration in a full-thickness scalding model. Overall, this innovative temperature-sensitive CRO-HBC injectable hydrogel dressing with smart anti-inflammatory performance has enormous potential for managing severe scald wounds.

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Major depressive disorder is one of the most common neuropsychiatric diseases and it is a global public health problem that leads to disabilities. Currently, there is a growing need to explore novel strategy to cure major depressive disorder due to the limitation of available treatments. Rannasangpei (RSNP) is a traditional Tibetan medicine which acts as a therapeutic agent in various acute or chronic diseases, including cardiovascular diseases and neurodegenerative diseases. Crocin-1 a coloring ingredient of saffron which exhibited anti-oxidative and anti-inflammatory properties. Here, we aimed to illustrate whether RSNP and its active ingredient crocin-1 rescue depressive-like phenotypes in chronic unpredictable mild stress (CUMS) induced mouse model of depression. Our results showed that peripheral administration of RSNP or crocin-1 ameliorated the depressive-like behaviors in CUMS-treated mice, as demonstrated by the forced swimming test and tail suspension test. Furthermore, RSNP or crocin-1 treatment reduced oxidative stress in the peripheral blood and hippocampus of the CUMS-treated mice. Additionally, the dysregulated immune system response, as demonstrated by the increased expression of the pro-inflammatory factors (tumor necrosis factor-α and interleukin-6) and the decreased expression of the anti-inflammatory factor-interleukin-10 in the prefrontal cortex and/or hippocampus of CUMS-treated mice, were at least partially restored by RSNP or crocin-1 treatment. RSNP or crocin-1 also restored apoptotic protein marker (Bcl-2 and Bax) levels in the prefrontal cortex and hippocampus of the CUMS-treated mice. Moreover, our data indicated that RSNP or crocin-1 increased astrocyte number and brain-derived neurotrophic factor levels in the hippocampus of CUMS-treated mice after RSNP or crocin-1 administration. Taken together, our study for the first time revealed an anti-depressant effect of RSNP and its active ingredient crocin-1 in a mouse model of depression, with involvement of oxidative stress, inflammatory response and apoptotic pathway.

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Crocins are the primary coloring ingredients of saffron. The low-glycosylated members of this compound family, such as crocin-1 (crocetin mono-glucosyl ester) and crocin-2' (crocetin di-glucosyl ester), are rarely distributed in nature and attracting interest for their therapeutic uses. In the present study, a one-pot reaction system was used for efficient preparation of crocin-1 and crocin-2' with in situ regeneration of UDP-Glc by coupling Bs-GT with At-SuSy, a sucrose synthase from Arabidopsis thaliana. Noticeably, DMSO was used as a cosolvent and resulted in improvement of the solubility of the substrate crocetin and regulation of the selectivity of glycosylation. With periodic addition of crocetin, the biosynthesis of crocin-2' was performed with a high yield of 3.25 g/L in 2% DMSO aqueous solution, whereas crocin-1 (2.12 g/L) was selectively obtained in a 10% DMSO aqueous solution. The present study provided a simple approach for the biosynthesis of crocin-1 and crocin-2'.

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SCOPE: Crocins are important apocarotenoids in the extract of saffron (Crocus sativus L.) and fruits of gardenia (Gardenia jasminoides E.). Crocins have shown versatile biological activities and thus they have been considered to be promising therapeutics for neurodegenerative and heart diseases. Metabolism studies report that crocetin-monoglucuronide (CM) is produced and detected in rat blood plasma after oral administration of crocins. However, due to the lack of standard compound of CM, its unambiguous identification, quantification, and bioactivity studies have been hindered. METHODS AND RESULTS: CM is synthetized and its existence in blood plasma in Sprague-Dawley (SD) rats is quantified. The pharmacokinetic studies show that CM is produced in blood and brain after oral administration of crocin-1. It is then discovered that CM possesses neuroprotective activity against beta-amyloid (Aß) toxicity in PC-12 cells and drosophila models. The enzymatic assay shows that CM can effectively inhibit AChE and docking studies indicate that CM may bind in the gorge channel of AChE. CONCLUSION: The work discovered that CM is a neuron-protective metabolite of the orally administrated crocin-1. It is demonstrated that AChE can be one of the targets of CM in its neuron-protective activity.

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Saffron, the stigma of Crocus sativus Linné (Iridaceae family), has been known to inhibit aggregation of ß-amyloid, a nerve tissue protein. α-Synuclein (αS) is a 140-amino acid protein found abundantly in various regions of the brain. Its abnormal aggregation and accumulation in nerve tissue are said to cause neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and multiple-system atrophy. This study (part of this study was presented at the 137th Annual Meeting of the Pharmaceutical Society of Japan) examined the effects of saffron, its constituents (crocin-1, crocin-2, crocetin, and safranal), and crocetin structural analogs (hexadecanedioic acid, norbixin, and trans, trans-muconic acid) on αS aggregation, and αS fibril dissociation. Saffron dose-dependently inhibited αS aggregation and dissociated αS fibrils by thioflavin T fluorescence assay. These effects were observed by transmission electron microscopy, which showed reduced and shortened αS fibrils. Crocin-1, crocin-2, and crocetin showed anti-aggregation and fibril dissociation effects, with crocetin being the most potent. The effects of norbixin were weaker than those of crocetin, and the other crocetin structural analogs showed no effects. These results show that saffron and its constituents (crocin-1, crocin-2, and crocetin) can be effective in preventing and treating diseases caused by abnormal αS aggregation.

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ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides Ellis (GJ) is one of the five constituents of Yueju pill, a Traditional Chinese Medicine for treatment of syndromes associated with mood disorders. Recently, preclinical and clinical studies suggest that Yueju pill confers rapid antidepressant effects. GJ is identified as the constituent primary for Yueju pill's rapid antidepressant effects. GJ's antidepressant action is temporally associated with up-regulated expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The present study aimed to identify chemical fractions responsible for the rapid antidepressant efficacy of GJ and its association with BDNF signaling. MATERIALS AND METHODS: Four fractions of GJ were extracted using standardized procedure. The four fractions were screened for rapid antidepressant potential, using the behavioral paradigm of forced swimming test (FST) and tail suspension test (TST) assessed at 24h post a single administration. A single dose of the putatively effective fractions was further tested in mice exposed to chronic mild stress (CMS), followed with a comprehensive behavioral testing including TST, FST, sucrose preference test (SPT), and novelty suppressed-feeding (NSF). To test the association of BDNF signaling with rapid antidepressant effects of effective factions, the expressions of BDNF and its receptor tropomyosin receptor kinase B (TrkB) in the hippocampus were assessed at different times post a single administration of effective fractions. RESULTS: Both petroleum ether (GJ-PE) and n-butyl alcohol fraction (GJ-BO) fractions of GJ displayed rapid antidepressant potential in the FST. In the TST, the antidepressant effects of GJ-PE lasted for a longer time than GJ-BO. Acute administration of either GJ-PE or GJ-BO significantly reversed the behavioral deficits in the tests of TST, FST, SPT and NSF in chronically stressed mice, confirming both fractions conferred rapid antidepressant efficacy. Interestingly, GJ-PE, but not GJ-BO, increased the expression of BDNF and TrkB in the hippocampus post a single administration. CONCLUSION: Two standardized fractions GJ-PE and GJ-BO exhibited comparable rapid antidepressant-like effects on the CMS mice. However, only the effects of GJ-PE was associated with BDNF signaling.

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Iridoid glycosides (mainly geniposide) and crocetin derivatives (crocins) are the two major active constituents in Gardenia jasminoides Ellis. In the present study, geniposide, crocins, crocin-1 and crocetin were separated from gardenia chromatographically. Then, mice were orally administrated with geniposide (400 mg/kg b.w.), crocins (400 mg/kg b.w.), crocin-1 (400 mg/kg b.w.) and crocetin (140 mg/kg b.w.) once daily for 7 days with CCl4. Hepatoprotective properties were evaluated by biochemical parameters: Administration of geniposide, crocins, crocin-1and crocetin significantlylowered serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) levels in CCl4-treated mice. The reduced glutathione (GSH) levels and antioxidant enzymes (SOD and CAT) activities were also increased by geniposide, crocins, crocin-1 and crocetin. Histopathological examination of livers showed that these components reduced deformability, irregular arrangement and rupture of hepatocyte in CCl4-treated mice. These biochemical results and liver histopathological assessment demonstrated that geniposide, crocetin derivatives and crocetin show comparative beneficialeffects on CCl4-induced liver damage via induction of antioxidant defense. Therefore, contents of geniposide and crocetin derivatives should be both considered for hepatoprotective efficacyof Gardenia jasminoides Ellis.

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Iridoid glycosides (mainly geniposide) and crocetin derivatives (crocins) are the two major active constituents in Gardenia jasminoides Ellis. In the present study, geniposide, crocins, crocin-1 and crocetin were separated from gardenia chromatographically. Then, mice were orally administrated with geniposide (400 mg/kg b.w.), crocins (400 mg/kg b.w.), crocin-1 (400 mg/kg b.w.) and crocetin (140 mg/kg b.w.) once daily for 7 days with CCl4. Hepatoprotective properties were evaluated by biochemical parameters: Administration of geniposide, crocins, crocin-1and crocetin significantly lowered serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) levels in CCl4-treated mice. The reduced glutathione (GSH) levels and antioxidant enzymes (SOD and CAT) activities were also increased by geniposide, crocins, crocin-1 and crocetin. Histopathological examination of livers showed that these components reduced deformability, irregular arrangement and rupture of hepatocyte in CCl4-treated mice. These biochemical results and liver histopathological assessment demonstrated that geniposide, crocetin derivatives and crocetin show comparative beneficial effects on CCl4-induced liver damage via induction of antioxidant defense. Therefore, contents of geniposide and crocetin derivatives should be both considered for hepatoprotective efficacy of Gardenia jasminoides Ellis.

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Objective: To investigate the effect of crocin-1 on behavior of learning and memory in rats under acute hypoxia and on the expression of silent information regulator l (SIRT1) in hippocampus of rats. Methods: SD rats were randomly divided into five groups: control, hypoxia model, low-, mid-, and high-dose (25, 50, and 100 mg/kg) crocin-1 groups. The SD rats in crocin-1 groups were im administered once daily for 3 d and then were stimulated for 72 h under hypoxia. Morris water maze was used to investigate the learning and memory behaviors. Immunohistochemical staining and Western blotting were used to detect the SIRT1 expression. Results: The escape latency in crocin-1 groups was shorter than that in hypoxia model group, while the frequency of bestriding platform was increased (P < 0.05). Immunohistochemical staining and Western blotting both showed that the expression level of SIRT1 was higher in crocin-1 groups than that in hypoxia model group (P < 0.05), and the expression levels in mid- and high-dose groups were obviously higher. Conclusion: Crocin-1 could increase the expression of SIRT1 in hippocampus of rats, which maybe one of the important mechanisms for crocin-1 improving learning and memory function of SD rats under acute hypoxia.

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OBJECTIVE: To elucidate the intestinal absorption and pharmacokinetic characteristics of crocin-1, a major active constituent of the stigmas of saffron (Crocus sativus L) in rats after oral administration. METHODS: Extracted plasma samples were eluted by the mobile phase composed of methanol-2% acetate acid (pH 2) (48: 52 for crocin-1 and 74: 36 for crocetin) on Agilent Zorbax SB-C18 column monitored at 420 nm. RESULTS: An accurate, precise and selective analysis method was developed to determine crocein in rat plasma with the quantitation limit of 10 ng · mL-1. No crocin-1 was detected in both original and β-glucuronidase treated plasma samples. However, appreciable crocetin, the aglycon form of crocin-1, was observed in the original plasma. The concentration of crocetin did not increase obviously after hydrolization by β-glucuronidase. The average concentration-time data after oral administration of 1 mg · kg-1 crocin-1 showed that crocin-1 was rapidly absorbed as erocein and remained above 50 ng · mL-1 for about 10 h. The first peak appeared at 20 min and the second peak at 6 h. The area under curve (AUC), mean residence time (MRT) during 0 - 24 h and elimination half-life (t1/2k) were calculated as (1.16 ± 0.22) μg · h · mL-1, (5.4 ± 0.7) and (3.0 ± 0.6) h, respectively. CONCLUSION: Crocin-1 is absorbed as its hydrolyzation metabolite and shows relatively good pharmacokinetic characteristics. Crocetin may be thereby related to the pharmacological activities of crocin-1 in vivo. Copyright 2012 by the Chinese Pharmaceutical Association.

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Objective To study the effect of Tibetan medicine Zuotai on in vivo pharmacokinetics of crocin-1 in rats.Methods After im injection of crocin-1 (5 mg/kg) in control (continuously ig normal saline for 7 d) and expermental (continuously ig Zuotai suspension for 7 d or 21 d) rats,The plasma concentration of crocin-1 was determined by RP-HPLC,and plasma concentration-time data were analyzed by DAS 2.0 software to get the related pharmacokinetic parameters of crocin-1.Results After continuously ig administration of Zuotai [10 mg/(kg?d)] for 7 d and 12 d in experimental rats,the pharmacokinetic parameters of crocin-1 changed significantly.The AUC,Cmax,and MRT were significantly greater in experimental rats than those in control rats,and the CL and Vd were significantly lower than those in control rats,and the AUC of crocin-1 was greater in the 21 d administration group than that in the 7 d administration group.Conclusion The result demonstrates that Tibetan medicine significantly affects the pharmacokinetics of crocin-1 in rats.After administration of Zuotai in rats,the absorption degree of crocin-1 is significantly increased and the clearance rate is significantly decreased.