Curcumol: a review of its pharmacology, pharmacokinetics, drug delivery systems, structure-activity relationships, and potential applications.

Curcumol (Cur), a guaiane-type sesquiterpenoid hemiketal, is an important and representative bioactive component extracted from the essential oil of the rhizomes of Curcumae rhizoma which is also known as "Ezhu" in traditional Chinese medicine. Recently, Cur has received considerable attention from the research community due to its favorable pharmacological activities, including anti-cancer, hepatoprotective, anti-inflammatory, anti-viral, anti-convulsant, and other activities, and has also exerted therapeutic effect on various cancers, liver diseases, inflammatory diseases, and infectious diseases. Pharmacokinetic studies have shown that Cur is rapidly distributed in almost all organs of rats after intragastric administration with high concentrations in the small intestine and colon. Several studies focusing on structure-activity relationship (SAR) of Cur have shown that some Cur derivatives, chemically modified at C-8 or C-14, exhibited more potent anti-cancer activity and lower toxicity than Cur itself. This review aims to comprehensively summarize the latest advances in the pharmacological and pharmacokinetic properties of Cur in the last decade with a focus on its anti-cancer and hepatoprotective potentials, as well as the research progress in drug delivery system and potential applications of Cur to date, to provide researchers with the latest information, to highlighted the limitations of relevant research at the current stage and the aspects that should be addressed in future research. Our results indicate that Cur and its derivatives could serve as potential novel agents for the treatment of a variety of diseases, particularly cancer and liver diseases.

A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis.

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. STATEMENT OF SIGNIFICANCE: Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.

Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study.

BACKGROUND: In China, depressive disorders have been estimated to be the second leading cause of years lived with disability. However, nationally representative epidemiological data for depressive disorders, in particular use of mental health services by adults with these disorders, are unavailable in China. The present study, part of the China Mental Health Survey, 2012-15, aims to describe the socioeconomic characteristics and the use of mental health services in people with depressive disorders in China. METHODS: The China Mental Health Survey was a cross-sectional epidemiological survey of mental disorders in a multistage clustered-area probability sample of adults of Chinese nationality (≥18 years) from 157 nationwide representative population-based disease surveillance points in 31 provinces across China. Trained investigators interviewed the participants with the Composite International Diagnostic Interview 3.0 to ascertain the presence of lifetime and 12-month depressive disorders according to DSM-IV criteria, including major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Participants with 12-month depressive disorders were asked whether they received any treatment for their emotional problems during the past 12 months and, if so, the specific types of treatment providers. The Sheehan Disability Scale (SDS) was used to assess impairments associated with 12-month depressive symptoms. Data-quality control procedures included logic check by computers, sequential recording check, and phone-call check by the quality controllers, and reinterview check by the psychiatrists. Data were weighted according to the age-sex-residence distribution data from China's 2010 census population survey to adjust for differential probabilities of selection and differential response, as well as to post-stratify the sample to match the population distribution. FINDINGS: 28 140 respondents (12 537 [44·6%] men and 15 603 [55·4%] women) completed the survey between July 22, 2013, and March 5, 2015. Ethnicity data (Han or non-Han) were collected for only a subsample. Prevalence of any depressive disorders was higher in women than men (lifetime prevalence odds ratio [OR] 1·44 [95% CI 1·20-1·72] and 12-month prevalence OR 1·41 [1·12-1·78]), in unemployed people than employed people (lifetime OR 2·38 [95% CI 1·68-3·38] and 12-month OR 2·80 [95% CI 1·88-4·18]), and in people who were separated, widowed, or divorced compared with those who were married or cohabiting (lifetime OR 1·87 [95% CI 1·39-2·51] and 12-month OR 1·85 [95% CI 1·40-2·46]). Overall, 574 (weighted % 75·9%) of 744 people with 12-month depressive disorders had role impairment of any SDS domain: 439 (83·6%) of 534 respondents with major depressive disorder, 207 (79·8%) of 254 respondents with dysthymic disorder, and 122 (59·9%) of 189 respondents with depressive disorder not otherwise specified. Only an estimated 84 (weighted % 9·5%) of 1007 participants with 12-month depressive disorders were treated in any treatment sector: 38 (3·6%) in speciality mental health, 20 (1·5%) in general medical, two (0·3%) in human services, and 21 (2·7%) in complementary and alternative medicine. Only 12 (0·5%) of 1007 participants with depressive disorders were treated adequately. INTERPRETATION: Depressive disorders in China were more prevalent in women than men, unemployed people than employed, and those who were separated, widowed, or divorced than people who were married or cohabiting. Most people with depressive disorders reported social impairment. Treatment rates were very low, and few people received adequate treatment. National programmes are needed to remove barriers to availability, accessibility, and acceptability of care for depression in China. FUNDING: National Health Commission and Ministry of Science and Technology of People's Republic of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Effect of Tetramethylpyrazine on Neuroplasticity after Transient Focal Cerebral Ischemia Reperfusion in Rats.

Tetramethylpyrazine (TMP) has been widely used in ischemic stroke in China. The regulation of neuroplasticity may underlie the recovery of some neurological functions in ischemic stroke. Middle cerebral artery occlusion (MCAO) model was established in this study. Rats were divided into three groups: sham group, model group, and TMP group. The neurological function was evaluated using modified neurological severity score (mNSS). Following the neurological function test, expression of synaptophysin (SYP) and growth-associated protein 43 (GAP-43) were analyzed through immunohistochemistry at 3 d, 7 d, 14 d, and 28 d after MCAO. Finally, the synaptic structural plasticity was investigated using transmission electron microscopy (TEM). The TMP group showed better neurological function comparing to the model group. SYP levels increased gradually in ischemic penumbra (IP) in the model group and could be enhanced by TMP treatment at 7 d, 14 d, and 28 d, whereas GAP-43 levels increased from 3 d to 7 d and thereafter decreased gradually from 14 d to 28 d in the model group, which showed no significant improvement in the TMP group. The results of TEM showed a flatter synaptic interface, a thinner postsynaptic density (PSD), and a wider synaptic cleft in the model group, and the first two alterations could be ameliorated by TMP. Then, a Pearson's correlation test revealed mNSS markedly correlated with SYP and synaptic ultrastructures. Taken together, TMP is capable of promoting functional outcome after ischemic stroke, and the mechanisms may be partially associated with regulation of neuroplasticity.

Simultaneous determination of four phenolic acids in traditional Chinese medicine by capillary electrophoresis-chemiluminescence.

Chlorogenic, ferulic, vanillic, and caffeic acids are phenolic acids found in natural drugs. They possess the biological activities of scavenging free radicals and inhibiting thrombus formation. Phenolic acids can inhibit the oxidation of low-density lipoprotein, as well as have anti-inflammatory effects. This paper reports for the first time a capillary electrophoresis-chemiluminescence (CE-CL) method for the simultaneous determination of the four phenolic acids found in traditional and proprietary Chinese medicine, including Lycium chinense Miller, Shuanghuanglian oral liquid, and Taraxacum mongolicum granules. Capillary electrophoretic separation was performed on a self-assembled CE-CL device with an uncoated fused-silica capillary (66 cm effective length, 50 µm i.d.), and the background electrolyte was composed of 3.0 × 10-5 M Ag(iii) (pH = 12.01), 3.0 mM luminol (pH = 9.20), and 10 mM sodium tetraborate solution. The injection time was 12 s (under gravity) and the separation voltage was 22 kV. The combination of solid-phase extraction (SPE) and CE-CL improves the sensitivity. Under optimal conditions, calibration graphs displayed a linear range between 0.625 and 20.0, 1.000 and 30.0, 0.150 and 1.50, and 0.045 and 1.00 µg mL-1 for chlorogenic, ferulic, vanillic, and caffeic acid, respectively. The detection limit ranged from 0.014 to 0.300 µg mL-1. The practicality of using the proposed method to determine the four target analytes in traditional Chinese medicine was also validated, in which recoveries ranged from 90.9% to 119.8%. Taken together, these results indicate that the developed method is sensitive and reliable. Furthermore, the method was successfully applied to real traditional Chinese medicine samples.

Correlating the Local Electrocatalytic Activity of Amorphous Molybdenum Sulfide Thin Films with Microscopic Composition, Structure, and Porosity.

Thin-film electrodes, produced by coating a conductive support with a thin layer (nanometer to micrometer) of active material, retain the unique properties of nanomaterials (e.g., activity, surface area, conductivity, etc.) while being economically scalable, making them highly desirable as electrocatalysts. Despite the ever-increasing methods of thin-film deposition (e.g., wet chemical synthesis, electrodeposition, chemical vapor deposition, etc.), there is insufficient understanding on the nanoscale electrochemical activity of these materials in relation to structure/composition, particularly for those that lack long-range order (i.e., amorphous thin-film materials). In this work, scanning electrochemical cell microscopy (SECCM) is deployed in tandem with complementary, colocated compositional/structural analysis to understand the microscopic factors governing the electrochemical activity of amorphous molybdenum sulfide (a-MoSx) thin films, a promising class of hydrogen evolution reaction (HER) catalyst. The a-MoSx thin films, produced under ambient conditions by electrodeposition, possess spatially heterogeneous electrocatalytic activity on the tens-of-micrometer scale, which is not attributable to microscopic variations in elemental composition or chemical structure (i.e., Mo and/or S bonding environments), shown through colocated, local energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) analysis. A new SECCM protocol is implemented to directly correlate electrochemical activity to the electrochemical surface area (ECSA) in a single measurement, revealing that the spatially heterogeneous HER response of a-MoSx is predominantly attributable to variations in the nanoscale porosity of the thin film, with surface roughness ruled out as a major contributing factor by complementary atomic force microscopy (AFM). As microscopic composition, structure, and porosity (ECSA) are all critical factors dictating the functional properties of nanostructured materials in electrocatalysis and beyond (e.g., battery materials, electrochemical sensors, etc.), this work further cements SECCM as a premier tool for structure-function studies in (electro)materials science.

Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth.

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming.

[Preventive Effect of Different Compatibilities of Ramulus Cinnamomi and Radix Paeomlae alba in Guizhi Decoction on Cardiac Sympathetic Denervation Induced by 6-OHDA].

OBJECTIVE: To observe the preventive effect of different compatibilities of Ramulus Cinnamomi (RC) and Radix Paeomiae alba (RPA) in Guizhi Decoction (GZD) on neurotransmitters and their rate-limiting enzymes, and neurotrophic factors of cardiac sympathetic denervation model rats induced by 6-hydroxydopamine (6-OHDA). METHODS: Totally 54 male Wistar rats were randomly divided into 6 groups, i.e., the blank control group, the model group, the methycobal group, the 2:1 (RC/RPA) Guishao group, the 1:2 Guishao group, and the 1:1 Guishao group, 9 in each group. Sympathetic denervation was induced by intraperitoneal injection of 6-OHDA for three successive days. Rats in the methycobal group and GZD groups were administered with corresponding decoction by gastrogavage 1 week before modeling (methycobal at the daily dose 0.15 mg/kg; GZD at the daily dose of 4.0, 5.5, 5.5 g crude drugs/kg for GZD 1:1, 1:2, and 2:1 groups). All medication lasted for 10 successive days. Levels of norepinephrine (NE), tyrosine hydroxylase (TH), choline acetyl-transferase (ChAT), nerve growth factor (NGF), growth associated protein43 (GAP-43) and ciliary neurotrophic factor (CNTF) in myocar- dial homogenates of right atrium and ventricular septum were detected by ELISA. RESULTS: Compared with the blank control group, levels of NE, TH, TH/ChAT ratio, and GAP-43 in myocardial homogenates of right atrium and ventricular septum decreased in the model group, and level of NGF increased (P < 0.01, P < 0.05). Compared with the model group, levels of NE and GAP-43 increased in the right atrium and interventricular septum; NGF level of the ventricular septum decreased in the methycobal group and each GZD groups. TH and TH/ChAT ratio in the right atrium increased in the 2:1 Guishao group and the 1:2 Guishao group (P < 0.01, P < 0.05); NGF levels in the right atrium and interventricular septum decreased only in the 1:1 Guishao group (P < 0.01, P< 0.05). Compared with the methycobal group, levels of NE, TH, and GAP-43 in the right atrium and interventricular septum increased, and NGF levels in the right atrium and interventricular septum decreased in the 1:1 Guishao group (P < 0.05). Compared with the methycobal group, levels of NE and GAP-43 in interventricular septum increased in the 2:1 Guishao group (P < 0.05). CONCLUSION: GZD (with the proportion between RC and RPA 2:1 and 1:1) could improve contents of neurotransmitters and their rate-limiting enzymes, as well as neurotrophic factors in cardiac sympathetic denervation model rats induced by 6-OHDA, alleviate cardiac sympathetic denervation induced by 6-OHDA, and maintain the balance of sympathetic-vagal nerve system.

[Effects of Different Compatibilities of Ramulus Cinnamomi and Peony in Guizhi Decoction on Diabetic Cardiac Autonomic Neuropathy].

OBJECTIVE: To observe the preventive effect different compatibilities of Ramulus Cinnamomi (RC) and peony in Guizhi Decoction (GD) on diabetic cardiac autonomic neuropathy (DCAN). METHODS: Totally 60 male rats were randomly divided into 5 groups, i.e., the blank control DM group, the model group, the methycobal group, the 1:1 (RC/peony) Guishao group, the 2:1 Guishao group, and the 1:2 Guishao group, 10 in each group. Rats were pretreated with corresponding drugs for 1 week, and then induced diabetes by intraperitoneal injection of STZ. Drugs were administrated by gastrogavage for 4 more weeks after STZ-injection. Enzyme-linked immunosorbent assay (ELISA) was employed to detect levels of tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), nerve growth factor. (NGF), and ciliary neurotrophic factor (CNTF) in myocardial homogenates. RESULTS: After 4-week modeling, body weight (BW) was obviously lower, but blood glucose (BG) was higher in STZ rats than in rats of the blank control DM group. There was no statistical difference in BW or BG among the 5 groups (P >0.05). Compared with the blank control group, TH, TH/CHAT, and NGF in left ventricle and ventricular septum increased, CHAT and CNTF increased in the model group (P < 0.05, P < 0.01). Compared with the model group, TH and TH/CHAT in left ventricle decreased (P < 0.05, P < 0.01), CNTF in left ventricle increased (P < 0.05), CHAT in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the methycobal group. TH and TH/CHAT in left ventricle and ventricular septum decreased, CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01), CHAT in left ventricle and ventricular septum increased (P < 0.01), NGF in ventricular septum decreased (P < 0.01) in the 1:1 Guishao group. TH/CHAT in left ventricle decreased (P < 0.01), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:2 Guishao group. Compared with the methycobal group, CHAT in left ventricle decreased, TH and TH/CHAT in left ventricle increased in the 2:1 Guishao group (P < 0.05, P < 0.01). TH and TH/CHAT in ventricular septum decreased (P < 0.05), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:1 Guishao group. Compared with the 1:2 Guishao group and the 2:1 Guishao group, CHAT in left ventricle increased, TH/CHAT in left ventricle decreased, TH and TH/CHAT in ventricular septum decreased, CHAT in ventricular septum increased, CNTF in left ventricle and ventricular septum also increased in the 1:1 Guishao group (all P < 0.01). CONCLUSIONS: STZ model rats had autonomic neural injury, manifested as lowered vagal nerve activity and hyperactive sympathetic nerves. GD could effectively suppress hyperactive cardiac sympathetic nerves and protect the vagus. Besides, GD (1:1) showed the optimal effect in regulating the balance of cardiac autonomic nerves and could be used in early prevention of DCAN.

[Diagnosis and treatment characteristics of head-wind sha in She medicine].

The diagnosis and treatment characteristics of head-wind sha in She medicine were analyzed and summarized. By visiting She-nationality villages and towns in Zhejiang province and Fujian province and interviewing hundreds of doctors of She medicine, the sha diagnosis, sha differentiation, experience and theory of treatment were arranged, and a comprehensive summary on theory and application of head-wind sha in She medicine such as pathogeny, name of disease, mechanism, diagnosis, differential diagnosis and treatment was made. It is believed that the methods of diagnosis and treatment in She medicine for head-wind sha could effectively enhance curative effect, safety and patients' quality of life, and the further research should be carried out.

Fibrin-sealant-delivered cisplatin chemotherapy versus cisplatin hyperthermic intraperitoneal perfusion chemotherapy for locally advanced gastric cancer without peritoneal metastases: a randomized phase-II clinical trial with a 40-month follow-up.

A new intraoperative cisplatin administration method for patients with locally advanced gastric cancer (AGC) and without peritoneal metastasis, fibrin-sealant-delivered cisplatin chemotherapy, was reported, and its safety, pharmacokinetics, and efficacy were compared with cisplatin hyperthermic intraperitoneal perfusion chemotherapy. Forty-two AGC patients were randomly divided into 2 groups: fibrin-sealant-delivered cisplatin chemotherapy (FS) (n = 21) and cisplatin hyperthermic intraperitoneal perfusion chemotherapy (CHIC) (n = 21). Both groups received 120 mg cisplatin after complete cytoreductive surgery. At different time points, cisplatin concentrations in patients' sera and urine samples were measured to determine time-dependent maximal concentration (Cmax) and the area under the curve (AUC). The primary and secondary end-points were overall survival (OS) and safety profiling, respectively. Occurrence of grade-3 to grade-4 liver or kidney dysfunction was less frequent in the FS group than in the CHIC group (28.6 % vs 47.6 %). Cisplatin Cmax and AUC for the serum and urine of the FS patients were significantly lower than that of the CHIC patients. Elimination half-life of cisplatin in the FS group was significantly longer than in the CHIC group (24.1 h vs 14.2 h). After a median follow-up of 40 months, 1-, 2-, and 3-years OS were 90.5 %, 71.4 %, and 61.9 % in the FS group, and 61.9 %, 47.6 %, and 42.8 % in the CHIC group, respectively. The median OS was 35.9 months in the FS group and 29.1 months in the CHIC group. Fibrin-sealant-delivered cisplatin chemotherapy was as effective and had a favorable pharmacokinetic profile with similar survival outcomes as cisplatin hyperthermic intraperitoneal perfusion chemotherapy following complete cytoreductive surgery of locally advanced GC without peritoneal metastases.

Study on antitubercular constituents from the seeds of Nigella glandulifera.

Two new compounds with five known compounds have been isolated from EtOH extract of the seeds of Nigella glandulifera. On the basis of their spectroscopic and chemical evidence, the new compounds were elucidated as methoxynigeglanine (1) and 6-methoxythymol-3-O-ß-D-glucopyranoside (4). Compounds 1-4 showed moderate antitubercular activity against Mycobacterium tuberculosis strain H37Rv with minimal inhibitory concentration (MIC) values of 32-250 µg/mL.

[Effect of long-term fertilization practices on mobility of phosphorus in a Huangnitu paddy soil receiving low P input in the Taihu Lake region, Jiangsu Province].

Analysis of mobile forms of phosphorus of a Huangnitu, a typical paddy soil in the Taihu Lake region, Jiangsu was conducted. The soil has been put into a scheme of longterm fertilization treatments for 13 years. Total P content varied in arrange of 0.3-0.5 g.kg-1 under a range of total P fertilizer input of 0-53 kg/(hm2.a). As estimated from the total P pool values by mass balance principle, the soil had been subjected to water loss of P 2-8 kg/(hm2.a), with that under chemical fertilizers only being the biggest. The ratio of soluble P to the total was in a range of 0.2%-0.4%, without significant influence by the different fertilization schemes. While chemical fertilizer plus pig slurry manure applications had remarkably enhanced the resin-P pool by 20-40 mg.kg-1, P mobilization was not observed due to combined application of chemical fertilizers and straw amendments despite of the increase of the SOM. Therefore, P water loss in paddy soils might have active under continuous chemical fertilization alone in agriculture of this region and could not be accounted for by dissolution in water and subsequent runoff migration. For reducing the present prominent non point source pollution of N and P in the region, it is suggested that chemical fertilizers are applied in combination with an appropriate amount of manure or straw return for reducing soil P loss and, in turn, the non-point source pollution loading.