Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy.

The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with self-stimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress.

Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.

[Arsenic speciation and valence].

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As_2S_2 or As_4S_4), orpiment(As_2S_3), and white arsenic(As_2O_3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.

[Varieties systematization and standards status analysis of fermented Chinese medicine].

Fermented Chinese medicine has long been used. Amid the advance for preservation of experience, the connotation of fermented Chinese medicine has been enriched and improved. However, fermented Chinese medicine prescriptions generally contain a lot of medicinals. The fermentation process is complicated and the conventional fermentation conditions fail to be strictly controlled. In addition, the judgment of the fermentation end point is highly subjective. As a result, quality of fermented Chinese medicine is of great difference among regions and unstable. At the moment, the quality standards of fermented Chinese medicine are generally outdated and different among regions, with simple quality control methods and lacking objective safe fermentation-specific evaluation indictors. It is difficult to comprehensively evaluate and control the quality of fermented medicine. These problems have aroused concern in the industry and also affected the clinical application of fermented Chinese medicine. This article summarized and analyzed the application, quality standards, and the modernization of fermentation technology and quality control methods of fermented Chinese medicine and proposed suggestions for improving the quality standards of the medicine, with a view to improving the overall quality of it.

X-Ray-triggered Carbon Monoxide and Manganese Dioxide Generation based on Scintillating Nanoparticles for Cascade Cancer Radiosensitization.

Carbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X-ray-triggered carbon monoxide (CO) and manganese dioxide (MnO2 ) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV-responsive Mn2 (CO)10 is not only indirectly activated to release CO by X-ray but can also be degraded into MnO2 . A high dose of CO can be used as a glycolytic inhibitor for tumor suppression; it will also sensitize tumor cells to radiotherapy. Meanwhile MnO2 , as the photolytic byproduct of Mn2 (CO)10 , has both glutathione (GSH) depletion and Fenton-like Mn2+ delivery properties to produce highly toxic hydroxyl radical (⋅OH) in tumors. Thus, this strategy can realize X-ray-activated CO release, GSH depletion, and ⋅OH generation for cascade cancer radiosensitization. Furthermore, X-ray-activated Mn2+ in vivo demonstrates an MRI contrast effect, making it a potential theranostic nanoplatform.

Huangqin decoction mitigates hepatic inflammation in high-fat diet-challenged rats by inhibiting TLR4/NF-κB/NLRP3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic hepatopathy worldwide, in which ectopic steatosis (5%) and inflammatory infiltration in the liver are the principal clinical characteristics. Huangqin decoction (HQD), a Chinese medicine formula used in the clinic for thousands of years, presents appreciable anti-inflammatory effects. Nevertheless, the role and mechanism of HQD against inflammation in NAFLD are still undefined. AIM OF THE STUDY: The objective of this study was to evaluate the curative efficacy and unravel the involved mechanism of HQD on a high-fat diet (HFD)-induced NAFLD. MATERIALS AND METHODS: First, HPLC was utilized to analyze the main chemical components of HQD. Then, NAFLD model was introduced by subjecting the rats to HFD for 16 weeks, and HQD (400 and 800 mg/kg) or polyene lecithin choline (PLC, 8 mg/kg) was given orally from week 8-16. Pharmacodynamic indicators including body weight, liver weight, liver index, as well as biochemical and histological parameters were assessed. As to mechanism exploration, the expressions of TLR4/NF-κB/NLRP3 pathway and molecular docking between major phytochemicals of HQD and key targets of TLR4/NF-κB/NLRP3 pathway were investigated. RESULTS: Seven main monomeric constituents of HQD were revealed by HPLC analysis. Of note, HQD could effectively attenuate the body weight, liver weight, and liver index, rescue disorders in serum transaminases and lipid profile, correct hepatic histological abnormalities, and reduce phagocytes infiltration into the liver and pro-inflammatory cytokines release in NAFLD rats. Mechanism investigation discovered that HQD harbored inhibitory effects on TLR4/NF-κB/NLRP3 pathway-regulated liver inflammation. Further exploration found that seven phytochemicals in HQD exhibited better binding modes with TLR4/NF-κB/NLRP3 pathway, in which baicalein, baicalin and liquiritin presented the highest affinity and docking score for protein TLR4, NF-κB, and NLRP3, respectively. CONCLUSIONS: These findings confirmed that HQD ameliorated hepatic inflammation in NAFLD rats by blocking the TLR4/NF-κB/NLRP3 pathway, with multi-components and multi-targets action pattern.

[Distribution of surface components in spray-dried powder of binary system of berberine hydrochloride and dextran based on hydrodynamic size].

The present study explored the correlation between the hydrodynamic size(i.e., hydrated particle size) and the surface component distribution of spray-dried powder based on the binary system model of berberine hydrochloride and dextran. A variety of mixture solutions containing substances of different proportions were prepared, and the hydrated particle sizes of the solutions were measured by laser light scattering technique. Then the effects of molecular weight and mixing proportion on the particle size were analyzed. After the solutions were spray-dried, the surface components of spray-dried powder were determined by X-ray photoelectron spectroscopy. The changes of hydrated particle size of the two substances in different solutions were measured with the altered solution environments, and the distribution of surface components after spray-drying was observed. The results of particle size measurement showed that different solution environments would change the hydrodynamic size of substances. Specifically, the particle size of berberine hydrochloride increased with the increase in ionic strength and solution pH, while the particle size of dextran decreased with the increase in ionic strength and increased with the increase in solution pH. The results of surface components of the spray-dried powder indicated that berberine hydrochloride was prone to accumulate on the surface of particles during spray-drying because of its large hydrodynamic size. Therefore, hydrodynamic size is considered an important factor affecting the surface component distribution of spray-dried powder. As revealed by scanning electron microscopy of the particle morphology of spray-dried powder, the particles of berberine hydrochloride spray-dried powder were irregularly elliptic, and the particles of dextran and mixture spray-dried powders were irregularly spherical with the shrunken surface. Finally, the FT4 powder rheometer and DVS instrument were used to determine the stability, adhesion, and hygroscopicity of the powder. The results showed that when berberine hydrochloride was enriched on the surface, the adhesion of the mixture increased and the fluidity became worse, but the hygroscopicity was improved to a certain extent. In addition, as found by hygroscopic kinetic curve fitting of spray-dried powder, the hygroscopic behaviors of all spray-dried powder conformed to the double exponential function.

Immunomodulatory effects of Radix isatidis polysaccharides in vitro and in vivo.

Radix isatidis (R. isatidis) is a commonly used traditional Chinese herbal medicine, which has been used for thousands of years in China and is believed to have the pharmacological properties of heat-clearing and detoxification. Heat-clearing and detoxification are theories of traditional Chinese medicine meaning that R. isatidis could treat febrile disease by clearing heat and reducing swelling. Polysaccharides isolated from R. isatidis by water extraction and alcohol precipitation have exhibited numerous biological activities, including antiviral and immunomodulatory effects. The present study was performed to investigate the immunomodulatory effects of water-soluble R. isatidis polysaccharides (RIPs) on RAW264.7 macrophages and murine splenocytes, and attempt to preliminarily identify the mechanism of immunomodulation. In vitro, RIPs had a low cytotoxicity, as shown by CellTiter 96® AQueous One Solution Cell Proliferation Assay. RAW264.7 cells treated with different concentrations of RIP displayed different morphological changes, from a round shape and aggregation to polygonal shape and dispersion in a dose-dependent manner. In the 5 mg/ml RIP-treated group, the changes of morphology were as same as the lipopolysaccharide-treated group. RIP also significantly enhanced the release of nitric oxide as shown by Griess method, and the secretion of TNF-α and IL-6 in RAW264.7 cells was confirmed by ELISA assay. Western blotting revealed a significant increase of toll-like receptor-4 (TLR-4) in RIP-treated RAW264.7, suggesting that TLR-4 may be associated with the immunomodulatory mechanism of RIP. Animal experiments also demonstrated through ELISA assays a significant increase in IFN-γ and IL-10 levels after the splenocytes of RIP-immunized mice were stimulated by inactivated herpes simplex virus type 2. The immune function of RIP-immunized mice was improved. The present study suggested that RIP could be potentially used as a novel immunomodulator.

Systematic Review and Meta-Analysis of Acupuncture for Pain Management in Women Undergoing Transvaginal Oocyte Retrieval.

OBJECTIVE: To obtain evidence-based conclusions about the effect of acupuncture on pain relief in women undergoing oocyte retrieval, the results of randomized controlled trials (RCTs) that met the criteria were assessed on the Pain Assessment Scale and pregnancy indicators. SEARCH METHODS: References were retrieved in MEDLINE, EMBASE, CNKI database, CBM database, VIP database, and Wanfang database from inception to June 26, 2021. Unpublished ongoing trials were searched in the Clinical Trials Registries. This review included RCTs that investigated the acupuncture analgesic effects during oocyte retrieval in women undergoing in vitro fertilization. RESULTS: Fourteen RCTs (2503 women in total) with six types of comparisons were finally included. The quality of concluding evidence was generally low or very low. Performance bias and outcome assessment bias was the main risk of bias of the included studies. Acupuncture combined with conscious sedation and analgesia (CSA) was associated with less intraoperative (SMD=-1.03; 95% CI: -1.71 to -0.36) and postoperative (SMD = -1.11; 95% CI: -1.51 to -0.71) pain compared to receive CSA alone in oocyte retrieval. Acupuncture with non-steroidal anti-inflammatory drugs (NSAIDs) was more effective than using NSAIDs alone for postoperative analgesia (MD = -1.76; 95% CI: -2.08 to -1.44). CONCLUSION: Acupuncture complex analgesic therapy is more effective than utilizing CSA or NSAIDs alone. Furthermore, there is no significant consensus on whether there is an analgesic effect of applying acupuncture alone during oocyte retrievals, which needs further research. The overall results should be interpreted with caution due to the high risk of bias/low-GRADE scores among these studies. PROTOCOL AND REGISTRATION: PROSPERO registration number: CRD42020170095.

Sodium Danshensu promotes the healing of stage 2 pressure injury wounds in ischemia/reperfusion injury rat models: possible regulation of apoptosis and inflammatory response.

OBJECTIVE: To investigate the protective effect and possible mechanism of sodium Danshensu (SDSS) against pressure injury caused by ischemia/reperfusion (I/R) injury. METHODS: Sprague-Dawley rats were randomly divided into five groups of eight rats each: control group, model group, 10 mg/kg SDSS-treated group, 20 mg/kg SDSS-treated group, and 40 mg/kg SDSS-treated group. We used two round ferrite magnetic plates of 15 mm diameter and 3 mm thickness to establish stage 2 pressure injury model rats. Each rat was subjected to five cycles of ischemia and reperfusion to induce pressure injury. One cycle consisted of 2 h of ischemia and 0.5 h of reperfusion, which meant that each cycle included 2 h of pressure and 0.5 h of pressure relief. The outline of the wound was delineated by butter paper and marker pen, and histopathological changes were observed by hematoxylin and eosin staining. In addition, the number of apoptotic cells and the activity of caspase-3 were assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling and caspase-3 assay kits, respectively. The expression of apoptosis-regulatory proteins and inflammatory mediators was investigated by enzyme-linked immunosorbent assay. RESULTS: Results showed that treatment with SDSS for 7 d after establishing the pressure injury model remarkably improved the healing rate of the wound. SDSS also inhibited the levels of tumor ne- crosis factor-α, myeloperoxidase, and intercellular cell adhesion molecule-1; decreased the number of apoptotic cells; increased the ratio of B-cell lymphoma-2 (Bcl-2) / Bcl-2-associated X (Bax); and regulated the expression and activity of caspase-3. CONCLUSION: Our results suggest that SDSS exhibits a treatment efficacy for pressure injury caused by I/R injury possibly by inhibiting apoptosis and inflammatory response.

Dose-dependent beneficial and harmful effects of berberine on mouse oocyte maturation and fertilization and fetal development.

Previous studies have shown that berberine, an isoquinoline alkaloid isolated from several traditional Chinese herbal medicines, suppresses growth and induces apoptosis in some tumor cell lines. It has also been shown that berberine possesses anti-atherosclerosis and antioxidant activities in hyperlipidemic model rats. Our previous study in mice found that berberine causes harmful effects on preimplantation and postimplantation embryonic development, both in vitro and in vivo, by triggering reactive oxygen species (ROS)-mediated apoptotic cascades in mouse blastocysts. In the current investigation, we further showed that berberine treatment has distinct dose-dependent effects on oocyte maturation and subsequent development. Preincubation of oocytes with 2.5 µM berberine significantly enhanced maturation and in vitro fertilization (IVF) rates, with subsequent beneficial effects on embryonic development. In contrast, preincubation with 10 µM berberine negatively impacted mouse oocyte maturation, decreased IVF rates and impaired subsequent embryonic development. Similar dose-dependent effects were also demonstrated in vivo. Specifically, intravenous injection of berberine significantly enhanced mouse oocyte maturation, IVF rate and early-stage embryo development after fertilization at a dose of 1 mg/kg body weight but significantly impaired oocyte maturation and IVF rates and caused harmful effects on early embryonic development at a dose of 5 mg/kg. Mechanistically, we found that berberine enhanced intracellular ROS production and apoptosis of oocytes at a concentration of 10 µM but actually significantly decreased total intracellular ROS content and had no apoptotic effect at a concentration of 2.5 µM. Moreover, pretreatment of oocytes with Ac-DEVD-cho, a caspase-3-specific inhibitor, effectively blocked berberine-induced negative impacts on oocyte maturation, fertilization and subsequent development. Collectively, these findings establish the dose-dependent beneficial versus deleterious effects of berberine and suggest that the mechanism underlying the deleterious effects of berberine involves a caspase-3-dependent apoptotic process acting downstream of an increase in intracellular ROS levels.

Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats.

Cardiac remodeling is an important pathological process ultimately leading to heart failure. Ubiquitin carboxy-terminal hydrolase 1 (UCHL1) is a deubiquitinase that plays a critical role in neurodegenerative diseases and cancer. However, its role in cardiac remodeling in spontaneously hypertensive rats remains unclear. Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were administered the UCHL1 inhibitor LDN-57444 (20 µg/kg/day) from 2 months of age for 4 months. Blood pressure, cardiac hypertrophy, fibrosis, inflammation, and oxidative stress were evaluated by the tail-cuff system, echocardiography, and histological analysis. Gene and protein expression levels were examined by real-time PCR and immunoblotting analysis. At 6 months of age, the expression of UCHL at the mRNA and protein levels was significantly upregulated in SHRs compared with WKYs. Moreover, systolic blood pressure, cardiac performance, left ventricular (LV) hypertrophy, fibrosis, inflammation, and superoxide production were significantly increased in SHRs compared with WKYs, and these effects were markedly attenuated by LDN-57444 after 4 months of administration. These beneficial actions were possibly associated with a reduction in blood pressure and inactivation of multiple signaling pathways, including AKT, ERK1/2, STAT3, calcineurin A, TGF-ß/Smad2/3, and NF-κB. In conclusion, the results indicate that UCHL1 is involved in hypertensive cardiac remodeling in SHRs, and targeting UCHL1 activity may be a novel potential therapeutic approach for the treatment of hypertensive heart diseases.

Prevalence, correlates, and impact of sleep disturbance in Chinese patients with primary Sjögren's syndrome.

AIM: Sleep disturbances are common in primary Sjögren's syndrome (pSS) patients and may lead to disease aggravation and decreased health-related quality of life (HRQoL). There are currently no known reported studies related to the prevalence, correlates, and impact of sleep disturbance in pSS patients from China. Therefore, this study aims to assess the sleep quality in Chinese pSS patients and evaluate its relationship with the disease activity, quality of life and mood disorders. METHODS: A self-report survey was administered to 221 pSS patients and 198 healthy individuals using the Pittsburgh Sleep Quality Index (PSQI) for sleep quality. Disease activity and damage were evaluated with the European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI). Independent samples t tests, Chi-square analysis, logistic regression were used to analyze these data. RESULTS: Our results found that the prevalence of poor sleep (PSQI ≥ 6) was 57.5% and the mean global score of PSQI was 6.57 (SD 3.19) in patients, which were significantly higher than the controls (32.3% and 4.93 [SD 2.86], respectively). When trying to fall asleep, patients with pSS had some sleep disturbances, reduced sleep efficiency, increased number of awakenings than controls. There were significant correlations among dryness, ocular surface disease, HRQoL, pain, disease activity, anxiety/depression and sleep quality in pSS patients. Meanwhile, logistic regression models identified depression and Short Form-36 mental composite score as predictors of poor sleep quality. CONCLUSIONS: Sleep disturbances are commonly reported in pSS patients and sleep quality is lower in pSS patients than in healthy controls. The data suggested the need for holistic assessment and management of pSS patients.

Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and systems. Mesenchymal stem cells (MSCs) from SLE patients have demonstrated defects such as impaired growth, senescence phenotype and immunomodulatory functions. Some studies have suggested the close connection between inflammation microenvironment and cellular senescence. In the current study, we detected cytokines levels in bone marrow supernatant by the quantitative proteomics analysis, and found the expression of HMGB1 was remarkably increased in bone marrow from SLE patients. Senescence associated-ß-galactosidase (SA-ß-gal) staining, F-actin staining and flow cytometry were used to detect the senescence of cells. After stimulation of HMGB1 in normal MSCs, the ratio of SA-ß-gal positive in BM-MSCs was increased, the organization of cytoskeleton was disordered, and TLR4-NF-κB signaling was activated. Finally, Ethyl pyruvate (EP) (40 mg/kg and 100 mg/kg, three times a week), a high security HMGB1 inhibitor, was injected intraperitoneally to treat MRL/lpr mice for 8 weeks. We demonstrated that EP alleviated the clinical aspects of lupus nephritis and prolonged survival of MRL/lpr mice. In the meantime, EP reversed the senescent phenotype of BM-MSCs from MRL/lpr mice. HMGB1 could be a promising target in SLE patients, and might be one of the reasons of recurrence after MSCs transplantation.

[Effect of N-acetyl-L-cysteine on bioavailability and brain distribution of curcumin by nasal delivery].

Curcumin( Cur) is a natural active substance extracted from the roots or tubers of traditional Chinese medicinal materials. It has anti-inflammatory and anti-tumor activities on brain diseases. Due to the poor stability,low solubility,poor absorption and low bioavailability of curcumin,N-acetyl-L-cysteine( NAC) was used as an absorption enhancer and mixed with curcumin to improve the absorption of curcumin in the body. In this paper,curcumin was smashed by airflow pulverization,and Cur-NAC mixtures were prepared by being grinded with liquid. Then,the raw material and the product were analyzed by differential scanning calorimetry( DSC),X-ray diffraction( XRD) for structural characterization. The dissolution was determined by high performance liquid chromatography( HPLC) analysis. The characteristic peaks of the samples prepared by grinding method were similar to those of the raw materials,while the melting temperature and the accumulated dissolution degree were not significantly changed. The crystal forms of the products were not changed,and no new crystal form was formed after grinding. After the administration of intranasal powder,blood samples were collected from the orbit,while the whole brain tissues were removed from the skull and dissected into 10 anatomical regions. The concentrations of curcumin in these samples were determined by UPLC-MS/MS. The concentrations of curcumin in plasma and brain were compared at different time points. After intranasal administration of two drugs,it was found that the concentration of curcumin after sniffing up the mixtures in plasma was high,and the concentration of the drug in the olfactory bulb,hippocampus,and pons was increased significantly. Within 0. 083-0. 5 h,the olfactory bulb,piriform lobe and hippocampus remained high concentrations,the endodermis,striatum,hypothalamus and midbrain reached high concentrations within 1-3 h; and the cerebellum,pons and brain extension maintained relatively high concentrations within 3-7 h. The experiment showed that nasal administration of Cur-NAC mixtures can significantly improve the bioavailability of curcumin,and lead to significant differences in brain tissue distribution.

Hepatoprotection of auraptene from the peels of citrus fruits against 17α-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor.

Cholestatic liver injury induced by estrogen is a common clinical syndrome in women undergoing oral administration of contraceptives, pregnancy or hormone replacement therapy. Estrogen-induced cholestasis is associated with the accumulation of endogenous bile acids, which play critical roles in the disease progression and symptoms. In the present study, we described the protective effect of auraptene, a simple coumarin present in the peels of citrus fruits, such as grapefruit, against 17α-ethinylestradiol (EE)-induced cholestasis, and further elucidated the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect. Auraptene treatment alleviated EE-induced cholestasis through increasing the bile flow and biliary bile acid output. The mechanism underlying the alleviated cholestasis by auraptene was associated with the increased efflux and inhibited hepatic uptake of bile acids via an induction of efflux transporters (Bsep and Mrp2) and downregulation of Ntcp. Furthermore, auraptene reduced the bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased the bile acid metabolism through an induction in the gene expression of Sult2a1. The mentioned genes involved in the bile acid homeostasis were modulated by FXR. We further demonstrated that the changes in transporters and enzymes, as well as ameliorated liver histology by auraptene, were abrogated by the FXR antagonist guggulsterone. In conclusion, auraptene alleviated EE-induced cholestasis due to FXR-mediated gene regulation.

Fargesin inhibits melanin synthesis in murine malignant and immortalized melanocytes by regulating PKA/CREB and P38/MAPK signaling pathways.

BACKGROUND: Fargesin is commonly used in the treatment of allergic rhinitis, inflammation, sinusitis and headache. OBJECTIVE: The aim of the study is to investigate a new function of fargesin against melanin production and its underlying molecular mechanism. METHODS: B16F10 mouse melanoma cells, Melan-a and human epidermal melanocytes were treated with different concentrations of fargesin for the indicated time. The extracellular and cellular melanin content was detected by spectrometry at 490 nm and 405 nm, respectively. RT-qPCR and Western blot analysis were used to exam the expression of melanogenic enzymes and the activities of PKA/CREB and p38 MAPK pathway components. Zebrafish was used as an in vivo model for studying the function of fargesin in regulating melanogenesis. RESULTS: Fargesin effectively inhibited melanin production at moderate dose in mouse B16F10 melanoma cells, normal melanocyte cell lines and zebrafish. The expression of microphthalmia-associated transcription factor (MITF), its downstream melanogenic enzymes and tyrosinase activity were also strongly reduced by fargesin. Moreover, the increase of melanin production induced by UVB and forskolin could be fully reversed by fargesin treatment. Fargesin also effectively inhibited the activation of PKA/CREB and p38 MAPK as well as their interactions, which in turn is responsible for the expression of MITF and melanogenic enzymes. CONCLUSIONS: These results show that fargesin can function as an anti-melanogenic agent, at least in part, by inhibiting PKA/CREB and p38/MAPK signaling pathways. Therefore, fargesin and its derivatives may potentially be used for preventing hyperpigmentation disorders in the future.

Yangonin protects against non-alcoholic fatty liver disease through farnesoid X receptor.

BACKGROUD: Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. Dyslipidemia, pathoglycemia and insulin resistance are the major risk factors for the development of NAFLD. To date, no effective drug therapies for this condition have been approved. PURPOSE: The present study was to investigate the protective effects of yangonin, a kavalactone isolated from Kava, against NAFLD and further elucidate the mechanisms in vivo and in vitro. STUDY DESIGN: A high-fat diet (HFD) induced mouse NAFLD model was used with or without yangonin treatment. METHODS: The body weight, relative liver weight and serum biochemical indicators were measured. H&E and Oil Red O staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic triglyceride, free fatty acids and total cholesterol were analyzed. siRNA, quantitative real-time PCR and Western blot assay were used to clarify the mechanisms underlying yangonin protection. RESULTS: Yangonin had obvious protective effects against NAFLD via farnesoid X receptor (FXR) activation. Through FXR activation, yangonin attenuated lipid accumulation in the liver via inhibition of hepatic lipogenesis-related protein including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase 1 (SCD1). Besides, yangonin promoted lipid metabolism through an induction in genes required for lipoprotein lipolysis and fatty acid ß-oxidation. Furthermore, yangonin modulated blood glucose homeostasis through regulation of gluconeogenesis-related gene phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and glycogen synthesis-related gene glycogen synthase kinase 3ß (GSK3ß) and pyruvate dehydrogenase (PDase). Also, yangonin increased insulin sensitivity through upregulating phosphorylation of insulin responsive substrate 1, 2 (IRS-1 and IRS-2). Then, in vivo and in vitro evidence further demonstrated the involvement of FXR activation in yangonin hepatoprotection. CONCLUSIONS: Yangonin protects against NAFLD due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and to promote lipid metabolism and glycogen synthesis, as well as insulin sensitivity.

Sitagliptin improves renal function in diabetic nephropathy in male Sprague Dawley rats through upregulating heme oxygenase-1 expression.

PURPOSE: Oxidative stress is an important mechanism for diabetic nephropathy. Studies showed that hemo oxygenase-1 (HO-1) expression in renal tissue of patients with diabetic nephropathy has upregulated, while the HO-1 can protect the body through anti-oxidative stress. The study aimed to preliminarily explore the molecular mechanism by observing the effect of Sitagliptin on HO-1 expression in renal tissue of rats with diabetic nephropathy. METHODS: The diabetic nephropathy rat model was established by STZ injection followed by intraperitoneal injection of sitagliptin with different concentrations. The mRNA expressions of HO-1 were detected by real-time PCR and Western blot and HO-1 enzyme activity change was detected by colorimetry. Human renal mesangial cell (HRMC) were cultured in vitro with high glucose concentration (30 µmol/L), phosphatidylinositol-3-kinase (PI3K) level and nuclear factor erythroid-2-related factor (Nrf2) content in cytoplasm and cell nucleus were observed before and after treatment with sitagliptin, as well as the action of in meditating HO-1 expression. RESULTS: HO-1 mRNA, protein level, and HO-1 enzyme activity in renal tissue of rats with diabetic nephropathy were significantly increased after treatment with sitagliptin (P < 0.05). As comparison, the 24 h urinary microalbumin, creatinine, and boold urea nitrogen were all decreased after treatment of sitagliptin (P < 0.05). Similar results were observed after CoPP (an agonist of HO-1) treatment (P < 0.05). In contrast, ZnPP, an inhibitor of HO-1, significantly abrogated the inhibitory effect of sitagliptin (P < 0.05). Phosphorylation of PI3K and Nrf2 nuclear translocation under high-glucose concentration condition was induced by sitagliptin in HRMC. HO-1 expression was suppressed by pretreating HRMC with PI3K inhibitor or RNA interference. CONCLUSIONS: Sitagliptin may induce HO-1 expression via activation of PI3K and Nrf2 in rats with diabetic nephropathy; HO-1 can improve the oxidative stress of diabetic nephropathy, eventually protect from diabetic nephropathy.

Artificial Sandwich Base for Monitoring Single-Nucleobase Changes and Charge-Transfer Rates in DNA.

Developing a convenient method to discriminate among different types of DNA nucleotides within a target sequence of the human genome is extremely challenging. We herein report an artificial ferrocene-base (Fe-base) that was synthesized and incorporated into different loci of a DNA strand. The Fe-base replacement on a nucleobase can interact with DNA bases and efficiently discriminate among A, T, G, and C DNA bases of the complementary locus on the basis of interacting electrochemical properties. Furthermore, cyclic-voltammetry (CV) studies demonstrated the electrochemical stability of DNA strands incorporated with Fe-bases and the reversibility of the incorporation. Square-wave voltammetry (SWV) was performed to measure current changes between Fe-bases and bases of interest in the DNA duplex. The changes in the charge-transfer rates appeared to be correlated with the position of the Fe-base in the DNA strand, allowing rapid and efficient sensing of single-nucleobase changes in DNA and showing promise for the design of Fe-oligomer chip technology as a tool for DNA sequencing.