Qingjie Huagong decoction inhibits pancreatic acinar cell pyroptosis by regulating circHipk3/miR-193a-5p/NLRP3 pathway.

BACKGROUND: Safer and more effective drugs are needed for the treatment of acute pancreatitis (AP). Qingjie Huagong decoction (QJHGD) has been applied to treat AP for many years and has shown good clinical effects. However, the potential mechanism has not yet been determined. PURPOSE: To investigate the role and underlying mechanism of the effects of QJHGD on AP both in vitro and in vivo. METHODS: QJHGD was characterized by UHPLC-Q-Orbitrap-MS. The protective effect of QJHDG and the underlying mechanism were investigated in MPC-83 cells in vitro. A caerulein-induced AP model was established to evaluate the protective effect of QJHGD in mice. CCK-8 assays were used to detect cell viability. The contents of inflammatory mediators were determined by ELISA. Expression levels of circRNA, miRNA and mRNA were determined by qRT-PCR. Protein expression was determined using Western blot. Pancreatic tissues were assessed by hematoxylin and eosin staining as well as immunohistochemical and immunofluorescence analyses. Pull-down and luciferase activity assays were performed to determine the regulatory relationships of circHipk3, miR-193a-5p and NLRP3. RESULTS: Our results confirmed that mmu-miR-193a-5p was sponged by mmu-circHipk3, and NLRP3 was a target of miR-193a-5p. In vitro experiments showed that QJHGD enhanced MPC-83 cell viability by regulating circHipk3 sponging mir-193a-5 targeting NLRP3 and inhibiting pyroptosis-related factors. Finally, we showed that QJHGD ameliorated pancreatic tissue injury in AP mice via this pathway. CONCLUSION: This study demonstrate that QJHDG exerted its anti-AP effects via the circHipk3/miR-193a-5p/NLRP3 pathway, revealing a novel mechanism for the therapeutic effect of QJHDG on AP.

Promoting Intratumoral Drug Accumulation by Bio-Membrane Regulated Active Targeting for Tumor Photothermal Therapy.

Introduction: Insufficient tumor permeability and inadequate nanoparticle retention continue to be significant limitations in the efficacy of anti-tumor drug therapy. Numerous studies have focused on enhancing tumor perfusion by improvement of tumor-induced endothelial leakage, often known as the enhanced permeability and retention (EPR) effect. However, these approaches have produced suboptimal therapeutic outcomes and have been associated with significant side effects. Therefore, in this study, we prepared tumor cell membrane-coated gold nanorods (GNR@TM) to enhance drug delivery in tumors through homogeneous targeting of tumor cell membranes and in situ real-time photo-controlled therapy. Methods: Here, we fabricated GNR@TM, and characterized it using various techniques including Ultraviolet-Visible (UV-Vis) spectrophotometer, particle size analysis, potential measurement, and transmission electron microscopy (TEM). The cellular uptake and cytotoxicity of GNR@TM were analyzed by flow cytometry, confocal laser scanning microscopy (CLSM), TEM, CCK8 assay and live/dead staining. Tissue drug distribution was determined by inductively coupled plasma mass spectrometry (ICP-MS) and immunofluorescence staining. Furthermore, to evaluate the therapeutic effect, mice bearing MB49 tumors were intravenously administered with GNR@TM. Subsequently, near-infrared (NIR) laser therapy was performed, and the mice's tumor growth and body weight were monitored. Results: The tumor cell membrane coating endowed GNR@TM with extended circulation time in vivo and homotypic targeting to tumor, thereby enhancing the accumulation of GNR@TM within tumors. Upon 780 nm laser, GNR@TM exhibited excellent photothermal conversion capability, leading to increased tumor vascular leakage. This magnification of the EPR effect induced by NIR laser further increased the accumulation of GNR@TM at the tumor site, demonstrating strong antitumor effects in vivo. Conclusion: In this study, we successfully developed a NIR-triggered nanomedicine that increased drug accumulation in tumor through photo-controlled therapy and homotypic targeting of the tumor cell membrane. GNR@TM has been demonstrated effective suppression of tumor growth, excellent biocompatibility, and significant potential for clinical applications.

Enhanced brain functional connectivity and activation after 12-week Tai Chi-based action observation training in patients with Parkinson's disease.

Introduction: Motor-cognitive interactive interventions, such as action observation training (AOT), have shown great potential in restoring cognitive function and motor behaviors. It is expected that an advanced AOT incorporating specific Tai Chi movements with continuous and spiral characteristics can facilitate the shift from automatic to intentional actions and thus enhance motor control ability for early-stage PD. Nonetheless, the underlying neural mechanisms remain unclear. The study aimed to investigate changes in brain functional connectivity (FC) and clinical improvement after 12 weeks of Tai Chi-based action observation training (TC-AOT) compared to traditional physical therapy (TPT). Methods: Thirty early-stage PD patients were recruited and randomly assigned to the TC-AOT group (N = 15) or TPT group (N = 15). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans before and after 12 weeks of training and clinical assessments. The FCs were evaluated by seed-based correlation analysis based on the default mode network (DMN). The rehabilitation effects of the two training methods were compared while the correlations between significant FC changes and clinical improvement were investigated. Results: The results showed that the TC-AOT group exhibited significantly increased FCs between the dorsal medial prefrontal cortex and cerebellum crus I, between the posterior inferior parietal lobe and supramarginal gyrus, and between the temporal parietal junction and clusters of middle occipital gyrus and superior temporal. Moreover, these FC changes had a positive relationship with patients' improved motor and cognitive performance. Discussion: The finding supported that the TC-AOT promotes early-stage PD rehabilitation outcomes by promoting brain neuroplasticity where the FCs involved in the integration of sensorimotor processing and motor learning were strengthened.

Vascular, valvular and kidney calcification manifested in mouse models of adenine-induced chronic kidney disease.

BACKGROUND: Ectopic calcification (EC) involves multiple organ systems in chronic kidney disease (CKD). Previous CKD-animal models primarily focused on a certain histological abnormality but did not show the correlation with calcified development among various tissues. This study compared calcified deposition in various tissues during CKD progression in mice. METHODS: Male 8-week-old C57BL/6J mice were randomly allocated to the seven groups: a basic, adenine, high-phosphorus, or adenine and high-phosphorus diet for 12-16 weeks (Ctl16, A12, P16, or AP16, respectively); an adenine diet for 4-6 weeks; and a high-phosphorus or adenine and high-phosphorus diet for 10-12 weeks (A6 + P10, A4 + P12, or A4 + AP12, respectively). RESULTS: Compared to the Ctl16 mice, the P16 mice only displayed a slight abnormality in serum calcium and phosphorus; the A12 mice had the most serious kidney impairment; the A4 + P12 and A6 + P10 mice had similar conditions of CKD, mineral abnormalities, and mild calcification in the kidney and aortic valves; the A4 + AP12 and AP16 groups had severe kidney impairment, mineral abnormalities and calcification in the kidneys, aortic valves and aortas. Furthermore, calcium-phosphate particles were deposited not only in the tubulointerstitial compartment but in the glomerular and tubular basement membrane. The elemental composition of EC in various tissues matched the calcification of human cardiovascular tissue as determined by energy dispersive spectroscopy. CONCLUSIONS: The severity of CKD was unparalleled with the progression of mineral metabolism disorder and EC. Calcification was closely related in different tissues and observed in the glomerular and tubular basement membranes.

Previous CKD-animal models primarily focused on a certain histological abnormality but lacked investigations of the interplay of EC in various tissues. This study compared calcified deposition in several tissues during CKD progression in mice, which was closely related. The severity of CKD was unparalleled with the development of ectopic calcification. Glomerular and tubular basement membrane calcification was detected in CKD mice, which has been considered extremely rare in clinical.

Acupuncture and acupressure with improved cancer-related depression of retrospective studies.

Introduction: Acupuncture and acupressure are widely used for treating cancer pain and depression and recognized as safe and effective by the international medical community. In this study, we systematically evaluated the efficacy, safety, and clinical significance of acupuncture and acupressure in treating cancer-related depression. Methods: We searched MEDLINE, PubMed, Science Direct, Google Scholar, Web of Science and Embase and Chinese-language databases for randomized clinical trials (RCTs). To assess efficacy, rating scales administered by clinicians or experts were preferred, including the Hamilton Depression Rating Scale (HAMD), Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), and Quality of Life Questionnaire-Core 30 (QLQ-C30) and the total effective rate after treatment. In all, Sixteen RCTs involving 1019 cancer patients were included in the Meta-analysis. Results: Eleven (69%) of these studies reported the post-treatment total effective rate. Three hundred fifty-three patients received antidepressants; the total effective rate was 72.5%. Three hundred sixty-one patients underwent acupuncture and acupressure; the total effective rate was 90%. Meta-analysis results showed I2 = 0%, no heterogeneity, (Z = 5.84, p < 0.00001); and combined OR = 3.55, (95% CI = 2.32 to 5.43). Discussion: This study found that acupuncture and acupressure are as effective as medication in the treatment of cancer-related depression, provide a reliable basis for the clinical use of acupuncture to treat cancer-related depression, help promote nonpharmacological treatment for cancer-related complications. These approaches thus help reduce drug resistance and adverse reactions and improve patients' quality of life.

[Study on residues of heavy metals and harmful elements in Qingqiao and Laoqiao based on chemometrics].

Forsythiae Fructus is divided into Qingqiao and Laoqiao due to different harvesting periods. So far, the accumulation of heavy metals in the two types of Forsythiae Fructus has not been reported. In this study, the residual levels of copper(Cu), lead(Pb), chromium(Cr), arsenic(As), cadmium(Cd) and mercury(Hg) in 29 batches of Laoqiao and 60 batches of Qingqiao were determined by inductively coupled plasma mass spectrometry(ICP-MS). The samples were collected from Shanxi, Shaanxi, Henan, and Hebei Provinces. In addition, the diversity and correlation of harmful elements in Qingqiao and Laoqiao were analyzed by multivariate statistical method. Furthermore, principal component analysis(PCA) was used to analyze the harmful elements concentrations of Qingqiao and Laoqiao. The results showed that there was a significant difference on the residual levels of heavy metals and harmful elements between Qingqiao and Laoqiao. Among them, the content of Pb in Laoqiao is significantly higher than that in Qingqiao(P<0.01), while the content of Cu is significantly lower than that in Qingqiao. However, the difference in harmful elements among different producing areas of Forsythiae Fructus is not significant. PCA analysis showed that Qingqiao and Laoqiao were successfully grouped into two categories. This study suggests significant difference in the residual levels of heavy metals and harmful elements between Qingqiao and Laoqiao. Besides, Forsythiae Fructus has a certain enrichment of Pb in the fruit ripening stage(Laoqiao). This study provides a reference for the quality classification and safety of Forsythiae Fructus.

[Effect and safety of electroacupuncture analgesia at the latent stage of labor on the epidural analgesia].

OBJECTIVE: To investigate the effect of electroacupuncture (EA) analgesia at the latent stage of labor on epidural analgesia, labor outcome and neonatal score so as to provide the reference to the clinical labor analgesia. METHODS: According to the random number table, 104 primipara of vaginal delivery were divided into three groups, named an EA group (37 cases), a sham-EA group (36 cases) and an epidural block group (31 cases). In the EA group, when the cervix opened up by 1 cm, Han's acupoint nerve stimulation apparatus was attached to bilateral Hegu (LI4) and bilateral Sanyinjiao (SP6) to achieve EA analgesia till the active stage (the cervix up 3 cm). In the sham-EA group, the procedure was same as the EA group, but with the sham-stimulation. In the epidural block, EA was not used in intervention. When the cervix opened up 3 cm, the epidural block and the patient-controlled epidural analgesia were all adopted in each group. The score of visual analogue scale (VAS) and the dosage of Sufentanil and Ropivacaine in patient-controlled analgesia pump at the different time points were compared among the groups. Respectively, in 1 h of EA stimulation (T1), 2 h of EA stimulation (T2), at the moment of epidural block (T3) and the complete open of the cervix (T6), the venous blood sample was collected to determine the concentration of beta-endorphin (beta-EP), and the use time of oxytocin, the bleeding amount and the state of newborn were recorded. RESULTS: There was no statistical difference in immediate of EA stimulation (T0) among the groups in VAS score (P>0.05). But, in T1 to T6, VAS score in the EA group was reduced obviously as compared with the sham-EA group and the epidural block group separately (P<0.05). There was no statistical difference in the use time of oxytocin among the three groups (P>0.05). In the sham-EA group and the epidural block group, bleeding amount during labor and in 24 h after labor was all higher than that of the EA group (P<0.05). In each group, the concentration of beta-EP in T3 and T6 was increased obviously as compared with that in T1 and T2 respectively (P<0.05). In the EA group, the concentration of beta-EP in T1 to T3 and in T6 was higher than that in sham-EA group and the epidural block group respectively (P<0.05). The dosage of Ropivacaine and Sufentanil in the EA group was less than that in either the sham-EA group or the epidural block group (P<0.05). There was no significant difference in amniotic fluid turbidity rate and Apgar score among the three groups (P>0.05). CONCLUSION: Electroacupuncture analgesia at the latent stage of labor effectively relieves labor pain of primipara, increases the concentration of beta-EP, enhances the effect of epidural block analgesia, reduces labor bleeding and has no side effect on newborn. The combination of electroacupuncture analgesia and the epidural anesthesia in the latent stage is applicable in the whole process of labor.

A chemiluminescence assay for determination of lysozyme based on the use of magnetic alginate-aptamer composition and hemin@HKUST-1.

Lysozyme aptamer-functionalized magnetic alginate hydrogel was prepared for separation and enrichment of lysozyme. Luminol-labeled aptamer was used as a signal tag, and the signal tag was adsorbed on magnetic carboxylated carbon nanotubes based on the π-interaction. When lysozyme was added, the aptamer specifically binds to the lysozyme, causing the signal tag to detach from the magnetic carboxylated carbon nanotubes. When the aptamer/lysozyme complex bound to the complementary single strand of aptamer on the hemin@HKUST-1, lysozyme was released. The released lysozyme can be recombined with the signal tag adsorbed on the magnetic carboxylated carbon nanotube, allowing more signal tag to be dispersed into the solution. Determination of lysozyme was achieved by releasing the luminol-labeled aptamer to generate a chemiluminescence signal at a wavelength of 425 nm. It was proved by experiments that the synthesized hemin@HKUST-1 had a strong catalytic effect on the luminol-NaOH-H2O2 system. The chemiluminescence signal was increased nearly 100 times. The complementary pairing allowed the luminol to be immobilized on the surface of hemin@HKUST-1. The generation and consumption of short-lived reactive oxygen species were concentrated on the surface of the MOFs, which improves the chemiluminescence efficiency. The introduction of hemin@HKUST-1 and DNA solved the defects of chemiluminescence analysis. The chemiluminescence assay was able to detect lysozyme with linear range of 1.05 × 10-6 U∙mg-1 (6.00 × 10-13 mol∙L-1)-1.25 × 10-2 U∙mg-1 (7.14 × 10-9 mol∙L-1); the detection limit was 3.50 × 10-7 U∙mg-1 (2.00 × 10-13 mol∙L-1) (R2 = 0.99). The recovery of lysozyme in spiked saliva samples was 97.4-102.8%. Graphical abstract Schematic presentation of chemiluminescence assay. Lysozyme (Lys) was captured by aptamer-modified magnetic sodium alginate (M-Alg-Apt); Glycine (pH = 2) as eluent for Lys. Luminol-modified Apt (Apt-luminol) as signal tag; magnetic carbon nanotubes (MCNTs) as adsorption matrix; cDNA was complementary to Apt; hemin@HKUST-1 as catalyst.

A "signal-on" chemiluminescence biosensor for thrombin detection based on DNA functionalized magnetic sodium alginate hydrogel and metalloporphyrinic metal-organic framework nanosheets.

A "signal-on" chemiluminescence biosensor was established for detecting thrombin. The thrombin aptamer1-functionalized magnetic sodium alginate (Malg-Apt1) hydrogel was synthesized by physical interaction between sodium alginate and Ca2+, and it was used in the biosensor for separating and enriching thrombin. Ethylenediamine tetraacetic acid (EDTA) was used to chelate with Ca2+ to dissolve the hydrogel and release thrombin. A metalloporphyrinic metal-organic framework nanosheet, named as Cu-TCPP(Co) MOFs, was prepared as signal amplification strategy. Cu-TCPP(Co) MOFs/Au-ssDNA (ssDNA: single-strand DNA) was synthesized for controllable further amplification of chemiluminescent signal. The thrombin aptamer2-functionalized magnetic carbon nanotubes (MCNTs-Apt2) were used as a matrix, and Cu-TCPP(Co) MOFs/Au-ssDNA was adsorbed on the MCNTs by the complementary pairing of the partial bases between ssDNA and Apt2. Compared with ssDNA, Apt2 has a stronger interaction with thrombin. Therefore, thrombin can trigger the release of Cu-TCPP(Co) MOFs/Au-ssDNA to achieve signal amplification. Under the optimal conditions, the biosensor could detect thrombin as low as 2.178 × 10-13 mol/L with the range from 8.934 × 10-13 to 5.956 × 10-10 mol/L and exhibited excellent selectively. Moreover, the "signal-on" chemiluminescence biosensor showed potential application for the detection of thrombin in body fluids.

[Effect of preemptive electroacupuncture on pain reactions in primiparous parturients during vaginal delivery].

OBJECTIVE: To investigate the effect of preemptive electroacupuncture (EA) plus epidural block (EB) on pain reactions and stress hormone levels in primiparous parturients during labor. METHODS: A total of 104 primiparous parturients undergoing vaginal delivery were randomly divided into PA group (n=31), sham EA group (n=36) and EA group (n=37). EA (2 Hz/100 Hz, a tolerable strength) was applied to bilateral Hegu (LI4) and Sanyinjiao (SP6) beginning from the latency of the 1st birth process when the orifice of uterus was opened to about 1 cm wider till the active stage when the orifice of the uterus opened about 3 cm wider. Patients in the sham EA group received shallow acupuncture needle stimulation (without cutaneous penetration of the needle tip, and without stimulation electric current output). All the patients of the 3 groups were given EB (1% Lidocaine, 0.05% Sufentanil and 0.1% Ropivacaine) and patient-controlled epidural analgesia (PCEA) when the orifice of the uterus opened about 3 cm wider. The pain severity was assessed by using Visual Analogue Scale (VAS) at time-points of immediately after EA, 1 h after EA, 2 h after EA, immediately after EB, 1 h after EB, 2 h after EB and full open of the uterus orifice. The contents of serum adrenocorticotrophic hormone (ACTH) and cortisol (COR) were assayed by using ELISA. RESULTS: There was no significant difference in the VAS score at the immediate time of post-EA among the three groups (P>0.05). Compared with the EB group, the VAS scores at all time-points except the immediate time of post-EA were significantly decreased in the EA group (P<0.05). One and 2 h after EB, and after full open of the uterus orifice, the VAS scores in the 3 groups were all evidently decreased (P<0.05), and those of the EA group were significantly lower than those of the sham EA and EB groups (P<0.05). The three groups had a significant increase in the levels of serum ACTH and COR at time-points of 1 and 2 h after EA, immediately after EB, and when the orifice of the uterus was fully opened (P<0.05), presenting a gradual increase of their level during the course of labor. Compared with the EB group, the levels of serum ACTH and COR contents were considerably decreased in the EA group (rather than in the sham EA group) (P<0.05). The dosages of Ropivacaine and Sufentanil, the total pressing times and the effective pressing times of PCEA pump were significantly lower in the EA group than those in the EB and sham EA groups (P<0.05). CONCLUSION: EA plus epidural analgesia, given during the latency period of labor, can effectively alleviate pain, inhibit stress response and reduce the dosage of anesthetics in primiparous parturients throughout the labor process.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

The clinical and pathological features of adefovir dipivoxil-related renal impairment
.

AIMS: To investigate the clinicopathological features and outcomes of adefovir dipivoxil (ADV)-related renal impairment in Chinese patients. MATERIALS AND METHODS: Clinical, pathological, and follow-up data from 15 patients with ADV-related renal impairment were studied. Proximal renal tubular dysfunction (PRTD) was defined by the presence of at least two of the following four abnormalities: hypophosphatemia, hypouricemia, nondiabetic glucosuria, and proteinuria. RESULTS: All patients were treated for 3 - 15 (mean 6.7) years with daily ADV of 10 mg. Renal impairment manifested as PRTD (12, 80%), elevated serum creatinine (12, 80%), and hematuria (2, 13.3%). Mild to moderate tubulointerstitial injury primarily affecting the proximal tubules by light microscopy, and enlarged, dysmorphic mitochondria with loss and disorientation of cristae by electron microscope were identified in all of our cases. Four patients had pathological evidence of IgA nephropathy. The phosphorus, serum uric acid, and creatinine levels were normalized after ADV cessation in 66.7% (8/12) of affected patients, 27.3% (3/11) of affected patients, and 25% (3/12) of affected patients, respectively; proteinuria was eliminated in 7 of 13 affected patients (53.8%); and glucosuria and hematuria both disappeared in all affected patients. These abnormalities had hardly any recovery, and even aggravated with new-onset glucosuria, new-onset hematuria in 3 patients who replaced ADV with tenofovir. CONCLUSION: Nephrotoxicity developed in patients undergoing long-term ADV treatment and was partially reversible after drug cessation. Tubulointerstitial lesions and heteromorphic mitochondria were the predominant pathological changes. Patients with ADV-induced renal impairment should replace ADV with other antiviral agents other than tenofovir.
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[Analysis of arsenic speciation in Sepiae Endoconcha and research on its limit standard].

Sepiae Endoconcha is a common marine animal medicine,which generally contains high concentration of arsenic( As).The Chinese Pharmacopoeia( 2010 edition,part I) stipulated that the total As content of Sepiae Endoconcha should not exceed 2 mg·kg~(-1),while this limit was revised to 10 mg·kg~(-1) in the 2015 edition. So far,there is no research on the speciation of As in Sepiae Endoconcha,which made it hard to accurately evaluate its security risk. In this study,32 batches of Sepiae Endoconcha from different sources were collected. The safety risk assessment was carried out by determining the total As content and As speciation,inorganic As[As( Ⅲ),As( Ⅴ) ]and organic As( MMA,DMA,As C,As B) by HPLC-ICP-MS,and then the limit standard was discussed. The results showed that As B was the main form of As in Sepiae Endoconcha,followed by DMA and As( Ⅴ) ． Of the 32 batches of Sepiae Endoconcha,9 batches( accounting for 28%) were detected possessing i As. The maximum concentration of As( Ⅲ) was 103. 3 µg·kg~(-1),and the maximum concentration of As( Ⅴ) was 222. 4 µg·kg~(-1). According to the limit of i As in food,18. 75% of the samples exceeded the standard. The results indicate that there is no simple positive correlation between total As and As morphology in Sepiae Endoconcha. Besides,there is a risk in the total As limit,especially after the relaxation of the total As limit. The problem of high i As content caused by pollution and other factors is difficult to regulate. Since the toxicity of inorganic As is much higher than that of organic As,it is of great practical significance to establish inorganic As form limits in Sepiae Endoconcha.

Aqueous Extract of Semen Ziziphi Spinosae Exerts Anxiolytic Effects during Nicotine Withdrawal via Improvement of Amygdaloid CRF/CRF1R Signaling.

Anxiety during nicotine withdrawal (NicW) is a key risk factor for smoking relapse. Semen Ziziphi Spinosae (SZS), which is a prototypical hypnotic-sedative herb in Oriental medicine, has been clinically used to treat insomnia and general anxiety disorders for thousands of years. Thus, the present study evaluated the effects of the aqueous extract of SZS (AESZS) on NicW-induced anxiety in male rats that received subcutaneous administrations of nicotine (Nic) (0.4 mg/kg, twice a day) for 7 d followed by 4 d of withdrawal. During NicW, the rats received four intragastric treatments of AESZS (60 mg/kg/d or 180 mg/kg/d). AESZS dose-dependently attenuated NicW-induced anxiety-like behaviors in the elevated plus maze (EPM) tests and 180 mg/kg/d AESZS inhibited NicW-induced increases in plasma corticosterone. Additionally, the protein and mRNA expressions of corticotropin-releasing factor (CRF) and CRF type 1 receptor (CRF1R) increased in the central nucleus of the amygdala (CeA) during NicW, but these changes were suppressed by 180 mg/kg/d AESZS. A post-AESZS infusion of CRF into the CeA abolished the attenuation of anxiety by AESZS and 180 mg/kg/d AESZS suppressed NicW-induced increases in norepinephrine and 3-methoxy-4-hydroxy-phenylglycol levels in the CeA. The present results suggest that AESZS ameliorated NicW-induced anxiety via improvements in CRF/CRF1R and noradrenergic signaling in the CeA.

Identifying external nutrient reduction requirements and potential in the hypereutrophic Lake Taihu Basin, China.

Reducing external nutrient loads is the first step for controlling eutrophication. Here, we identified external nutrient reduction requirements and potential of strategies for achieving reductions to remediate a eutrophic water body, Lake Taihu, China. A mass balance approach based on the entire lake was used to identify nutrient reduction requirements; an empirical export coefficient approach was introduced to estimate the nutrient reduction potential of the overall program on integrated regulation of Taihu Lake Basin (hereafter referred to as the "Guideline"). Reduction requirements included external total nitrogen (TN) and total phosphorus (TP) loads, which should be reduced by 41-55 and 25-50%, respectively, to prevent nutrient accumulation in Lake Taihu and to meet the planned water quality targets. In 2010, which is the most seriously polluted calendar year during the 2008-2014 period, the nutrient reduction requirements were estimated to be 36,819 tons of N and 2442 tons of P, and the potential nutrient reduction strategies would reduce approximately 25,821 tons of N and 3024 tons of P. Since there is a net N remaining in the reduction requirements, it should be the focus and deserves more attention in identifying external nutrient reduction strategies. Moreover, abatement measures outlined in the Guideline with high P reduction potential required large monetary investments. Achieving TP reduction requirement using the cost-effective strategy costs about 80.24 million USD. The design of nutrient reduction strategies should be enacted according to regional and sectoral differences and the cost-effectiveness of abatement measures.

Randomized, Double-Blind, Placebo-Controlled Trial of Shuanghua Baihe Tablets to Prevent Oral Mucositis in Patients With Nasopharyngeal Cancer Undergoing Chemoradiation Therapy.

PURPOSE: Oral mucositis is a common unpreventable complication associated with chemoradiation therapy. Shuanghua Baihe tablets have been approved by the Chinese Food and Drug Administration for treating recurrent oral mucosa ulceration. This study assessed whether Shuanghua Baihe tablets could prevent oral mucositis during chemoradiation therapy for locally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS: This multicenter, randomized, double-blind, placebo-controlled trial was conducted at 11 hospitals in China between January 22, 2014, and September 21, 2015. Eligible patients (N=240, 18-70 years old) with pathologically diagnosed locally advanced nasopharyngeal carcinoma were randomly assigned (computer-block randomization; 1:1) to receive Shuanghua Baihe tablets or a placebo (4 tablets, 3 times a day, for 7 weeks) at the initiation of chemoradiation therapy. Administration of Shuanghua Baihe tablets could be ended if grade 3 or higher oral mucositis developed and patients were unwilling to continue taking the drug. The primary endpoints were oral mucositis incidence and latency. RESULTS: The incidence of oral mucositis during this study was significantly lower in the Shuanghua Baihe group (85.0%; 95% confidence interval [CI], 78.6%-91.4%) than in the placebo group (96.6%; 95% CI, 93.4%-99.9%; P=.0028). The median latency period was 28 days in the Shuanghua Baihe group and 14 days in the placebo group (hazard ratio, 0.17; 95% CI, 0.12-0.23; P<.0001). Compared with placebo, Shuanghua Baihe tablets significantly reduced the oral mucositis severity scores recorded by the investigators (Oral Mucositis Score, 24.0 [range, 0.0-67.8] vs 57.5 [range, 0.0-98.0]; P<.0001), full-time nurses (Oral Assessment Guide score, 462.0 [range, 392.0-664.7] vs 520.4 [range, 392.0-714.0]; P<.0001), and patients (score for soreness of mouth and throat, 4.0 [range, 0-10] vs 6.0 [range, 0-10]; P<.0001). No serious adverse events were observed, and the incidence of mild or moderate gastrointestinal adverse events associated with Shuanghua Baihe tablets was 3.3%. The short-term response rate was similar in patients receiving Shuanghua Baihe tablets and those receiving placebo during chemoradiation therapy during this study. CONCLUSIONS: Shuanghua Baihe tablets reduced the occurrence, latency, and severity of oral mucositis in patients with nasopharyngeal cancer during chemoradiation therapy treatment.

Astragaloside IV inhibits metastasis in hepatoma cells through the suppression of epithelial-mesenchymal transition via the Akt/GSK-3ß/ß-catenin pathway.

Our previous studies demonstrated that traditional Chinese herbal medicine 'Songyou Yin' inhibited the growth and invasion of hepatocellular carcinoma (HCC) cells, and altered epithelial­mesenchymal transition (EMT) markers in oxaliplatin­treated HCC tissues and cell lines. In the present study, we aimed to explore whether astragaloside IV (AS-IV), a component of 'Songyou Yin', can affect the growth and invasion of HCC cells and the underlying mechanism involved. Human HCC cell lines Huh7 and MHCC97-H, with low and high metastatic potential, respectively, were treated with increasing doses of AS-IV. The Cell Counting Kit-8 (CCK-8), plate clone formation, Transwell, wound healing and immunofluorescence assays were used to investigate the effects of AS-IV on HCC cell proliferation, migration and invasion. The protein expression levels were analyzed by western blotting and immunofluorescence assay. The CCK-8 and plate clone formation assays showed that AS-IV had little effect on the proliferation of HCC cells in vitro. However, the Transwell and wound healing assays demonstrated that AS-IV inhibited the migration and invasion of HCC cells in a dose-dependent manner and the morphology of HCC cells was altered from spindle into oval shaped in the AS-IV pretreated groups. The upregulation of E-cadherin and downregulation of N-cadherin, vimentin, α-SMA and Slug were also observed in the AS-IV pretreated groups. Additionally, AS-IV treatment resulted in a profound decrease in the phosphorylated forms of Akt and GSK-3ß, which in turn inhibited the expression of ß-catenin. Thus, we conclude that AS-IV attenuates the invasive and migratory abilities of HCC cells through the inhibition of EMT by targeting the Akt/GSK-3ß/ß-catenin pathway.

Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study.

Objective. To evaluate the efficacy and safety of Kangfuxin Solution, a pure Chinese herbal medicine, on mucositis induced by chemoradiotherapy in nasopharyngeal carcinoma patients. Methods. A randomized, parallel-group, multicenter clinical study was performed. A total of 240 patients were randomized to receive either Kangfuxin Solution (test group) or compound borax gargle (control group) during chemoradiotherapy. Oral mucositis, upper gastrointestinal mucositis, and oral pain were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and the Verbal Rating Scale (VRS). Results. Of 240 patients enrolled, 215 were eligible for efficacy analysis. Compared with the control group, the incidence and severity of oral mucositis in the test group were significantly reduced (P = 0.01). The time to different grade of oral mucositis occurrence (grade 1, 2, or 3) was longer in test group (P < 0.01), and the accumulated radiation dose was also higher in test group comparing to the control group (P < 0.05). The test group showed lower incidence of oral pain and gastrointestinal mucositis than the control group (P < 0.01). No significant adverse events were observed. Conclusion. Kangfuxin Solution demonstrated its superiority to compound borax gargle on mucositis induced by chemoradiotherapy. Its safety is acceptable for clinical application.

Baicalin ameliorates experimental inflammatory bowel disease through polarization of macrophages to an M2 phenotype.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract. Baicalin, originally isolated from the root of the Chinese herb Huangqin (Scutellaria baicalensis Georgi) and its main active ingredient, has a protective effect against inflammatory responses in several diseases. The present study investigated the effects of baicalin on macrophage polarization and its therapeutic role in IBD. Murine peritoneal macrophages and mice with colitis were treated with baicalin. Macrophage subset distribution, M1 and M2 macrophage-associated mRNA expression, and interferon regulatory factor 4 and 5 (IRF4 and IRF5) expression were analyzed. siRNA transfection into mouse peritoneal macrophages was utilized to suppress IRF4. Fluorescence-activated cell sorting, western blot, and real-time PCR analyses were performed. Baicalin (50µM) limited lipopolysaccharide (LPS)-induced M1 macrophage polarization; decreased LPS-induced tumor necrosis factor α, interleukin (IL)-23, and IRF5 expression; and increased IL-10, arginase-1 (Arg-1), and IRF4 expression. siRNA-mediated IRF4 silencing significantly impaired baicalin activity. Furthermore, pretreatment with baicalin (100mg/kg) in mice with dextran sodium sulfate (DSS)-induced colitis ameliorated the severity of colitis and significantly decreased the disease activity index (baicalin group, 3.33±0.52 vs. DSS group, 5.67±1.03). Baicalin (100mg/kg) also repressed IRF5 protein expression and promoted IRF4 protein expression in the lamina propria mononuclear cells, and induced macrophage polarization to the M2 phenotype. In summary, our results showed that baicalin upregulates IRF4 protein expression and reverses LPS-induced macrophage subset redistribution. Thus, baicalin alleviates DSS-induced colitis by modulating macrophage polarization to the M2 phenotype.

Genetic discovery for oil production and quality in sesame.

Oilseed crops are used to produce vegetable oil. Sesame (Sesamum indicum), an oilseed crop grown worldwide, has high oil content and a small diploid genome, but the genetic basis of oil production and quality is unclear. Here we sequence 705 diverse sesame varieties to construct a haplotype map of the sesame genome and de novo assemble two representative varieties to identify sequence variations. We investigate 56 agronomic traits in four environments and identify 549 associated loci. Examination of the major loci identifies 46 candidate causative genes, including genes related to oil content, fatty acid biosynthesis and yield. Several of the candidate genes for oil content encode enzymes involved in oil metabolism. Two major genes associated with lignification and black pigmentation in the seed coat are also associated with large variation in oil content. These findings may inform breeding and improvement strategies for a broad range of oilseed crops.