Wake-Promoting Effect of Bloodletting Puncture at Hand Twelve Jing-Well Points in Acute Stroke Patients: A Multi-center Randomized Controlled Trial.

OBJECTIVE: To assess the effect and safety of bloodletting puncture at hand twelve Jing-Well points (HTWPs) in acute stroke patients with conscious disturbance. METHODS: In this multi-center and randomized controlled trial, 360 patients suffered from ischemic or hemorrhagic stroke with conscious disturbance within 48 h from the onset of symptom were divided into bloodletting (180 cases) and control (180 cases) groups using a block randomization. Patients in both groups received routine Western medicine, and patients in the bloodletting group received additional bloodletting puncture at HTWPs on admission immediately before conventional treatment. The primary outcome measure was Glasgow Coma Scale (GCS) score and the secondary outcomes included blood pressure, respiratory rate and pulse rate. All variables were evaluated at baseline (before bloodletting), 0 (after bloodletting immediately), 15, 30, 50 and 80 min post bloodletting. RESULTS: At 80 min post bloodletting, the proportion of patients with improved consciousness in the bloodletting group was greater than the control group (P<0.05). In the separate analysis of moderate consciousness disturbance subgroup, bloodletting therapy benefited ischemic patients, and improved the eye and language response of GCS score at 15, 30, 50, 80 min post bloodletting (P<0.05 or P<0.01). No significant differences were observed regarding the secondary outcomes between two groups (P>0.05). CONCLUSION: The bloodletting puncture at HTWPs was safe and could improve conscious levels of ischemic stroke patients, highlighting a first-aid intervention for acute stroke. (Registration No. ChiCTR-INR-16009530).

Antidepressant-like effects of Xiaochaihutang in perimenopausal mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT) is a traditional Chinese medicine prescription for thousand years in China. Our previous researches show that XCHT has antidepressant-like effects in several depression models, but effect and mechanism of XCHT in perimenopausal depression are still vague. AIM OF THE STUDY: To reveal the antidepressant-like effect and mechanism of XCHT in perimenopausal mice. MATERIALS AND METHODS: Perimenopausal depression model is executed by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Tail suspension test (TST), forced swim test (FST), elevated plus-maze (EPM), novelty suppressed feeding (NSF) and locomotor activity are used to assess antidepressant-like effects of XCHT. The Level of estradiol (E2), follicle-stimulating hormone (FSH), gonadotrophin releasing hormone (GnRH), corticosterone (CORT), adrenocorticotrophic hormone (ACTH) and corticotropin releasing hormone (CRH) are evaluated by ELISA. Antidepressant mechanisms of XCHT in OVX-CUMS mice are analyzed by 5-hydroxytryptamine (5-HT), tryptophan hydroxylase 2 (TPH2) and estrogen receptor α and ß (ERα/ß). RESULTS: The results show that OVX-CUMS significantly increases the immobility time in TST and FST, increases latency to feed, decreases food consumption in NSF and both the time spend and number of entries in open arms in EPM. While, oral administration of XCHT can significantly normalize above depression-like behaviors in OVX-CUMS mice. Moreover, XCHT also remarkably normalized levels of 5-HT, 5-HIAA, E2, GnRH, CORT, ACTH and CRH in OVX-CUMS mice. Finally, the expression of ERß and TPH2 are decreased by OVX-CUMS in prefrontal cortex and hypothalamus, and XCHT can restore these decrease. CONCLUSION: Current findings suggest XCHT can alleviate perimenopausal depression-like behaviors, restore 5-HT and hormones in OVX-CUMS mice, which may be related to normalizing the functions of HPA/HPO axis and enhancing expression of ERß and TPH2 in prefrontal cortex and hypothalamus.

Comparison of effectiveness between warm acupuncture with local-distal points combination and local distribution points combination in breast cancer-related lymphedema patients: a study protocol for a multicenter, randomized, controlled clinical trial.

BACKGROUND: Lymphedema is the most common complication after breast cancer treatment, but management of lymphedema remains a clinical challenge. Several studies have reported the beneficial effect of acupuncture for treating breast cancer-related lymphedema (BCRL). Our objective is to verify the effectiveness of warm acupuncture on BCRL and compare the effectiveness of a local distribution acupoint combination with a local-distal acupoint combination for BCRL. METHODS: This is a study protocol for a multicenter, three-arm parallel, assessor blinded, randomized controlled trial. A total of 108 participants diagnosed as BCRL will be randomly allocated in equal proportions to a local distribution acupoint (LA) group, a local-distal acupoint (LDA) group, or a waiting-list (WL) group. The LA and LDA groups will receive 20 acupuncture treatment over 8 weeks with local distribution acupoint combination and local-distal acupoint combination, respectively. The WL group will receive acupuncture treatment after the study is concluded. The primary outcome is the mean change in inter-limb circumference difference from baseline to week 8. The secondary outcomes include volume measurement, skin hardness, common terminology criteria for adverse events 4.03 (edema limbs criteria), stages of lymphedema from the International Society of Lymphology, Disabilities of the Arm, Shoulder and Hand questionnaire, and the Medical Outcome Study 36-item Short-form Health Survey. DISCUSSION: This study aims to provide data on warm acupuncture as an effective treatment for BCRL and at the same time compare the effectiveness of different acupoint combinations. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT03373474 . Registered on 14th December 2017.

Quantitative proteomics reveal antidepressant potential protein targets of xiaochaihutang in corticosterone induced model of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT), one of famous Chinese herbal prescription for treating Shaoyang symptom, has been used successfully in depressive disorders for many years. Our laboratory has demonstrated that XCHT remarkably alleviated various depressive behaviors induced by several depressive animal models, but previous studies only focused on one or several protein targets, lacked dynamic change and interrelation of proteins. Therefore, potential protein targets and mechanisms are required further systematic investigation. AIM OF THE STUDY: To discover and assess the differentially expressed proteins (DEPs) of hippocampus after oral administration of XCHT in corticosterone (CORT) induced model of depression by using isobaric tags for relative and absolute quantification (iTRAQ) analysis. MATERIALS AND METHODS: The antidepressant effects of XCHT were assessed by two behavioral despair models (forced swimming test and tail suspension test) in CORT induced model of depression. The DEPs of hippocampus after XCHT treatment were investigated by iTRAQ analysis. Potential protein targets and mechanisms were assessed by gene ontology (GO), Kyoto encyclopedia of gene and genomes (KEGG) and protein-protein interaction (PPI) network. RESULTS: Our data demonstrated XCHT could significantly improve depressive behaviors. A total of 241 DEPs were identified after XCHT treatment, including 68 up regulation and 173 down regulation proteins. GO enrichment results indicated that XCHT mainly regulated intracellular structural proteins involved in cellular response to stress, transferase activity and steroid hormone. KEGG enrichment analysis showed that endocytosis might be the principal pathway of XCHT on depression. PPI analysis predicted cell division cycle and apoptosis regulator protein 1 (Ccar1) and Calretinin (Calb2) might play the central roles in XCHT's antidepressant network. CONCLUSION: Our results indicate that XCHT plays the important roles in antidepressant action by restoring DEPs, which results in the dysregulation of hippocampal neurogenesis, neurotransmitter and steroid hormone. The current results wish to provide novel perspectives for revealing the potential protein targets of XCHT on depression.

Efficacy differences of electroacupuncture with single acupoint or matching acupoints for chemotherapy-induced nausea and vomiting: study protocol for a randomized controlled trial.

BACKGROUND: Previous studies have shown that acupuncture is beneficial for the alleviation of chemotherapy-induced nausea and vomiting. However, there is a lack of clinical evidence concerning the effects of acupoint-matching on chemotherapy-induced nausea and vomiting. METHODS/DESIGN: This is a parallel randomized controlled trial to evaluate the occurrence of nausea and vomiting after chemotherapy (the incidence of nausea and vomiting, frequency, VAS score, RINVR rating) as the main outcome for cancer. Quality of life, anxiety and depression scores are the secondary outcomes. Quality of life, anxiety and depression scores are the secondary phase. Use of remedy drugs, routine blood examination, and blood biochemical tests are the safety evaluation. We also compare the different effects of ST36 (single acupoint), CV12 (single acupoint), and ST36-CV12 matching groups. DISCUSSION: The results of this trial are expected to explore the effects of matching different acupoints and to offer biologic plausibility for the use of acupuncture in the treatment of chemotherapy-induced nausea and vomiting (CINV). TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov NCT02195921 , The date of registration was 17 July 2014.

Chronic Toxicity Test in Cynomolgus Monkeys For 98 Days with Repeated Intravenous Infusion of Cynomolgus Umbilical Cord Mesenchymal Stem Cells.

BACKGROUND/AIMS: Stem cell-based therapy is attractive in many clinical studies, but current data on the safety of stem cell applications remains inadequate. This study observed the safety, immunological effect of cynomolgus monkey umbilical cord mesenchymal stem cells (mUC-MSCs) injected into cynomolgus monkeys, in order to evaluate the safety of human umbilical cord mesenchymal stem cells (hUC-MSCs) prepared for human clinical application. METHODS: Eighteen cynomolgus monkeys were divided into three groups. Group 1 is control group, Group 2 is low-dose group, Group 3 is high-dose group. After repeated administrations of mUC-MSCs, cynomolgus monkeys were observed for possible toxic reactions. RESULTS: During the experiment, no animal died. There were no toxicological abnormalities in body weight, body temperature, electrocardiogram, coagulation and pathology. In the groups 2 and 3, AST and CK transiently increased, and serum inorganic P slightly decreased. All animals were able to recover at 28 days after the infusion was stopped. In the groups 2 and 3, CD3+ and IL-6 levels significantly increased, and recovery was after 28 days of infusion. There were no obvious pathological changes associated with the infusion of cells in the general and microscopic examinations. CONCLUSIONS: The safe dosage of repeated intravenous infusion of mUC-MSCs in cynomolgus monkeys is 1.0 × 107/kg, which is 10 times of that in clinical human use.

Xiaochaihutang attenuates depressive/anxiety-like behaviors of social isolation-reared mice by regulating monoaminergic system, neurogenesis and BDNF expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT), as a classical herbal formula for the treatment of "Shaoyang syndrome" has been demonstrated to exert an antidepressant effect in multiple animal models of depression as shown in our previous studies. However, the effects of XCHT on social isolation (SI)-reared mice have not been investigated. This study aims to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice, and its implicated mechanisms, including alterations in the monoaminergic system, neurogenesis and neurotrophin expression. MATERIALS AND METHODS: Male C57 BL/6J mice (aged 4 weeks after weaning) were reared isolatedly for 8 weeks and XCHT (0.8, 2.3, 7.0g/kg) were given by gavage once a day. Forced swimming test (FST), tail suspension test (TST), open field test (OFT), elevated-plus maze test (EPM) and intruder-induced aggression test were used to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice after administration of XCHT for 6 weeks. HPLC-MS/MS was performed to quantify the levels of neurotransmitters in the hippocampus by in vivo microdialysis, while western immunoblotting was used to evaluate the action of XCHT on the synthesis, transport and degradation of monoamine neurotransmitters. Immunofluorescence was used to study the effects of XCHT on neurogenesis and neurotrophin expression, including Ki-67, DCX, BrdU and BDNF. RESULTS: Our results showed that administration of XCHT (0.8, 2.3 and 7.0g/kg) for 6 weeks significantly attenuated the increase in immobility time in TST and FST, improved the anxiety-like behaviors in OFT and EPM, and improved the aggressive behaviors of SI-reared mice. XCHT significantly elevated monoamine neurotransmitters levels and inhibited 5-HT turnover (5-HIAA/5-HT) in hippocampal microdialysates of SI-reared mice. In addition, we found XCHT enhanced monoamine neurotransmitter synthesis enzymes (TPH2 and TH) expressions, inhibited serotonin transporter (SERT) expression and decreased monoamine neurotransmitter degradation enzyme (MAOA) expression in the hippocampus of SI-reared mice for the first time. Moreover, XCHT significantly augmented hippocampal neurogenesis and BDNF expression in hippocampus of SI-reared mice. CONCLUSIONS: Our results showed for the first time that XCHT improved depressive/anxiety-like behaviors of SI-reared mice by regulating the monoaminergic system, neurogenesis and neurotrophin expression. The findings indicate that XCHT may have a therapeutic application for early-life stress model of depression and in turn provide further evidence supporting XCHT a novel potential antidepressant from a distinct perspective.

Antidepressant-like effects of Xiaochaihutang in a neuroendocrine mouse model of anxiety/depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is often observed in the pathophysiology of depression. Antidepressant therapy can restore hippocampal neurogenesis to rescue the HPA axis regulation defects. Xiaochaihutang (XCHT), a famous Chinese herbal formula, has been used clinically in depressive disorders in China. Our previous studies have demonstrated XCHT improved depressive-like behaviors in chronic unpredictable mild stress rat, but the underlying mechanisms of XCHT on hippocampal neurogenesis and the HPA axis were still unclear. MATERIALS AND METHODS: We used chronic corticosterone (CORT)-induced mouse model of anxiety/depression to investigate antidepressant-like effects of XCHT by several physical and behavioral testing, including body weight, coat state, open field test, elevated plus maze, tail suspension test and forced swimming test. The integrity of negative feedback function on HPA axis was assessed by the dexamethasone (DEX) suppression test. In addition, Ki-67 and doublecortin (DCX) were performed to assess hippocampal cell proliferation and neurogenesis by immunohistochemistry. Chemical profile of active constituents in brain after oral administration of XCHT was revealed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Our results showed that oral administration of XCHT (2.3, 7 and 21g/kg) for 30 days remarkably normalized chronic CORT-induced the slowness in weight gain, the deterioration in coat state, the escape behavior in open field test and elevated plus maze, and the increase of immobility time in tail suspension test and forced swimming test. Moreover, XCHT significantly reversed chronic CORT-induced the reduction of DEX-induced plasma corticosterone/c-Fos suppression and Ki-67/DCX positive cells. Finally, a total 13 potential active constituents in brain were identified by UPLC-MS/MS after oral administration of XCHT, including 10 prototype components and 3 metabolites. CONCLUSIONS: Our findings showed that XCHT could remarkably alleviate chronic CORT-induced anxiety/depression-like behaviors, which were probably attribute to promoting hippocampal neurogenesis and remodeling the integrity of the negative feedback loop on HPA axis. The constituents identified in brain might contribute to understanding the therapeutic basis of XCHT on depression.

Establishing a tree shrew model of systemic lupus erythematosus and cell transplantation treatment.

BACKGROUND: The establishment of a tree shrew model for systemic lupus erythematosus (SLE) provides a new method to evaluate the pathogenesis of autoimmune diseases. METHODS: Eighty tree shrews were randomly divided into four groups receiving either an intraperitoneal injection of pristane, lipopolysaccharide (LPS), or pristane and LPS, or no injection. Three weeks after injection, the SLE model tree shrews were divided into the model group and the treatment group. Tree shrews in the treatment group and the normal control group were infused with umbilical cord mesenchymal stem cells (UC-MSCs). The cells were labeled with DiR. Two weeks after transplantation, three groups of tree shrews were analyzed for urine protein, serum antinuclear antibodies and antiphospholipid, and inflammatory cytokine antibody microarray detection. The heart, liver, spleen, lung, and kidney were collected from the three groups and subjected to hematoxylin and eosin (HE) staining and detection of renal immune complex deposition. RESULTS: HE staining indicated pathology in the model group. Red fluorescence revealed immune complex deposition in the kidneys from the model group. CONCLUSIONS: The combined intraperitoneal injection of pristane and LPS is the best way to induce SLE pathological changes. The pathological changes improved after UC-MSC treatment.

Neurological mechanism of Xiaochaihutang's antidepressant-like effects to socially isolated adult rats.

OBJECTIVES: Xiaochaihutang (XCHT) has antidepressant effects in multiple animal models of depression in our previous studies. But the antidepressant effects and exact mechanisms of XCHT in a rat model of chronic social isolation stress (CSIS) have never been studied. We therefore aimed to investigate the effects of XCHT on depressive/anxiety-related behaviours of CSIS-exposed rats and understand the neurological mechanism involving neurogenesis. METHODS: We established the CSIS model and then investigated the effects of XCHT on behavioural change. HPLC-MS/MS was adopted to quantify neurotransmitter levels in the cerebrospinal fluid (CSF). Immunofluorescence technology was used to study the effects of XCHT on neurogenesis; while expressions of 5-HT1A receptor signalling pathway in the hippocampus were measured using Western blotting. KEY FINDINGS: Xiaochaihutang significantly alleviated depressive/anxiety-like behaviours of CSIS-exposed rats. XCHT significantly regulated levels of monoamine neurotransmitters in the CSF without affecting Glu, GABA and ACh. XCHT also significantly increased neurogenesis in CSIS-exposed rats. Additionally, XCHT reversed CSIS-induced decrease of 5-HT1A receptor expression and promoted the expression of BDNF in the hippocampus. CONCLUSION: Our results suggest that XCHT could significantly regulate the depressive/anxiety-like behaviours induced by CSIS, which are likely attributed to the promotion of hippocampal neurogenesis and neurotrophin expressions through the activation of serotonergic system.

Efficacy and safety of electroacupuncture with different acupoints for chemotherapy-induced nausea and vomiting: study protocol for a randomized controlled trial.

BACKGROUND: Many patients experience nausea and vomiting during chemotherapy treatment. Evidence demonstrates that electroacupuncture is beneficial for controlling chemotherapy-induced nausea and vomiting (CINV). However, the acupoint or matching acupoint with the best efficacy for controlling CINV still remains unidentified. METHODS/DESIGN: This study consists of a randomized controlled trial (RCT) with four parallel arms: a control group and three electroacupuncture groups (one with Neiguan (PC6), one with Zhongwan (CV12), and one with both PC6 and CV12). The control group received standard antiemetic only, while the other three groups received electroacupuncture stimulation with different acupoints besides the standard antiemetic. The intervention is done once daily from the first day (day 1) to the fourth day (day 4) during chemotherapy treatment. The primary outcome measures include frequency of nausea, vomiting and retching. The secondary outcome measures are the grade of constipation and diarrhea, electrogastrogram, assessment of quality of life, assessment of anxiety and depression, and other adverse effects during the chemotherapy. Assessments are scheduled from one day pre-chemotherapy (day 0) to the fifth day of chemotherapy (day 5). Follow-ups are done from day 6 to day 21. DISCUSSION: The aim of this study is to evaluate the efficacy and safety of electro-acupuncture with different acupoints in the management of CINV. TRIAL REGISTRATION: The register number of randomized controlled trial is NCT02195908 . The date of registration was 21 July 2014.

[The effect of protein metabolism and immunologic function of glutamine after operation in elder gastrointestinal tumor].

AIM: To explore the effect of protein metabolism and immunologic function of glutamine after operation in elder gastrointestinal tumor. METHODS: Form march 2007 to 2010, 87 cases of elder gastrointestinal tumor were given parenteral nutrition and glutamine 0.6 g/( Kg x d).The period of treatment were 8 days. IgA, IgG, IgM were CD4, measured by single immunodiffusion, CD3(+), CD4(+), CD8(+), CD4(+) /CD8(+) were measured by immunohistochemical method, and the index(Alb, PAB, TF, nitrogen equilibrium) were monitored the proteid catabolism distribution. RESULTS: After the treatment, CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+), IgG, IgA, IgM were evidently declined( P <0.05). Alb, PAB, TF were evidently declined in 4 days postoperatively (P < 0.05), the restore were more obvious in 8 days postoperatively (P < 0. 05). Nitrogen equilibrium was worse in the early postoperative and the restore were more obvious in 8 days postoperatively (P < 0.05). CONCLUSION: Glutamine can improve patient's nutrition, enhance their immunologic function.

Effects of brucine combined with glycyrrhetinic acid or liquiritin on rat hepatic cytochrome P450 activities in vivo / 药学学报

Abstract: The activities of four CYP450 enzymes (CYP3A, 1A2, 2El and 2C) and the mRNA expression levels of CYP1A2, 2El, 2Cll and 3A1 in rat liver were determined after Wistar rats were orally administered with brucine (BR) at three dosage levels (3, 15 and 60 mg.kg-1 per day) and the high dose of BR combined with glycyrrhetinic acid (GA, 25 mg.kg-1 per day) or liquiritin (LQ, 20 mg.kg-1 per day) for 7 consecutive days. Compared with the control, brucine caused 24.5% and 34.6% decrease of CYP3A-associated testosterone 6beta-hydroxylation (6betaTesto-OH) and CYP2C-associated tolbutamide hydroxylation (Tol-OH), respectively, and 146.1% increase of CYP2El-associated para-nitrophenol hydroxylation (PNP-OH) at the high dose level. On the other hand, (BR+GA) caused 51.4% and 33.5% decrease, respectively, of CYP2El-associated PNP-OH and CYP1A2-associated ethoxyresorufin-O-de-ethylation (EROD) as compared with the high dose of BR group. Meanwhile, (BR+LQ) caused 41.1% decrease of CYP2El-associated PNP-OH and 37.7% increase of CYP2C-associated Tol-OH. The results indicated that the co-administration of BR with GA or LQ had effect on mRNA expression and activities of the CYP450 enzymes mentioned above to some extent, and the in vivo antagonism of LQ on BR-induced CYPs adverse effects and the in vivo inhibitory action of GA on CYP2E1 and 1A2 might play an important role in the detoxification of Radix Glycyrrhizae against Strychnos nux-vomica L.

Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid.

Up-regulation of folate receptor (FR) type-beta in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-beta in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent in FR-beta from AML cells from patient marrow, which bound folate. From flow cytometric analysis of 78 AML bone marrow specimens of different subtypes, 68% expressed FR-beta, most of which were also CD34+. In model cell lines that are FR - (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR + (KG-1, L1210 JF, and recombinant CHO-FR-beta), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-beta-expressing KG-1 human AML cells, treatment with ATRA further increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery in FR-beta + AMLs.