Effect of acupuncture timing on functional impairment at 6 months post-onset in patients with first-ever stroke: a prospective cohort study. / é’ˆåˆºæ—¶æœºå¯¹é¦–æ¬¡ä¸­é£Žæ‚£è€ å‘ç— åŽ6ä¸ªæœˆåŠŸèƒ½éšœç¢çš„å½±å“ï¼šå‰çž»æ€§é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: To observe the effect of acupuncture intervention in the acute phase on functional impairment at 6 months post-onset in patients with first-ever stroke, and provide evidence for selecting optimal acupuncture timing in the real-world setting. METHODS: A total of 601 patients with first-ever stroke were divided into an acute intervention group (onset within 14 days, 256 cases) and a non-acute intervention group (onset between 15 and 90 days, 345 cases) based on whether they received acupuncture treatment in the acute phase. The assessments were conducted at baseline and 6 months post-onset, including modified Rankin scale (mRS) score, total number of acupuncture sessions, total number of combined therapies (moxibustion, cupping, tuina and rehabilitation treatment), recurrence, death events and disability. Logistic regression analysis was used to analyze the association between acupuncture timing and the risk of disability at 6 months post-onset. The mRS transition method was employed to assess the effect of acupuncture timing on functional improvement at 6 months post-onset. RESULTS: Without adjusting for confounding factors, compared with the non-acute intervention group, the patients in the acute intervention group had reduced risk of disability at 6 months post-onset (OR=0.434, 95%CI: 0.309-0.609, P=0.000). After adjusting for variables i.e. severity of illness, number of acupuncture sessions, and number of cupping sessions, compared with the non-acute intervention group, the patients in the acute intervention group had reduced risk of disability at 6 months post-onset (OR=0.588, 95%CI: 0.388-0.890, P=0.012). After adjusting for all confounding factors, including severity of illness, number of acupuncture sessions, number of cupping sessions, gender, smoking and drinking history, comorbidities, and diagnosis, compared with the non-acute intervention group, the patients in the acute intervention group continued to have a reduced risk of disability at 6 months post-onset (OR=0.629, 95%CI: 0.408-0.971, P=0.036). Both groups showed an overall shift towards lower mRS scores at 6 months post-onset compared to baseline, with a more significant shift towards lower scores in the acute intervention group than the non-acute intervention group. CONCLUSIONS: In the real-world setting, acupuncture intervention in the acute phase in patients with first-ever stroke, compared to acupuncture intervention after the acute phase, reduces the risk of disability at 6 months post-onset and improves functional status.

Application and underlying mechanism of acupuncture for the nerve repair after peripheral nerve injury: remodeling of nerve system.

Peripheral nerve injury (PNI) is a structural event with harmful consequences worldwide. Due to the limited intrinsic regenerative capacity of the peripheral nerve in adults, neural restoration after PNI is difficult. Neurological remodeling has a crucial effect on the repair of the form and function during the regeneration of the peripheral nerve after the peripheral nerve is injured. Several studies have demonstrated that acupuncture is effective for PNI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve the nervous system remodeling in the process of nerve repair. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating related neurotrophins retrograde transport, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), N-cadherin, and MicroRNAs. Peripheral nerve injury enhances the perceptual response of the central nervous system to pain, causing central sensitization and accelerating neuronal cell apoptosis. Together with this, the remodeling of synaptic transmission function would worsen pain discomfort. Neuroimaging studies have shown remodeling changes in both gray and white matter after peripheral nerve injury. Acupuncture not only reverses the poor remodeling of the nervous system but also stimulates the release of neurotrophic substances such as nerve growth factors in the nervous system to ameliorate pain and promote the regeneration and repair of nerve fibers. In conclusion, the neurological remodeling at the peripheral and central levels in the process of acupuncture treatment accelerates nerve regeneration and repair. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of PNI.

Silencing circPalm2 inhibits sepsis-induced acute lung injury by sponging miR-376b-3p and targeting MAP3K1.

The apoptosis and inflammation of pulmonary epithelial cells are important pathogenic factors of sepsis-induced acute lung injury (ALI). Upregulation of circPalm2 (circ_0001212) expression levels has been previously detected in the lung tissue of ALI rats. Herein, the biological significance and detailed mechanism of circPalm2 in ALI pathogenesis were investigated. In vivo models of sepsis-induced ALI were established by treating C57BL/6 mice with cecal ligation and puncture (CLP) surgery. Murine pulmonary epithelial cells (MLE-12 cells) were stimulated with lipopolysaccharide (LPS) to establish in vitro septic ALI models. MLE-12 cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry analysis, respectively. The pathological alterations of the lung tissue were analysed based on hematoxylin-eosin (H&E) staining. Cell apoptosis in the lung tissue samples was examined by TUNEL staining assay. LPS administration suppressed the viability and accelerated the inflammation and apoptotic behaviours of MLE-12 cells. CircPalm2 displayed high expression in LPS-stimulated MLE-12 cells and possessed circular characteristics. The silencing of circPalm2 impeded apoptosis and inflammation in LPS-stimulated MLE-12 cells. Mechanistically, circPalm2 bound with miR-376b-3p, which targeted MAP3K1. In rescue assays, MAP3K1 enhancement reversed the repressive effects of circPalm2 depletion on LPS-triggered inflammatory injury and MLE-12 cell apoptosis. Furthermore, the lung tissue collected from CLP model mice displayed low miR-376b-3p expression and high levels of circPalm2 and MAP3K1. CircPalm2 positively regulated MAP3K1 expression by downregulating miR-376b-3p in murine lung tissues. Importantly, circPalm2 knockdown attenuated CLP-induced inflammation, apoptosis, and pathological alterations in lung tissues collected from mice. Silenced circPalm2 inhibits LPS-induced pulmonary epithelial cell dysfunction and mitigates abnormalities in lung tissues collected from CLP-stimulated mice via the miR-376b-3p/MAP3K1 axis in septic ALI. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-022-00169-7.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

AIMS: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). METHODS: Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. RESULTS: Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. CONCLUSION: In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Neural stem cell therapy for brain disease.

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovascular diseases, and traumatic brain injuries, are among the major disorders influencing human health, currently with no effective therapy. Due to the low regeneration capacity of neurons, insufficient secretion of neurotrophic factors, and the aggravation of ischemia and hypoxia after nerve injury, irreversible loss of functional neurons and nerve tissue damage occurs. This damage is difficult to repair and regenerate the central nervous system after injury. Neural stem cells (NSCs) are pluripotent stem cells that only exist in the central nervous system. They have good self-renewal potential and ability to differentiate into neurons, astrocytes, and oligodendrocytes and improve the cellular microenvironment. NSC transplantation approaches have been made for various neurodegenerative disorders based on their regenerative potential. This review summarizes and discusses the characteristics of NSCs, and the advantages and effects of NSCs in the treatment of brain diseases and limitations of NSC transplantation that need to be addressed for the treatment of brain diseases in the future.

Acupuncture for Hypertension in Animal Models: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study was to summarize and evaluate the efficacy of acupuncture in hypertension animal study. METHODS: Studies were searched from six databases, including Medline, Embase, Chinese National Knowledge Infrastructure, Wanfang Data, VIP information database, and Chinese Biomedical Literature Database. Study quality of each included study was evaluated according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, and the risk of bias was evaluated by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were selected as outcomes. Meta-analyses were performed using Stata 12.0 software. The effect size was calculated by combining SBP/DBP/MAP data with the random effects model, respectively. RESULTS: 67 studies containing 1522 animals were included. According to the ARRIVE guideline, 8 items were assessed as poor and 4 items were assessed as excellent. According to the SYRCLE tool, all studies were judged as having high risk of bias. Compared with the hypertension group, the pooled results showed significant antihypertension effects of acupuncture for SBP, DBP, and MAP. Similarly, compared with the sham-acupuncture group, the pooled results showed significant antihypertension effects of acupuncture for SBP, DBP, and MAP. CONCLUSION: Although pooled data suggested that the acupuncture group was superior to the hypertension group or sham-acupuncture group for SBP/DBP/MAP, the presentation of poor methodological quality, high risk of bias, and heterogeneity deserves cautious interpretation of the results.

[RhoA/ROCK pathway involved in effects of Sanjiao acupuncture on learning and memory and synaptic plasticity in Alzheimer's disease mice].

OBJECTIVE: To observe the effect of Sanjiao acupuncture(triple energizer acupuncture)on the small G protein guanosine triphosphate enzyme subfamily protein RhoA/Rho kinase (ROCK) pathway in Alzheimer's disease mice, and explore its effect on learning and memory function and neurosynaptic plasticity. METHODS: Forty SAMP8 senile dementia mice were randomly divided into model, Sanjiao acupuncture (acupuncture), non acupoint acupuncture (non-acupoint) and fasudil groups, with 10 mice in each group, another 10 SAMR normal aging mice were selected as normal aging group. Mice in the acupuncture group were treated with acupuncture intervention on "Danzhong"(CV18), "Zhongwan"(CV13), "Qihai"(BL24) and bilateral "Xuehai"(SP10) and "Zusanli" (ST36). Mice in the non-acupoint group were treated with acupuncture at each of the left and right non-acupoints under the ribs and mice in the fasudil group were intraperitoneally injected with fasudil (25 mg/kg). The mice in each group were given medicine or acupuncture on the second day after grouping for 28 continuously days, once a day. Morris water maze test was used to test the learning and memory ability of mice. HE staining was used to observe the pathological changes of neurons in hippocampus. The number of hippocampal neuron dendritic spine was detected by FD fast Golgi staining kit. The contents of ß-amyloid 42 (Aß42) and phosphorylated tau protein (p-tau) in hippocampus were detected by ELISA. Western blot was used to detect the protein relative expression levels of RhoA, ROCK, F-actin and p-cofilin in hippocampus. RESULTS: Compared with those in the normal aging group, the hippocampal neurons of the model group were disorderly arranged, the number of neuron was reduced, the escape latency, hippocampal Aß42 and p-tau contents, RhoA and ROCK protein expressions increased (P<0.05), the number of crossing the original platform, the number of neuronal dendritic spines, expressions of F-actin and p-cofilin decreased (P<0.05). After the interventions, there was no statistically significant difference in the above indicators in the non-acupoint group relevant to the model group (P>0.05). The acupuncture group and fasudil group improved the hippocampal pathological damage. The escape latency, hippocampal Aß42 and p-tau contents, the expressions of RhoA and ROCK protein decreased (P<0.05), and the number of crossing the original platform, the number of hippocampal neuron dendritic spines, expressions of F-actin and p-cofilin increased (P<0.05) in both of the acupuncture and fasudil groups in contrast to the model and non-acupoint groups. Compared with the acupuncture group, there was no significant difference in the above indicators in the fasudil group (P>0.05). CONCLUSION: Sanjiao acupuncture may inhibit the activation of the RhoA/ROCK pathway, so as to improve the learning and memory function of AD mice, increase the number of hippocampal neuron dendritic spines, and promote synaptic plasticity.

Acupuncture accelerates neural regeneration and synaptophysin production after neural stem cells transplantation in mice.

BACKGROUND: Synaptophysin plays a key role in synaptic development and plasticity of neurons and is closely related to the cognitive process of Alzheimer's disease (AD) patients. Exogenous neural stem cells (NSCs) improve the damaged nerve function. The effects of Sanjiao acupuncture on cognitive impairment may be related to the regulation of the NSC microenvironment. AIM: To explore the anti-dementia mechanism of acupuncture by regulating the NSC microenvironment. METHODS: NSCs were isolated from pregnant senescence-accelerated mouse resistant 1 (SAMR1) mice, labeled with BrdU, and injected into the hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old senescence-accelerated mice (SAM) were randomly divided into six groups: SAMR1 (RC), SAMP8 (PC), sham transplantation (PS), NSC transplantation (PT), NSC transplantation with acupuncture (PTA), and NSC transplantation with non-acupoint acupuncture (PTN). Morris water maze test was used to study the learning and memory ability of mice after NSC transplantation. Hematoxylin-eosin staining and immunofluorescence were used to observe the his-topathological changes and NSC proliferation in mice. A co-culture model of hippocampal slices and NSCs was established in vitro, and the synaptophysin expression in the hippocampal microenvironment of mice was observed by flow cytometry after acupuncture treatment. RESULTS: Morris water maze test showed significant cognitive impairment of learning and memory in 8-mo-old SAMP8, which improved in all the NSC transplantation groups. The behavioral change in the PTA group was stronger than those in the other two groups (P < 0.05). Histopathologically, the hippocampal structure was clear, the cell arrangement was dense and orderly, and the necrosis of cells in CA1 and CA3 areas was significantly reduced in the PTA group when compared with the PC group. The BrdU-positive proliferating cells were found in NSC hippocampal transplantation groups, and the number increased significantly in the PTA group than in the PT and PTN groups (P < 0.05). Flow cytometry showed that after co-culture of NSCs with hippocampal slices in vitro, the synaptophysin expression in the PC group decreased in comparison to the RC group, that in PT, PTA, and PTN groups increased as compared to the PC group, and that in the PTA group increased significantly as compared to the PTN group with acupoint-related specificity (P < 0.05). CONCLUSION: Acupuncture may promote nerve regeneration and synaptogenesis in SAMP8 mice by regulating the microenvironment of NSC transplantation to improve the nerve activity and promote the recovery of AD-damaged cells.

[Advances of Study on Relationship Among Immune Inflammation Reaction and Prehypertension and Its Target Organ Damage and Protective Effects of Acupuncture Intervention].

Prehypertension is an independent risk factor for end stage of heart, brain and renal diseases. The immune inflammatory imbalance promotes the occurrence of damage of target organs in the pre-hypertension stage. This article focuses on the relationship between the immune-inflammation and prehypertension and its target organ damage. It was found that acupuncture treatment can lower blood pressure, postpone the development of prehypertension, improve vascular endothelia function and immune function, down-regulate the levels of serum proinflammatory cytokines, and reduce inflammatory reactions of the heart and kidney, possible by way of regulating cellular signal pathways as TLR 4/NF-κB, p 38/MAPK, CaM-eNOS-NO, TGF-ß 1/Smads, etc. and playing a protective effect on the target organs. However, its detailed mechanisms remain largely unknown up to now.

Combined acupuncture and HuangDiSan treatment affects behavior and synaptophysin levels in the hippocampus of senescence-accelerated mouse prone 8 after neural stem cell transplantation.

Sanjiao acupuncture and HuangDiSan can promote the proliferation, migration and differentiation of exogenous neural stem cells in senescence-accelerated mouse prone 8 (SAMP8) mice and can improve learning and memory impairment and behavioral function in dementia-model mice. Thus, we sought to determine whether Sanjiao acupuncture and HuangDiSan can elevate the effect of neural stem cell transplantation in Alzheimer's disease model mice. Sanjiao acupuncture was used to stimulate Danzhong (CV17), Zhongwan (CV12), Qihai (CV6), bilateral Xuehai (SP10) and bilateral Zusanli (ST36) 15 days before and after implantation of neural stem cells (5 × 105) into the hippocampal dentate gyrus of SAMP8 mice. Simultaneously, 0.2 mL HuangDiSan, containing Rehmannia Root and Chinese Angelica, was intragastrically administered. Our results demonstrated that compared with mice undergoing neural stem cell transplantation alone, learning ability was significantly improved and synaptophysin mRNA and protein levels were greatly increased in the hippocampus of mice undergoing both Sanjiao acupuncture and intragastric administration of HuangDiSan. We conclude that the combination of Sanjiao acupuncture and HuangDiSan can effectively improve dementia symptoms in mice, and the mechanism of this action might be related to the regulation of synaptophysin expression.

miR-22 exerts anti-alzheimic effects via the regulation of apoptosis of hippocampal neurons.

To investigate the expression of miR-22 in the hippocampus of amyloid ß (1-42)-induced alzheimic rats, and to assess the underlying mechanism. A total of 60 male Sprague Dawley rats weighing between 274.65 and 293.97 g (mean weight = 284.31 ± 9.66 g) and aged 12 to 14 weeks were randomly assigned to three groups: control group (n = 20), Alzheimer's disease group (AD group; n = 20) and AD + miR-22 mimic group (ADMM group; n = 22). Rat AD model was established by injecting a solution of Aß1-42 into the hippocampal CA1 regions. After 24 h, rats in the ADMM group also received intraventricular injection of miR-22 mimic continuously for 28 days. The escape latency of rats, neuronal damage in the hippocampus, synaptic structure, brain-derived neurotrophic factor (BDNF), and the expressions of apoptosis-related proteins were assessed or determined, as appropriate. The expression of miR-22 in hippocampus of the AD group was significantly lower than that in the control group (p < 0.05). However, after 28 days of intraventricular injection of miR-22 mimic into AD rats, the expression was significantly increased, relative to control (p < 0.05). The escape latency of AD rats was significantly prolonged, and the number of platform sites significantly reduced when compared to the control group (p < 0.05). However, the escape latency was significantly shortened and the number of platform sites significantly increased in the ADMM group, relative to the control and AD groups. Results of transmission electron microscopy showed that the expression of miR-22 significantly reversed the degradation of synaptic structures in the hippocampus of AD rats as evidenced by recovery of abnormal synaptic cleft width and the length of synaptic active zones (p < 0.05). Results of Nissl staining revealed significant proliferation of gliacyte and loss of Nissl bodies. After miR-22 injection, the number of gliacytes in the hippocampus of AD rats was significantly reduced, while the number of Nissl bodies was significantly increased (p < 0.05). The expressions of BDNF in CA1 and CA2/3 regions of AD rats were significantly lower than those in the control group, and BDNF in the hippocampus of AD rats was significantly increased after 28 days of continuous injection of miR-22 (p < 0.05). The positive expression of Tunnel in the ADMM group (22.67 ± 2.96 %) was significantly higher than that in the AD group (4.49 ± 1.23 %), but significantly lower than that of control (39.51 ± 3.66 %) (p < 0.05). After 28 days of intraventricular injection of miR-22 mimic into AD rats, the expression of Bax protein was significantly down-regulated, while bcl-2 protein was significantly up-regulated (p < 0.05). The expression of miR-22 in the hippocampus of patients with AD inhibits neuronal apoptosis, thereby improving learning and memory dysfunction.

Influence of pretreatment of piperazine ferulate on pharmacokinetic parameters of methotrexate in methotrexate-induced renal injury model rats by HPLC-MS.

The present study was designed to investigate the influence of the pretreatment of piperazine ferulate on pharmacokinetic parameters of methotrexate in methotrexate-induced renal injury rats. A simple and efficient high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) method was developed to determine methotrexate in rat plasma. Methotrexate and syringic acid (internal standard) were extracted from rat plasma samples by protein precipitation with acetonitrile. The analysis was performed on a CAPCELL PAK C18 column (150 mm × 4.6 mm, 5 µm) with acetonitrile and 5 mmol/l ammonium acetate aqueous (10:90, v/v). The linear range was 5.0 × 10-2 to 100.0 µg/ml for methotrexate. Other parameters were all within the acceptance criteria. The validated method was successfully applied the pharmacokinetic study of methotrexate between two methotrexate treated groups (with and without the pretreatment of piperazine ferulate). Compared with the methotrexate treated alone group, the pharmacokinetic parameters in the methotrexate with the pretreatment of piperazine ferulate group showed significantly lower MRT(0-t), MRT(0-∞) and T 1/2. Results suggested that methotrexate can be rapidly eliminated, cleared or metabolized in rat blood, which might be related to the pretreatment of piperazine ferulate. The method provided deeper insights into rational clinical use of methotrexate with the pretreatment of piperazine ferulate on cancer patients with renal dysfunction.

Degradation kinetics of larotaxel and identification of its degradation products in alkaline condition.

Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC-MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH (1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0) and temperature (0, 25, 37 and 45 °C). The linear range was 0.5-25 µg/mL, the intra- and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4-104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 kJ/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q-TOF-MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.

Acupuncture Improves Cerebral Microenvironment in Mice with Alzheimer's Disease Treated with Hippocampal Neural Stem Cells.

Transplantation with neural stem cells (NSCs) is a promising clinical therapy for Alzheimer's disease (AD). However, the final fate of grafted NSCs is mainly determined by the host microenvironment. Therefore, this study investigated the role of Sanjiao acupuncture in the NSCs-treated hippocampus of a mouse model, senescence-accelerated mouse prone 8 (SAMP8) using Western blot, real-time fluorescent PCR, and immunofluorescence techniques. Meanwhile, we developed a co-culture model of hippocampal tissue specimens and NSCs in vitro, to observe the effects of acupuncture on survival, proliferation and differentiation of grafted NSCs using flow cytometry. Results showed that acupuncture pre- and post-NSCs transplantation significantly improved senescence-induced cognitive dysfunction (P < 0.05); upregulated the expression of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and brain-derived neurotrophic factor (BDNF) (P < 0.05); and also increased the count of neuron-specific nuclear protein (NeuN)- and glial fibrillary acidic protein (GFAP)-positive cells (P < 0.05). Therapeutic acupuncture may regulate the cytokine levels associated with survival, proliferation, and differentiation of NSCs in hippocampal microenvironment, to promote the repair of damaged cells, resulting in improved cognitive performance in mice.

Investigation of the protective effect of Paeonia lactiflora on Semen Strychni-induced neurotoxicity based on monitoring nine potential neurotoxicity biomarkers in rat serum and brain tissue.

Semen Strychni has been widely used as a traditional Chinese herb medicine, but its clinical use was limited for its potential neurotoxicity and nephrotoxicity. This study aimed to investigate S. Strychni-induced neurotoxicity and the neuro-protective effect of Paeonia lactiflora based on monitoring nine potential neurotoxicity biomarkers in rat serum and brain tissue. A sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to monitor serotonin, tryptophan, dopamine, tyrosine and glutamate in serum and five brain regions (prefrontal cortex, hippocampus, striatum, cerebellum and hypothalamus). Analytes were separated on a CAPCELL CORE PC column (150 mm × 2 mm, 2.7 µm) with a gradient program of acetonitrile-water (0.2 % formic acid) and a total runtime of 7.5 min. In addition, enzyme-linked immunosorbent assay was conducted to determine four kinds of protein (tryptophan hydroxylase, tyrosine hydroxylase, endogenous brain-derived neurotrophic factor and nerve growth factor). Results demonstrated that the administration of S. Strychni could cause certain endogenous substances disorder. These analytes were found significantly changed (p < 0.05) in serum (except glutamate) and in certain tested brain regions in S. Strychni extract group. Pretreatment of P. lactiflora could significantly reverse the S. Strychni-induced neurotoxicity and normalize the levels of such endogenous substances. The study could be further used in predicting and monitoring neurotoxicity caused by other reasons, and it was expected to be useful for improving clinical use of S. Strychni through pretreatment with P. lactiflora.

Simultaneous Determination of Five Specific and Sensitive Nephrotoxicity Biomarkers in Serum and Urine Samples of Four Drug-Induced Kidney Injury Models.

In clinical diagnosis, serum creatinine (CR) was commonly used as the routine markers for the evaluation of kidney injury. To investigate the specific and sensitive nephrotoxicity biomarkers in different drug-induced kidney injury (DKI) models, receiver operating characteristic (ROC) analysis was applied in this study. The quantification data were acquired by the LC-MS determination. Histopathology results showed that different kinds of kidney injuries were observed in different DKI models (gentamycin, cisplatin, methotrexate and amphotericin B models), indicating the injuries might be caused by different mechanisms. Then, five typical biomarkers were simultaneously determined by a newly developed and validated LC-MS method. Uric acid, CR, hippuric acid, 3-indoxyl sulfate and phenaceturic acid were separated by an Apollo C18 column and a methanol/water (5 mM ammonium acetate) gradient program. The prepared calibration curves showed good linearity with regression coefficients all above 0.9927. Of all the analytes, the precision were below 9.9% and the accuracy were from -10.3% to 9.2%. ROC results showed that different nephrotoxicity biomarkers were specific in different DKI models. The changes of different biomarkers might be induced by different nephrotoxic mechanisms in the DKI models. These specific and sensitive biomarkers in combination with serum CR are promising in the clinical diagnosis of DKI.

Antidepressant-like effect of the water extract of the fixed combination of Gardenia jasminoides, Citrus aurantium and Magnolia officinalis in a rat model of chronic unpredictable mild stress.

BACKGROUND: Water extract of the fixed combination of Gardenia jasminoides Ellis fruit, Citrus aurantium L. fruit and Magnolia officinalis Rehd. et Wils. bark, traditional name - Zhi-Zi-Hou-Po (ZZHPD) is used for treatment of depressive-like symptoms in traditional Chinese medicine for centuries. HYPOTHESIS/PURPOSE: The present study aimed to explore antidepressant-like effects and potential mechanisms of ZZHPD in a rat model of chronic unpredictable mild stress (CUMS). STUDY DESIGN: Antidepressant-like effects of ZZHPD were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system, neurotrophin and hippocampal neurogenesis. METHODS: Antidepressant-like effects of ZZHPD (3.66, 7.32 and 14.64 g/kg/day) were estimated through coat state test, sucrose preference test, forced swimming test and open-field test. Effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were evaluated by hormones measurement and dexamethasone suppression test. In addition, the expression of brain-derived neurotrophic factor (BDNF) in hippocampus was measured, as well as hippocampal neurogenesis was investigated by doublecortin (DCX) and 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN). RESULTS: The results demonstrated that ZZHPD significantly reversed the depressive-like behaviors, normalized the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), restored the negative feedback loop of HPA axis and improved the levels of BDNF, DCX and BrdU/NeuN compared with those in CUMS-induced rats. CONCLUSION: The above results revealed that ZZHPD exerted antidepressant-like effects possibly by normalizing HPA axis function, increasing expression of BDNF in hippocampus and promoting hippocampal neurogenesis.

Determination of depression biomarkers in rat plasma by liquid chromatography-mass spectrometry for the study of the antidepressant effect of Zhi-Zi-Hou-Po decoction on rat model of chronic unpredictable mild stress.

Zhi-Zi-Hou-Po decoction (ZZHPD), a traditional Chinese medicine (TCM) formula, has been used for treatment of depressive-like symptoms for centuries. However, studies of its antidepressant effect and mechanism are challenging, owing to the complex pathophysiology of depression and complexity of ZZHPD with multiple constituents acting on different metabolic pathways. The present study was designed to develop a liquid chromatography-mass spectrometry (LC-MS) method for simultaneous determination of depression biomarkers: tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), indole-3-acetic acid (IAA), hippuric acid (HA), phenaceturic acid (PA), creatinine (Cr), glutamic acid (Glu), succinic acid (SA) and γ-aminobutyric acid (GABA), as well as to study the antidepressant effect and potential mechanism of ZZHPD based on holistic view of an organism. The analysis was performed on a CAPCELL PAK C18 column with methanol and 0.01% formic acid in water using gradient elution. The method showed a good linearity (r(2)>0.99) with the other validation parameters were within acceptance range. The results demonstrated Trp, Phe, Tyr, IAA, HA, Cr, Glu and SA levels were significant lower in model group, while PA and GABA were significant higher than those in control group. The rats with ZZHPD treatment showed a tendency of bringing the levels of all these biomarkers to normal except Cr and Glu. It could be a powerful manner to provide mechanistic insights into the therapeutic effects of complex prescriptions and further understand pathophysiology of depression to assist in clinical diagnosis.

Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism.

PURPOSE: To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. METHODS: A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC. RESULTS: C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T(½), AUC(0-24), AUC(0-infinity), and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs. CONCLUSION: Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

[Study on electroacupuncture at shuigou (GV 26) for treatment of mild and moderate shock: a multicentral and randomized controlled trial].

OBJECTIVE: To probe into the effect of electroacupuncture (EA) at Shuigou (GV 26) on mild and moderate shock. METHODS: With 3-center randomized control study method, 276 cases were assigned to an EA plus medicine group and a medication group, 138 cases in each group. They were treated respectively with western medicine plus EA at Shuigou (GV 26), and simple western medicine. Their curative effects were observed after treatment for 6 hours. RESULTS: The blood pressure was immediately increased in the EA plus medicine group and the increase of blood pressure was earlier than that in the medication group (P<0.001). The markedly effective rate of 52.9% in the EA plus medicine group was significantly higher than 18.1% in the medication group (P<0.001). CONCLUSION: The therapeutic effect of EA at Shuigou (GV 26) plus western medicine on mild and moderate shock is better than that of simple western medicine.