Role of phytochemicals in colorectal cancer prevention

Although the incidence of colorectal cancer(CRC) has been declining in recent decades,it remains a major public health issue as a leading cause of cancer mortality and morbidity worldwide. Prevention is one milestone for this disease. Extensive study has demonstrated that a diet containing fruits,vegetables,and spices has the potential to prevent CRC. The specific constituents in the dietary foods which are responsible for preventing CRC and the possible mechanisms have also been investigated extensively. Various phytochemicals have been identified in fruits,vegetables,and spices which exhibit chemopreventive potential. In this review article,chemopreventive effects of phytochemicals including curcumin,polysaccharides(apple polysaccharides and mushroom glucans),saponins(Paris saponins,ginsenosides and soy saponins),resveratrol,and quercetin on CRC and the mechanisms are discussed. This review proposes the need for more clinical evidence for the effects of phytochemicals against CRC in large trials. The conclusion of the review is that these phytochemicals might be therapeutic candidates in the campaign against CRC.

Baicalin treatment regulates hyperactivity of HPA axis and alters SIRT1 related inflammation in the hypothalamus in a model of depression

OBJECTIVE Hyperactivityof hypothalamic-pituitary-adrenal(HPA) axis is an important aetiological risk factor for the development of depression. Previous studies have demonstrated that the phenolic monomer baicalin has antidepressant-like effects and decreases serum corticosterone levels.However,the mechanism by which baicalin regulates hyperactivity of HPA axis remains unclear. This work aimed to investigate the effects of baicalin on hyperactivity of HPA axis using the olfactory bulbectomised(OBX) rat model of depression. METHODS Animals were anaesthetised with 10% chloral hydrate(3.3 mL·kg^(-1),ip). Using disinfected surgical equipment,the skull covering the olfactory bulbs was exposed by a midline incision. Two burr holes(2 mm diameter) were drilled 8 mm anterior to the bregma and 2 mm lateral to the midline. Both olfactory bulbs were aspirated and the holes filled with glass ionomer cement. The scalp was sutured closed. Sham-operated rats underwent every surgical procedure except the aspiration of the bulbs. The animals received penicillin(8×10~5U) intramuscularly(0.2 mL/300 g) once per day for 3 d post-surgery to prevent infection,and were subsequently housed alone in polypropylene cages. The experiments continued after 14 d of rehabilitation. The following groups were used for experiments: sham-operated(underwent surgical procedure without aspiratedolfactory bulbs and administration of vehicle only),OBX-model(underwent every surgical procedure and administration of vehicle only),OBX-amitriptyline treated(10 mg·kg^(-1)),and OBX-baicalin treatment(20 and 40 mg·kg^(-1)). Amitriptyline and baicalin were dissolved in physiological saline. RESULTS We examined how baicalin altered OBX-induced changes in serum glucocorticoid level as wel as inflammatory responses,sirtuin 1(SIRT1) expression,and p65 acetylation in the hypothalamus. Similar experiments were performed to analyse the effects of baicalin on lipopolysaccharide-induced inflammatory responses inhypothalamus. CONCLUSION Our results indicate that activation of the SIRT1 in the hypothalamus contributes to hyperactivity of HPA axis,which can be alleviated by baicalin.

Histochemistry of microinfarcts in the mouse brain after injection of fluorescent microspheres into the common carotid artery

The mouse model of multiple cerebral infarctions,established by injecting fluorescent microspheres into the common carotid artery,is a recent development in animal models of cerebral ischemia.To investigate its effectiveness,mouse models of cerebral infarction were created by injecting fluorescent microspheres,45–53μm in diameter,into the common carotid artery.Six hours after modeling,fluorescent microspheres were observed directly through a fluorescence stereomicroscope,both on the brain surface and in brain sections.Changes in blood vessels,neurons and glial cells associated with microinfarcts were examined using fluorescence histochemistry and immunohistochemistry.The microspheres were distributed mainly in the cerebral cortex,striatum and hippocampus ipsilateral to the side of injection.Microinfarcts were found in the brain regions where the fluorescent microspheres were present.Here the lodged microspheres induced vascular and neuronal injury and the activation of astroglia and microglia.These histopathological changes indicate that this animal model of multiple cerebral infarctions effectively simulates the changes of various cell types observed in multifocal microinfarcts.This model is an effective,additional tool to study the pathogenesis of ischemic stroke and could be used to evaluate therapeutic interventions.This study was approved by the Animal Ethics Committee of the Institute of Acupuncture and Moxibustion,China Academy of Chinese Medical Sciences(approval No.D2021-03-16-1)on March 16,2021.

A Case of Alzheimer’s Disease Was Kept Relative Stable with Sequential Therapy for Eight Years

Background: Although Alzheimer’s disease (AD) has been intensively investigated for many years, the effective treatments are largely missing. Commonly used conventional therapy, such as cholinesterase inhibitors (ChEI) and N-methyl D-asparate receptor antagonist, have been generally considered as having symptom-relieving rather than disease-modifying effects. Thus, how to improve cognitive function beyond such effect & time limitations has become a serious challenge. Aim: In order to solve this challenge, a sequential therapy with the integration of conventional therapy and herbal therapy was applied to AD patients. Careful clinical observation was conducted in our outpatient setting. Case Presentation: A case of probable AD received the sequential therapy has achieved relative stable cognition and overall status in eight years. Conclusion: During the treatment of this AD case in eight years, sequential therapy showed great potential in stabilizing and improving cognition and overall status. Well designed preclinical and clinical studies are needed to investigate the efficacy of sequential therapy for AD and other type of dementia.

The effect of Zhusha Anshen Wan decoction on states of the sleep-waking cycle in insomnic rats

BACKGROUND： Sedative and hypnotic chemical drugs prolong the total-sleep time （TST） by a decrease in slow-wave sleep 2 （SWS2） and rapid-eye-movement sleep （REMS） and a relative increase in slow-wave sleep 1 （SWS1）. OBJECTIVE： To investigate the effect of the Chinese medicine Zhusha Anshen Wan at different doses on each sleeping state in insomnic rats, and to identify its mode of action in improving sleep. DESIGN, TIME AND SETTING： A randomized controlled study in rats. This study was performed in the Department of Pharmacology of Chinese Materia Medica, Heilongjiang University of Traditional Chinese Medicine during the period from January 2005 to July 2006. MATERIALS： Twenty-four male Wistar rats, weighing （220±5） g, were selected. The main components in Zhusha Anshen Wan, Cinnabaris, Rhizoma Coptidis, Radix Glycyrrhixae, Prepared Radix Glycyrhizae Radix Angelicae Sinensis, and Rehmannia Pride Rhizome, were authenticated by Dr Xiaowei Du, Professor of Pharmacology. ND-97 Digital Polysomnography was purchased from the Shanghai Medical Instrument High Technology Company and Footplate Electrical Stimulator from the Harbin Research Institute of Electrical Instruments. METHODS： Rats were deprived of sleep by using the Footplate Electrical Stimulator. Insomnic rats were randomized into high-, mid- and low-dose Zhusha Anshen Wan groups, eight rats in each group. Animals were administrated with different doses of Zhusha Anshen Wan （equal to crude drug 7.2, 3.6, 1.8 g/kg） consecutively for seven days. MAIN OUTCOME MEASURES： 30 minutes after the last administration, rats of each group suffered 8 hours foot-shocks while electroencephalography signals were recorded using Digital Polysomnography. Total time of waking （W）, SWS1, SWS2, REMS and TST were calculated for pre- and post-administration, respectively. RESULTS： All 24 rats were included in the statistical analysis of the results without any loss. In the low-dose Zhusha Anshen Wan group, SWS2 was increased significantly compared with pre-administration. In the middle-dose Zhusha Anshen Wan group, W was decreased significantly, but SWS1, SWS2 and TST were increased markedly compared with pre-administration, and there were significant differences between pre- and post-administration （P 〈 0.05-0.01）. In the high-dose Zhusha Anshen Wan group, the duration of W was significantly decreased after administration, but SWS1, SWS2, REMS and TST were significantly longer than pre-administration （P 〈 0.05-0.01）. CONCLUSION： The effect of Zhusha Anshen Wan on sleeping states is dose-dependent. Zhusha Anshen Wan acts by extending SWS1 and SWS2 to increase the total sleeoing time.

Ginkgo Leaf Extract and Armillariella Mellea Powders Oral(银杏蜜环口服溶液) attenuates inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis in post stroke depression

OBJECTIVE The Ginkgo Leaf Extract and Armillariella Mellea Powders Oral(Yinxingmihuan Koufu Rongye,YXMH),a representative drug for"Treating both Brain and Heart",showed considerable clinical effects in isch⁃emic cardiovascular and cerebral vascular diseases.Recently,it is reported that YXMH has the potential for treating myocardial and cerebral ischemia related mental disorders,such as post stroke depression(PSD)and chronic heart disease(CHD)associated anxiety disorder.However,its mechanism has not been clearly elucidated.Meanwhile,increasing evidence revealed that there are close functional links between depression and habenular nucleus.The present study investigates the underlying mechanism of YXMH on attenuating the inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis in in a rat model of PSD.METHODS Rats were randomly devided into sham group,model group,Ginaton group(18 mg·kg^-1),Armillariella Mellea group(600 mg·kg-1),Fluoxetine group(10 mg·kg^-1),YXMH high-dose group(618 mg·kg^-1)and YXMH low-dose group(309 mg·kg^-1).The PSD model was induced by transarterial microembolization combined with sleep deprivation(2-Chloro-D-phenylalanine,PCPA,IH,200 mg·kg^-1,for 3 times,before the behavior test)in SD male rats.Then rats were treated with corresponding medicaments through gavage once a day until 3 weeks later,followed by body mass measurement,neurological deficit score evaluation,gripping strength and thermal withdrawl latency measurement,as well as depression related behavioral indicators,the open field test(OFT)and sucrose preference test.The pathological morphological changes of habenular nucleus was observed by HE staining,the expression of IBA-1 was measured and analyzed by immunohistochemistry staining,and alterations of proteins and genes related to the CX3CL1-CX3CR1 axis were analyzed using Western blotting(CX3CL1,CX3CR1)and real-time polymerase chain reaction(PCR)(CX3CL1,CX3CR1).RESULTS Compared with the sham group,rats in the model group manifested as decreased body mass,deficient neurological behavior and gripping strength,reduced loco⁃motor activity and sugar water consumption,as well as elevated thermal withdrawl latency(P<0.05,P<0.01).Mean⁃while,the pathological morphology of the habenular nucleus on the ischemic hemisphere showed significant neuronal degeneration,microglial proliferation,inflammatory cells and glia cells infiltration,together with up-regualted expression of IBA-1,CX3CL1,CX3CR1 protein and CX3CL1,CX3CR1 mRNA.YXMH attenuated inflammation of microglia in habenular nucleus through improving pathological morphology,inhibiting IBA-1 activation,down-regulating the expres⁃sion of CX3CL1 and CX3CR1 proteins and genes,and thus improved the behavior performance of ischemic injury and depression.CONCLUSION YXMH ameliorates neurological deficit and depressive behavior in rat model of PSD induced by transarterial microembolization combined with sleep deprivation,and the mechanism is probably related to attenu⁃ating inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis.

Mechanism of charged interface of stargazin EX1 on AMPAR opening and desensitization

OBJECTIVE AMPA-subtype iono⁃tropic glutamate receptors(iGluRs)mediate fast excitatory synaptic transmission in the mammali⁃an central nervous system(CNS).It plays the key role in many central nerves disorder such as epilepsy,depression and schizophrenia.Star⁃gazin(STZ,also named TARP-γ2),as the first TARPs found in CNS,potentiates AMPAR activity by attenuating deactivation and desensitization,enhancing recovery from desensitization,and facilitating agonist affinity and efficacy.However,it is still not fully understanding howγ-2 modu⁃late AMPAR gating.METHODS AND RESULTS The desensitization for different mutation of AMPAR andγ-2 was compared.It was shown that the electric attraction was involved in the interaction of AMPAR andγ-2.In addition,the interaction of KGK motif in ligand binding domain and pre-M1 chain of AMPAR and EX1 ofγ-2 modulate AMPAR opening and desensitization.Substitution of these charged residues had sur⁃prisingly effects on AMPAR desensitization kinet⁃ics.CONCLUSION The electric attraction has two impacts on the channels gating process the first destablizing the receptor closed state and enabling the channel opening,the second pro⁃moting the channels entering desensitization state upon the channel opening.

Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species

The canonical transient receptor potential channel(TRPC)proteins form Ca^(2+)-permeable cation channels that are involved in various heart diseases.However,the roles of specific TRPC proteins in myocardial ischemia/reperfusion(I/R)injury remain poorly understood.We observed that TRPC1 and TRPC6 were highly expressed in the area at risk(AAR)in a coronary artery ligation induced I/R model.Trpc1/mice exhibited improved cardiac function,lower serum Troponin T and serum creatine kinase level,smaller infarct volume,less fibrotic scars,and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6/mice.Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury.Furthermore,Trpc1 deficiency protected adult mouse ventricular myocytes(AMVMs)and HL-1 cells from death during hypoxia/reoxygenation(H/R)injury.RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species(ROS)generation in Trpc1/cardiomyocytes.Among these genes,oxoglutarate dehydrogenase-like(Ogdhl)was markedly downregulated.Moreover,Trpc1 deficiency impaired the calcineurin(CaN)/nuclear factorkappa B(NF-kB)signaling pathway in AMVMs.Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions.Chromatin immunoprecipitation assays confirmed NF-kB binding to the Ogdhl promoter.The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-kB and Ogdhl in cardiomyocytes.In conclusion,our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R,leading to increased Ca^(2+) influx into associated cardiomyocytes.Subsequently,this upregulates Ogdhl expression through the CaN/NF-kB signaling pathway,ultimately exacerbating ROS production and aggravating myocardial I/R injury.

Recent advances of traditional Chinese medicine on the prevention and treatment of COVID-19

Coronavirus disease-2019(COVID-19)is a new highly infectious disease caused by a novel coronavirus.Recently,the number of new cases infected pneumonia in the world continues to increase,which has aroused great concern from the international community.At present,there are no small-molecule specific anti-viral drugs for the treatment.The high mortality rate seriously threatens human health.Traditional Chinese medicine(TCM)is a unique health resource in China.The combination of TCM and Western medicine has played a positive and important role in combating COVID-19 in China.In this review,through literature mining and analysis,it was found that TCM has the potential to prevent and treat the COVID-19.Then,the network pharmacological studies demonstrated that TCM played roles of anti-virus,anti-inflammation and immunoregulation in the management of COVID-19 via multiple components acting on multiple targets and multiple pathways.Finally,clinical researches also confirmed the beneficial effects of TCM on the treatment of patients.This review may provide meaningful and useful information on further drug development of COVID-19 and other viral infectious diseases.

Human bone marrow mesenchymal stem cell transplantation attenuates axonal injury in stroke rats

Previous studies have shown that transplantation of human bone marrow mesenchymal stem cells promotes neural functional recovery after stroke, but the neurorestorative mechanisms remain largely unknown. We hypothesized that functional recovery of myelinated axons may be one of underlying mechanisms. In this study, an ischemia/reperfusion rat model was established using the middle cerebral artery occlusion method. Rats were used to test the hypothesis that intravenous transplantation of human bone marrow mesenchyrnal stem cells through the femoral vein could exert neuroprotective effects against cerebral ischemia via a mechanism associated with the ability to attenuate axonal injury. The results of behavioral tests, infarction volume analysis and immunohistochemistry showed that cerebral ischemia caused severe damage to the myelin sheath and axons. After rats were intravenously transplanted with human bone marrow mesenchymal stem cells, the levels of axon and myelin sheath-related proteins, including microtubule-associated protein 2, myelin basic protein, and growth-associated protein 43, were elevated, infarct volume was decreased and neural function was improved in cerebral ischemic rats. These findings suggest that intravenously transplanted human bone marrow mesenchymal stem cells promote neural function. Possible mechanisms underlying these beneficial effects include resistance to demyelination after cerebral ischemia, prevention of axonal degeneration, and promotion of axonal regeneration.

Baicalin inhibits cell growth and induces autophagy via AMPK/ULK1 activation in MDA-MB-231 cells

OBJECTIVE To investigate the effects and molecular mechanisms of Baicalin,a natural flavonoid compound derived from Scutellariabaicalensis Georgi,in the triple-negative human breast cancer cell line MDAMB-231.METHODS Cel s(1.0×105mL-1)were seeded in96-well plates,6-well plates or 25 cm2flasks.After overnight incubation,various concentrations of Baicalin were added to cells for another 48 h.Cell viability was measured using XTT Assay.Cell growth and migration was measured using colony formation assay and wound healing assay,autophagy-related proteins were observed using Western blotting analysis.RESULTS A dose-dependent decrease in cell viability was induced by Baicalin(IC50=48.6μg·m L-1).The colony-forming activity of MDA-MB-231 cells was significantly reduced by various concentrations of baicalin(25,50,100μg·m L-1)(85.2±12.7%,41.3±12.3%,19.6±6.6%).Wound healing assay showed that the recovery rateof baicalin-treated groups(25,50,100μg·m L-1)were significantly lower than those of the untreated group(88.3±15.1%,52.1±15.5%,28.3±9.6%).Western blot showed that the AMP-activated protein kinase and ULK1 was clearly up-regulated and activated by Baicalin(25,50,100μg·m L-1)in a dose-dependent manner,and the expression level of autophagic marker Beclin-1 and LC3A/B was also unregulated by the same treatment.CONCLUSION The study revealed that baicalin interferes with breast cancer growth by inducing autophagy,which at least in part through AMPK/ULK1 activation.

Cholinergic dysfunction-induced insufficient activation of alpha7 nicotinic acetylcholine receptor drives the development of rheumatoid arthritis through promoting protein citrullination via the SP3/PAD4 pathway

Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA.Cholinergic function and protein citrullination levels in patients with RA and collageninduced arthritis(CIA)mice were collected.In both neuron-macrophage coculture system and CIA mice,the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases(PADs)was assessed by immunofluorescence.The key transcription factors for PAD4 expression were predicted and validated.Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues.The cholinergic or alpha7 nicotinic acetylcholine receptor(a7nAChR)deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo,respectively.Especially,the activation deficiency of a7nAChR induced the earlier onset and aggravation of CIA.Furthermore,deactivation of a7nAChR increased the expression of PAD4 and specificity protein-3(SP3)in vitro and in vivo.Our results suggest that cholinergic dysfunction-induced deficient a7nAChR activation,which induces the expression of SP3 and its downstream molecule PAD4,accelerating protein citrullination and the development of RA.

Antidepressant-like effect of essential oil of Perilla frutescens in a chronic, unpredictable, mild stress-induced depression model mice

Perilla frutescens(Perilla leaf), a garnishing vegetable in East Asian countries, as well as a plant-based medicine, has been used for centuries to treat various conditions, including depression. Several studies have demonstrated that the essential oil of P. frutescens(EOPF) attenuated the depressive-like behavior in mice. The present study was designed to test the anti-depressant effects of EOPF and the possible mechanisms in an chronic, unpredictable, mild stress(CUMS)-induced mouse model. With the exposure to stressor once daily for five consecutive weeks, EOPF(3, 6, and 9 mg·kg-1) and a positive control drug fluoxetine(20 mg·kg-1) were administered through gastric intubation to mice once daily for three consecutive weeks from the 3rd week. Open-field test, sucrose consumption test, tail suspension test(TST), and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine(5-HT) and its metabolite, 5-hydroxyindoleacetic acid(5-HIAA), in mouse hippocampus were determined by HPLC–ECD. Serum interleukin(IL)-1, IL-6, and tumor necrosis factor(TNF)-α levels were evaluated by enzyme-linked immunosorbent assay(ELISA). The results showed that CUMS significantly decreased the levels of 5-HT and 5-HIAA in the hippocampus, with an increase in plasma IL-6, IL-1β, and TNF-α levels. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. EOPF administration could effectively reverse the alterations in the concentrations of 5-HT and 5-HIAA; reduce the IL-6, IL-1β, and TNF-α levels. Moreover, EOPF could effectively reverse alterations in immobility duration, sucrose consumption, and open-field activity. However, the effect was not dose-dependent. In conclusion, EOPF administration exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of EOPF might be related to the relation between alteration of serotonergic responses and anti-inflammatory effects.

Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and Rho A GTPases and activation of the PI3K/Akt and JNK signaling pathways

Tetrandrine （Tet）, the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synovioeytes （RA-FLS） and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet （0.3, 1 μmol L-1） was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC （against PI3K, Akt, JNK, ERK, p38 MAPK and NF-kB-p65, respectively） were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac 1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Racl, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.

Protective effects of Huanglian Wendan Decoction aganist cognitive deficits and neuronal damages in rats with diabetic encephalopathy by inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampus

Huanglian Wendan decoction(HLWDD) has been used for the treatment of symptom of "Re", one of major causes in diabetes and metabolic disorders, according to the theory of traditional Chinese medicine. The present study aimed at investigating the cerebral protective effects of HLWDD on diabetic encephalopathy(DE), one of the major diabetic complications. The effects of HLWDD and metformin were analyzed in the streptozocin(STZ) + high-glucose-fat(HGF) diet-induced DE rats by gastric intubation. In the present study, the effects of HLWDD on cognition deficits were investigated after 30-day intervention at two daily dose levels(3 and 6 g·kg^(-1)). To explore the potential mechanisms underlying the effects of HLWDD, we detected the alterations of neuronal damages, inflammatory cytokines, and impaired insulin signaling pathway in hippocampus of the DE rats. Based on our results from the present study, we concluded that the protective effects of HLWDD against the cognitive deficits and neuronal damages through inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampus of the DE rats.

Ma Huang Tang ameliorates asthma though modulation of Th1/Th2 cytokines and inhibition of Th17 cells in ovalbumin-sensitized mice

AIM： Ma Huang Tang （Ephedra decoction, MHT） is a famous classical formula from Shang Han Lun by Zhang Zhongjing in the Han Dynasty. The anti-asthmatic effects of MHT and the possible mechanisms were tested. METHOD： An asthma model was established by ovalbumin （OVA）-induction in mice. A total of forty-eight mice were randomly assigned to six experimental groups： control, model, dexamethasone （2 mg·kg^-1） and MHT （5, 10, and 20 mg·kg^-1）. Airway resistance （Raw） was measured by the forced oscillation technique, histological studies were evaluated by hematoxylin and eosin （HE） staining, Thl/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay （ELISA）, and Thl7 cells were evaluated by flow cytometry （FCM）.RESULTS： This study demonstrated that MHT inhibited OVA-induced increases in Raw and eosinophil cotmt; interleukin （IL）-4 and IL-17 levels were recovered in bronchoalveolar lavage fluid, increased IFN-γ level in bronchoalveolar lavage fluid. Histological studies demonstrated that MHT substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry studies demonstrated that MHT substantially inhibited Thl 7 cells.CONCLUSION： These findings suggest that MHT may effectively ameliorate the progression of asthma, and could be further investigated for potential use as a therapy for patients with allergic asthma,

Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

Although the etiology of inflammatory bowel disease is still tmcertain, increasing evidence indicates that the excessive activation of NLRP3 inflammasome plays a major role. Norisoboldine （NOR）, an alkaloid isolated from Radix Linderae, has previously been demonstrated to inhibit inflammation and IL-1,8 production. The present study was to examine the effect of NOR on colitis and the underlying mechanism related to NLRP3 inflammasome activation. Our results showed that NOR alleviated colitis symptom in mice induced by 2, 4, 6-trinitrobenzene sulfonic acid （TNBS）. Moreover, it significantly reduced expressions of cleaved IL-lfl, NLRP3 and cleaved Caspase-1 but not ASC in colons of mice. In THP-1 cells, NOR suppressed the expressions of NLRP3, cleaved Caspase-1 and cleaved IL-1β but not ASC induced by lipopolysaccharide （LPS） and adenosine triphosphate （ATP）. Furthermore, NOR could activate aryl hydrocarbon receptor （AhR） in THP-1 cells, inducing CYP1A1 mRNA expression, and promoting dissociation of AhR/HSP90 complexes, association of AhR and ARNT, AhR nuclear translocation, XRE reporter activity and binding activity of AhR/ARNT/XRE. Both siAhR and a-naphthoflavone （a-NF） markedly diminished the inhibition of NOR on NLRP3 inflammasome activation. In addition, NOR elevated Nrf2 level and reduced ROS level in LPS- and ATP-stimulated THP-1 cells, which was reversed by either siAhR or α-NF treatment. Finally, correlations between activation of AhR and attenuation of colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 level in colons were validated in mice with TNBS-induced colitis. Taken together, NOR ameliorated TNBS-induced colitis in mice through inhibiting NLRP3 inflammasome activation via regulating AhR/Nrf2/ROS signaling pathway.

Comparative pharmacokinetics of bergenin,a main active constituent of Saxifraga stolonifera Curt.,in normal and hepatic injury rats after oral administration

Bergenin, isolated from the herb of Saxifrage stolonifera Curt.(Hu-Er-Cao) has hepatoprotective, anti-inflammatory, antitussive, and neuroprotective activities. The aim of the present study was to establish a simple, rapid, and sensitive RP-HPLC method for determination of bergenin in rat plasma and compare its oral pharmacokinetic behaviors in normal and CCl_4-induced hepatic injury rats. With norisoboldine as an internal standard, chromatographic separation was performed on a C_(18) analytical column with acetonitrile and water(11 : 89, V/V) containing 0.1% formic acid as the mobile phase. A good linearity was obtained over the range of 100^(–1)0 000 ng·m L^(–1). The lower limit of quantification was 50 ng·m L~(^(–1)). The developed method was successfully applied to a study of the pharmacokinetic difference of bergenin(100 mg·kg^(–1)) between normal and hepatic injury rats after oral administration. Marked alterations of pharmacokinetic parameters in hepatic injury rats were observed. Compared to normal rats, the AUC_((0–∞)) of bergenin in hepatic injury rats was elevated to 2.11-fold and C_(max) was increased by 130%, whereas CL value was only 55% of the normal rats, suggesting that the systemic exposure of bergenin was significantly increased under hepatic injury status.

Effects of ethanol extract of Bombax ceiba leaves and its main constituent mangiferin on diabetic nephropathy in mice

The present study was designed to explore the mechanism by which ethanol extract of Bombax ceiba leaves(BCE) and its main constituent mangiferin(MGF) affect diabetic nephropathy by combating oxidative stress. Oral administration of BCE and MGF to normal and streptozotocin(STZ)-induced diabetic mice were carried out. Fasting blood glucose, 24-h urinary albumin, serum creatinine, and blood urea nitrogen were tested, histopathology, and immunohistochemical analysis of kidney tissues were performed. Moreover, mesangial cells were treated with BCE and MGF for 48 h with or without 25 mmol·L^(-1) of glucose. Immunofluorescence, Western blot and apoptosis analyses were used to investigate their regulation of oxidative stress and mitochondrial function. BCE and MGF ameliorated biochemical parameters and restored STZ-induced renal injury in the model mice. In vitro study showed that high glucose stimulation increased oxidative stress and cell apoptosis in mesangial cells. BCE and MGF limited mitochondrial membrane potential(Δψm) collapse by inhibiting Nox4, mitochondrially bound hexokinase II dissociation, and subsequent ROS production, which effectively reduced oxidative stress, cleaved caspase-3 expression and cell apoptosis. Our work indicated that BCE and MGF had protective effects on diabetic caused kidney injury and prevented oxidative stress in mesangial cells by regulation of hexokinase II binding and Nox4 oxidase signaling.

Antihyperglycemic,antihyperlipidemic and antioxidant effects of standard ethanol extract of Bombax ceiba leaves in high-fat-diet-and streptozotocin-induced Type 2 diabetic rats

The present study aimed at exploring the therapeutic potential of standard extract of Bombax ceiba L.leaves(BCE) in type 2 diabetic mellitus(T2DM).Oral administration of BCE at doses of 70,140,and 280 mg·kg^(-1),to the normal rats and the high-fat-diet-and streptozotocin-induced T2 DM rats were carried out.Effects of BCE on blood glucose,body weight,and a range of serum biochemical parameters were tested,and histopathological observation of pancreatic tissues was also performed.HPLC-ESI-Q/TOF-MS/MS analysis indicated that the chemical composition of BCE mainly contained mangiferin,isoorientin,vitexin,isomangiferin,isovitexin,quercetin hexoside,2'-trans-O-cumaroyl mangiferin,and nigricanside.BCE caused a significant decrease in the concentrations of fasting blood glucose,glycosylated hemoglobin,total cholesterol,triglyceride,low density lipoprotein-cholesterol,serum insulin,and malondialdehyde,and increases in oral glucose tolerance,high density lipoprotein-cholesterol,and superoxide dismutase in the T2 DM model rats.Moreover,considerable pancreatic β-cells protection effect and stimulation of insulin secretion from the remaining pancreatic β-cells could be observed after BCE treatment.The results indicated that BCE exhibited an excellent hypoglycemic activity,and alleviated dyslipidemia which is associated with T2 DM.Antioxidant activity and protecting pancreatic β-cells are the possible mechanisms involved in anti-diabetic activity of BCE.