Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Black radish root extract alleviates sodium valproate-induced liver damage via inhibiting mitochondrial membrane potential collapse and oxidative stress in mice

Objective:To explore the effect of black radish(Raphanus sativus L.var niger)root extract on liver enzymes,oxidative stress,and histopathological alterations in mice with sodium valproate-induced hepatotoxicity.Methods:Thirty-two mice were divided into four groups:the control group received drinking water by gavage,the second group was administered with 100 mg/kg of sodium valproate,the third group received 300 mg/kg of black radish root extract,and the fourth group was given both sodium valproate(100 mg/kg)and black radish root extract(300 mg/kg).After 28 days,the mice were euthanized,and serum levels of aspartate aminotransferase(AST),alanine aminotransferase(ALT),and alkaline phosphatase(ALP),along with liver malondialdehyde(MDA),reactive oxygen species(ROS),mitochondrial parameters,tumor necrosis factor-alpha(TNF-α)gene expression,and histopathological changes were assessed.Results:Sodium valproate caused hepatic damage in mice,characterized by elevated serum levels of liver enzymes,increased MDA and ROS levels and TNF-αgene expression,as well as histopathological alterations.The black radish root extract significantly alleviated sodium valproate-caused hepatic injury by decreasing the serum levels of ALT and AST,MDA,ROS,TNF-αgene expression,as well as mitochondrial impairment,but did not have a significant effect on sodium valproate-induced histopathological changes.Conclusions:The black radish root extract demonstrates protective effects against sodium valproate-induced liver injury,possibly through mitigating oxidative stress,mitochondrial impairment,and inflammatory mediator expression.

Textile dyeing wastewater negatively influences the hematological profile and reproductive health of male Swiss albino mice

Objective:To determine the effects of textile dyeing industrial wastewater on the hematological parameters and reproductive health including histoarchitecture of male gonad(testes)of mice.Methods:Twenty-four Swiss albino mice at 4-weeks old were divided into four groups(n=6 per group).Mice of group 1 supplied with normal drinking water were served as the control group.Mice of group 2,3 and 4 were supplied normal drinking water mixed with textile dyeing wastewater at 5%,10% and 20% concentration,respectively.After completing 24 weeks of treatment,different hematological profile,weight of testes,gonadosomatic index(GSI),sperm concentration and morphology were measured.Moreover,histopathological changes in testes were examined.Results:Hematocrit value and hemoglobin concentrations were decreased in all groups of wastewater-treated mice compared to the control group.Likewise,weight of testes,GSI and sperm concentration were decreased significantly in wastewater-treated mice in comparison to the control group.The percentage of morphologically healthy epididymal sperm was significantly reduced in wastewater-treated mice.Histopathological examination revealed degenerative changes in seminiferous tubules,a smaller number of spermatogenic cells,elongation of seminiferous tubules and degenerative changes of seminiferous tubules in wastewater-treated mice.Conclusions:Textile dyeing wastewater has harmful effects on hematological profile and reproductive health of male mice.

Gut-microbiome-brain axis:the crosstalk between the vagus nerve,alpha-synuclein and the brain in Parkinson's disease

This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,is involved in the regulation of immune response,digestion,heart rate,and control of mood.It can detect microbiota metabolites through its afferents,transferring this gut information to the central nervous system.Preclinical and clinical studies have shown the important role played by the gut microbiome and gut-related factors in disease development and progression,as well as treatment responses.These findings suggest that the gut microbiome may be a valuable target for new therapeutic strategies for Parkinson's disease.More studies are needed to better understand the underlying biology and how this axis can be modulated for the patient's benefit.

Phosphate,calcium,and vitamin D signaling,transport,and metabolism in the endometria of cyclic ewes

Background Recent evidence suggests important roles for progesterone(P4)and interferon tau in the regulation of calcium,phosphate,and vitamin D signaling in the uteri of pregnant sheep.However,the effects of P4 and estradiol(E2),with respect to the expression of their receptors PGR and ESR1,respectively,in uterine epithelia on mineral signaling during the estrous cycle has not been investigated.Estrous cycles of mature Suffolk ewes were synchronized,prostaglandin F2αwas administered,and ewes were observed for estrus(designated as Day 0)in the presence of vasectomized rams.On Days 1,9,or 14 of the estrous cycle,hysterectomies were performed.Results 25-hydroxyvitamin D was more abundant in plasma from ewes on Day 14 than Day 1(P<0.05).Expression of fibroblast growth factor receptor 2(FGFR2),a disintegrin and metalloprotease 17(ADAM17),and parathyroid hormone-related protein(PTHrP)mRNAs was greater in endometria on Day 9 compared to Days 1 and 14(P<0.01).Similarly,expression of transient receptor potential cation channel subfamily V member 6(TRPV6)mRNA was greater in endometria on Day 9 than Day 1(P<0.05).ATPase plasma membrane Ca^(2+)transporting 4(ATP2B4)and S100 calcium binding protein G(S100G)mRNA expression was greater in endometria on Day 14 than on Days 1 and 9(P<0.01).In contrast,endometrial expression of vitamin D receptor(VDR)mRNA was lower on Days 9 and 14 than Day 1(P<0.01).Expression of klotho(KL)(P<0.05)and cytochrome P450 family 24 subfamily A member 1(CYP24)(P<0.01)mRNAs was lower on Day 14 than Days 1 and 9.ADAM17,FGF23,CYP2R1,CYP27B1,KL,and VDR proteins immunolocalized to the uterine myometrium,blood vessels,and uterine luminal(LE),superficial glandular(sGE),and glandular(GE)epithelia.S100A9 protein was weakly expressed in the uterine myometrium,LE,sGE,and GE.Immunoreactivity of CYP2R1 and KL proteins in uterine LE and sGE was less on Day 1 than on Days 9 and 14.In contrast,S100G protein was expressed exclusively by GE,and immunoreactive S100G protein was less on Day 9.S100A12 protein localized to stromal cells of the uterine stratum spongiosum and blood vessels,but not by uterine epithelial cells.Conclusion Collectively,these results implicate E2,P4,and PGR in the regulation of phosphate,calcium,and vitamin D signaling in cyclic ewes.

Anticancer potential of Ferula assa-foetida and its constituents,a powerful plant for cancer therapy

Cancer is one of the main challenges of the health system around the world.This disease is increasing in developing countries and imposes heavy costs on patients and governments.On the other hand,despite various drugs,the death rate among cancer patients is still high and the current treatments have many harmful effects.In the traditional medicine of different countries,there are many medicinal plants that can be effective in the treatment of cancer.Ferula plants are traditionally used as spices and food or for medicinal purposes.Ferula assa-foetida is one of the famous plants of this genus,which has been used for the treatment of various diseases since ancient times.Among the main compounds of this plant,we can mention monoterpenes,sulfide compounds and polyphenols,which can show different therapeutic effects.This article has been compiled with the aim of collecting evidence and articles related to the anti-cancer effects of extracts,derived compounds,essential oils and nanoparticles containing Ferula assa-foetida.This review article was prepared by searching the terms Ferula assa-foetida and cancer,and relevant information was collected through searching electronic databases such as ISI Web of Knowledge,PubMed,and Google Scholar.Fortunately,the results of this review showed that relatively comprehensive studies have been conducted in this field and shown that Ferula assa-foetida can be very promising in the treatment of cancer.

Comparison of emergency surgical cricothyroidotomy and percutaneous cricothyroidotomy by experienced airway providers in an obese,in vivo porcine hemorrhage airway model

Background: Emergency front-of-neck airway(eFONA) is a life-saving procedure in “cannot intubate, cannot oxygenate”(CICO). The fastest and most reliable method of eFONA has not been determined. We compared two of the most advocated approaches: surgical cricothyroidotomy and percutaneous cricothyroidotomy, in an obese, in vivo porcine hemorrhage model, designed to introduce real-time physiological feedback, relevant and high provider stress. The primary aim was to determine the fastest method to secure airway. Secondary aims were arterial saturation and partial pressure of oxygen, proxy survival and influence of experience.Methods: Twelve pigs [(60.3±4.1) kg] were anesthetized and exposed to 25%–35% total blood volume hemorrhage before extubation and randomization to Seldinger technique “percutaneous cricothyroidotomy”(n=6) or scalpelbougie-tube technique “surgical cricothyroidotomy”(n=6). Specialists in anesthesia and intensive care in a tertiary referral hospital performed the eFONA, simulating an actual CICO-situation.Results: In surgical cricothyroidotomy vs. percutaneous cricothyroidotomy, the median(interquartile range, IQR) times to secure airway were 109(IQR 71–130) s and 298(IQR 128–360) s(P=0.0152), arterial blood saturation(SaO2) were 74.7(IQR 46.6–84.2)% and 7.9(IQR 4.1–15.6)%(P=0.0167), PaO_(2) were 7.0(IQR 4.7–7.7) kPa and 2.0(IQR 1.1–2.9) kPa(P=0.0667), and times of cardiac arrest(proxy survival) were 137–233 s, 190(IQR 143–229) s, from CICO. All six animals survived surgical cricothyroidotomy, and two of six(33%) animals survived percutaneous cricothyroidotomy. Years in anesthesia, 13.5(IQR 7.5–21.3), did not influence time to secure airway.Conclusions: eFONA by surgical cricothyroidotomy was faster and had increased oxygenation and survival, when performed under stress by board certified anesthesiologists, and may be an indication of preferred method in situations with hemorrhage and CICO, in obese patients.

Zataria multiflora and its constituent,carvacrol,counteract sepsis-induced aortic and cardiac toxicity in rat:Involvement of nitric oxide and oxidative stress

Background:Zataria multiflora and carvacrol showed various pharmacological prop-erties including anti-inflammatory and anti-oxidant effects.However,up to now no studies have explored its potential benefits in ameliorating sepsis-induced aortic and cardiac injury.Thus,this study aimed to investigate the effects of Z.multiflora and carvacrol on nitric oxide(NO)and oxidative stress indicators in lipopolysaccharide(LPS)-induced aortic and cardiac injury.Methods:Adult male Wistar rats were assigned to:Control,lipopolysaccharide(LPS)(1 mg/kg,intraperitoneal(i.p.)),and Z.multiflora hydro-ethanolic extract(ZME,50–200 mg/kg,oral)-and carvacrol(25–100 mg/kg,oral)-treated groups.LPS was in-jected daily for 14 days.Treatment with ZME and carvacrol started 3 days before LPS administration and treatment continued during LPS administration.At the end of the study,the levels of malondialdehyde(MDA),NO,thiols,and antioxidant enzymes were evaluated.Results:Our findings showed a significant reduction in the levels of superoxide dis-mutase(SOD),catalase(CAT),and thiols in the LPS group,which were restored by ZME and carvacrol.Furthermore,ZME and carvacrol decreased MDA and NO in car-diac and aortic tissues of LPS-injected rats.Conclusions:The results suggest protective effects of ZME and carvacrol on LPS-induced cardiovascular injury via improved redox hemostasis and attenuated NO pro-duction.However,additional studies are needed to elucidate the effects of ZME and its constituents on inflammatory responses mediated by LPS.

Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

Unraveling the potential of acute intermittent hypoxia as a strategy for inducing robust repair in multiple sclerosis

Multiple sclerosis(MS)is a debilitating inflammatory disease of the central nervous system characterized by immune-mediated segmental demyelination and variable degrees of axonal and neuronal degeneration that contribute to disability.Inducing efficient and effective repair programs following demyelination is a major goal and challenge in MS.Conventional MS therapies focus largely on modulating the immune aspects of the disease contributing to lesions.While this alleviates some symptoms and mitigates damage,it does not tackle the fundamental challenge of effective remyelination,which few MS patients experience,especially in the progressive phase of the disease.

Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents:A narrative review

Glaucoma,an irreversible optic neuropathy,primarily affects retinal ganglion cells(RGC)and causes vision loss and blindness.The damage to RGCs in glaucoma occurs by various mechanisms,including elevated intraocular pressure,oxidative stress,inflammation,and other neurodegenerative processes.As the disease progresses,the loss of RGCs leads to vision loss.Therefore,protecting RGCs from damage and promoting their survival are important goals in managing glaucoma.In this regard,resveratrol(RES),a polyphenolic phytoalexin,exerts antioxidant effects and slows down the evolution and progression of glaucoma.The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina.Additionally,RES plays protective roles in RGCs by promoting cell growth,reducing apoptosis,and decreasing oxidative stress in H_(2)O_(2)-exposed RGCs.RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways.RES could alleviate retinal function impairment by suppressing the hypoxia-i nducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway.Therefore,RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.

Physiology of bile secretion

The formation of bile depends on the structural and functional integrity of the bile-secretory apparatus and its impairment, in different situations, results in the syndrome of cholestasis. The structural bases that permit bile secretion as well as various aspects related with its composition and flow rate in physiological conditions will first be reviewed. Canalicular bile is produced by polarized hepatocytes that hold transporters in their basolateral (sinusoidal) and apical (canalicular) plasma membrane. This review summarizes recent data on the molecular determinants of this primary bile formation. The major function of the biliary tree is modification of canalicular bile by secretory and reabsorptive processes in bileduct epithelial cells (cholangiocytes) as bile passes through bile ducts. The mechanisms of fluid and solute transport in cholangiocytes will also be discussed. In contrast to hepatocytes where secretion is constant and poorly controlled, cholangiocyte secretion is regulated by hormones and nerves. A short section dedicated to these regulatory mechanisms of bile secretion has been included. The aim of this revision was to set the bases for other reviews in this series that will be devoted to specific issues related with biliary physiology and pathology.

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% &#x000b1; 0.4% vs 7.9% &#x000b1; 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 &#x000b1; 3.5 &#x003bc;g/mL vs 3.9 &#x000b1; 2.7 &#x003bc;g/mL, P = 0.06) and triglyceride levels (1.26 &#x000b1; 0.43 mmol/L vs 2.80 &#x000b1; 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 &#x003bc;g/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance

BACKGROUND： Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions.DATA SOURCES： The data of mouse hepatic models and rele- vant human liver diseases presented in this review are system- atically collected from PubMed, ScienceDirect and the Web of Science databases published in English. RESULTS： The hepatotoxic liver injury in mice induced by the metabolites of CC14, acetaminophen or alcohol represent ne- crotic cell death with activation of cytochrome pathway, for- mation of reactive oxygen species （ROS） and mitochondrial damage. The Fas or TNF-a induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrat- ed the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The a-GalCer-induced liver injury was mediated by TNF-a. The LPS-induced hepatitis involved TNF-a, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly（I：C） induced liver injury was mediated by natural killer cells and TNF-a signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune ceils and cell death mediators in viral hepatitis （HBV, HCV）, drug-induced liver injury, non-alcohol- ic fatty liver disease and alcoholic liver disease in human were discussed. CONCLUSIONS： The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.

Food intake regulation by leptin:Mechanisms mediating gluconeogenesis and energy expenditure

Regulation of blood glucose levels and body fat is critical for survival.Leptin circulates freely in blood and controls body weight and food intake mainly through hypothalamic receptors and regulates glucose metabolism in the liver both directly through leptin receptors and indirectly via the hypothalamic receptors of central nervous system.Leptin affects food intake regulation and eventually glucose metabolism, lipometabolism,endocrine and immune functions, reproductive function, adipose tissue metabolism and energy expenditure.Leptin also exerts peripheral effects directly on glucose metabolism and gluconeogenesis.Most of obese human subjects have elevated plasma levels of leptin associated to the size of their total adipose tissue mass.Hence gluconeogenic function may be an essential factor in the regulation of nutritional intake and weight gain.The aim of this review is therefore to identify and module the possible effects of leptin with special application in gluconeogenesis.In addition, this review includes the study of fat consumption and energy expenditure in the body.Specific modulation of leptin receptors and adipose tissues functioning could have important inference on therapeutic strategies.

Screening of ethyl acetate extract of Bridelia micrantha for hepatoprotective and anti-oxidant activities on Wistar rats

Objective:To explore the hepatoprotective and anti-oxidant activities of the methanolic leaf extract of Bridelia micrantha(B.micrantha) on paracetamol induced liver damage in Wistar rats. Methods:Parameters were measured including alanine aminotransaminase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),bilirubin and total protein.The anti-oxidant effects were studied using the 1,l-Diphenynl-2-Picrylhydrazyl(DPPH) and Ferric Reducing Antioxidant Power(FRAP) assay methods.Results:B.micrantha extract decreased the level of AST in the rats given PCM from(129.47±0.921) IU/L to(57.78±1.71) IU/L(P【0.05).This was lower than the value for Silymarin which was(59.92±1.41) IU/L.ALT concentration was reduced from (150.18±2.23) IU/L to(79.10±2.01) IU/L(P【0.05).ALP was reduced from(49.86±0.85) IU/L to(29.64±1.53) IU/L(P【0.05).Total bilirubin was reduced from(2.14±0.10 mg/dL) to(0.18±0.07) mg/dL (P【0.05) while total protein was increased from(4.26±0.30) mg/dL to(6.20±0.19) mg/dL(P【0.05). Concentrations ranging from 10 - 400μg/mL of B.micrantha were assayed for antioxidant activities.The DPPH assay showed 98%antioxidant activity at concentration of 400μg/mL. The FRAP values were 0.016,0.39,0.455,0.601 and 1.382μM at 10.50,100,200 and 400μg/ mL respectively.Conclusions:Results suggest that B.micrantha has hepatoprotective and anti oxidant potentials.However,further work involving fractionation needs to done to isolate the active compound responsible for the hepatoprotective activity.

Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia

AIM:To determine the expression of neurokinin-1receptor(NK-1R),phosphorylated epidermal growth factor receptor(p EGFR),cyclooxygenase-2(Cox-2),and vitamin D receptor(VDR)in normal,inflammatory bowel disease(IBD),and colorectal neoplasia tissues from Puerto Ricans.METHODS:Tissues from patients with IBD,colitisassociated colorectal cancer(CAC),sporadic dysplasia,and sporadic colorectal cancer(CRC),as well as normal controls,were identified at several centers in Puerto Rico.Archival formalin-fixed,paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R,p EGFR,Cox-2,and VDR.Pictures of representative areas of each tissues diagnosis were taken and scored by three observers using a4-point scale that assessed intensity of staining.Tissues with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia,in addition to the areas of cancer,within each tissue.Differences in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons test.The mean scores for normal tissues and tissues with IBD,dysplasia,CRC,and CAC were calculatedand statistically compared using one-way analysis of variance and Dunnett’s multiple comparisons test.Correlations between protein expression patterns were analyzed with the Pearson’s product-moment correlation coefficient.Data are presented as mean±SE.RESULTS:On average,patients with IBD were younger(34.60±5.81)than normal(63.20±6.13,P<0.01),sporadic dysplasia(68.80±4.42,P<0.01),sporadic cancer(74.80±4.91,P<0.001),and CAC(57.50±5.11,P<0.05)patients.NK-1R in cancer tissue(sporadic CRC,1.73±0.34;CAC,1.57±0.53)and sporadic dysplasia(2.00±0.45)were higher than in normal tissues(0.73±0.19).p EGFR was significantly increased in sporadic CRC(1.53±0.43)and CAC(2.25±0.47)when compared to normal tissue(0.07±0.25,P<0.05,P<0.001,respectively).Cox-2 was significantly increased in sporadic colorectal cancer(2.20±0.23 vs 0.80±0.37 for normal tissues,P<0.05).In comparison to normal(2.80±0.13)and CAC(2.50±0.33)tissues,VDR was significantly decreased in sporadic dysplasia(0.00±0.00,P<0.001 vs normal,P<0.001 vs CAC)and sporadic CRC(0.47±0.23,P<0.001 vs normal,P<0.001 vs CAC).VDR levels negatively correlated with NK-1R(r=-0.48)and p EGFR(r=-0.56)in normal,IBD,sporadic dysplasia and sporadic CRC tissue,but not in CAC.CONCLUSION:Immunohistochemical NK-1R and p EGFR positivity with VDR negativity can be used to identify areas of sporadic colorectal neoplasia.VDR immunoreactivity can distinguish CAC from sporadic cancer.

Optimization of Ultrasonic-Assisted Extraction Process of Polysaccharides from American Ginseng and Evaluation of Its Immunostimulating Activity

Ultrasonic-assisted extraction （UAE） of American ginseng polysaccharides （AGP） was investigated using response surface methodology. Three-factor-three-level Box-Behnken design was employed to optimize the ultrasonic power, extraction time and ratio of water to raw material to obtain a high AGP yield. The analysis of variance and response surface plots indicated that ultrasonic power was the most important factor affecting the extraction yield. The optimal conditions were ultrasonic power 400 W, extraction time 71 min, and ratio of water to raw material 33 mL g-1. Under these conditions, the yield of AGP was 8.09%, which was agreed closely to the predicted value. Gas chromatography （GC） analysis showed that AGP was composed of arabinose, rhamnose, galactose, glucose, and galacturonic acid. Fourier transform infrared spectra revealed the general characteristic absorption peaks of AGP. In addition, AGP exhibited good immunostimulating activities by up-regulating the production of nitric oxide and cytokines. Compared with hot water extraction, UAE required shorter extraction time and gave a higher extraction yield, without changing the structure and immunostimulating activity of AGP. The results indicated that UAE could be an effective and advisable technique for the large scale production of plant polysaccharides.

Effects of genistein and equol on human and rat testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities

The objective of the present study was to investigate the effects of genistein and equol on 3β-hydroxysteroid de- hydrogenase （3β-HSD） and 17β-hydroxysteroid dehydrogenase 3 （17β-HSD3） in human and rat testis microsomes. These enzymes （3β-HSD and 17β-HSD3）, along with two others （cytochrome P450 side-chain cleavage enzyme and cytochrome P450 17α-hydroxylase/17-20 lyase）, catalyze the reactions that convert the steroid cholesterol into the sex hormone testosterone. Genistein inhibited 3β-HSD activity （0.2 μmol L^-1 pregnenolone） with half-maximal inhibition or a half-maximal inhibitory concentration （IC50） of 87 ± 15 （human） and 636 ± 155 nmol L^-1 （rat）. Genistein＇s mode of action on 3β-HSD activity was competitive for the substrate pregnenolonrge and noncompetitive for the cofactor NAD＋. There was no difference in genistein＇s potency of 3β-HSD inhibition between intact rat Leydig cells and testis microsomes. In contrast to its potent inhibition of 3β-HSD, genistein had lesser effects on human and rat 17β-HSD3 （0.1 μmol L^-1 androstenedione）, with an IC50 〉 100μmol L^-1. On the other hand, equol only inhibited human 3β-HSD by 42%, and had no effect on 3β-HSD and 17β-HSD3 in rat tissues. These observations imply that the ability of soy isoflavones to regulate androgen biosynthesis in Leydig cells is due in part to action on Leydig cell 3β- HSD activity. Given the increasing intake of soy-based food products and their potential effect on blood androgen levels, these findings are greatly relevant to public health.