Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

Tibolone modulates neuronal plasticity through regulating Tau, GSK3β/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles （NFTs）; these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone （TIB） have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB （0.01 mg/kg and 1mg/kg, intragastrically for 12 weeks） on the content of total and hyperphosphorylated Tau （PHF-1） proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB： it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes.

Hepatoprotective properties of oleanolic and ursolic acids in anti-tubercular drug-induced liver damage

Objective:To estimate to what extent the mixture of ursolic acid and oleanolic acid,in addition to the antitubercular standard regime,affects the hepatotoxicity profile.Methods:Liver injury was induced in male BALB/c mice by administering,per os and daily for 11 weeks,a combination of anti-Tubercular(anti-TB) agents Rifampicin(10 mg/kg),Isoniazid(10 mg/kg),and Pyrazinamide(30 mg/kg).The ursolic acid and oleanolic acid mixture at doses of 100 or 200 μg/mouse/day was subcutaneously injected throughout the entire study period(11 weeks).Biochemical and hematological analysis was supplemented by liver histological examination.Results:Animals treated with the mixture of triterpenic acids exhibited significantly decreased aspartate transaminase and alanine aminotransferase levels and amelioration of the histopathological alterations produced by the anti-TB drugs.Conclusions:The triterpene mixture is able to prevent the steatosis induced by the anti-TB drugs.

Hyperammonemia,brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

AIM:To study the blood-brain barrier integrity,brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS:Adults male Wistar rats were divided into four groups.Group Ⅰ:sham operation;Ⅱ:Prehepatic portal hypertension,produced by partial portal vein ligation;Ⅲ: Acetaminophen intoxication and Ⅳ:Prehepatic portal hypertension plus acetaminophen.Acetaminophen was administered to produce acute hepatic injury.Portal pressure,liver serum enzymes and ammonia plasma levels were determined.Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity.Reflexes and behavioral tests were recorded. RESULTS:Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ.Uver enzymes and ammonia plasma levels were increased in groups Ⅱ,Ⅲ and Ⅳ.Prehepatic portal hypertension (group Ⅱ),acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia.Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ.Behavioral test (rota rod) was altered in group Ⅳ. CONCLUSION:These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (oltotoxic).Group Ⅳ,with behavioral altered test,can be considered as a model for study at an early stage of portal-systemic encephalopathy.

Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercular drugs: A review

Drug-induced liver injury encompasses a spectrum of diseases ranging from mild biochemical abnormalities to acute liver failure; example of this scenery is hepatotoxicity caused by the first-line antituberculous drugs isoniazid, rifampin and pyrazinamide, which are basic for treatment of drug-sensible and drug-resistant tuberculosis. In the search for pharmacological alternatives to prevent liver damage, antitubercular drugs have been the subject of numerous studies and published reviews, a great majority of them carried out by Asian countries. At the same time, hepatoprotectors from plant source are now emerging as a possible alternative to counteract the toxic effects of these therapeutic agents. The present review aims to highlight the most recent studies on the subject, based information published in scientific databases such as Scopus and Pub Med.

Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

AIM： To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 dafer ligation when portal pressure is spontaneously normalized. METHODS： Adult male Wistar rats were divided into four groups： Group Ⅰ： Sham14d, sham operated; Group Ⅱ： PHil, portal vein stenosis, （both groups were used 14 days after surgery）; Group Ⅲ： Sham4od, Sham operated and Group Ⅳ： PH4od Portal vein stenosis （Groups Ⅱ and Ⅳ used 40 d afer surgery）. Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS： Forty days afer stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION： The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.

Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet

AIM To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system.METHODS Sprague-Dawley rats were fed with 8% NaCl high-salt （HS） or 0.4% NaCl （normal-salt, NS） diet for 3 wk, with or without tempol （T） （1 mmol/L, administered in drinking water）. Mean arterial pressure （MAP）, glomerular fltration rate （GFR）, and urinary sodium excretion （UVNa） were measured. We evaluated angiotensin Ⅱ （Ang Ⅱ）, angiotensin 1-7 （Ang 1-7）, angiotensin converting enzyme 2 （ACE2）, mas receptor （MasR）, angiotensin type 1 receptor （AT1R） and angiotensin type 2 receptor （AT2R） in renal tissues by immunohistochemistry.RESULTSThe intake of high sodium produced a slight but signifcant increase in MAP and differentially regulated components of the renal renin-angiotensin system （RAS）. This included an increase in Ang Ⅱ and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang Ⅱ and AT1R, as increase in AT2, ACE2, Ang （1-7） and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang （1-7） and MasR.CONCLUSION These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang Ⅱ. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS.

Natural compounds and extracts from Mexican medicinal plants with anti-leishmaniasis activity: An update

Leishmaniasis is considered as an emerging, uncontrolled disease and is endemic in 98 countries. Annually, about 2 million cases of cutaneous and 500000 cases of visceraltype leishmaniasis are recorded and 60000 persons died from the disease. In Mexico,cutaneous leishmaniasis is known as chiclero's ulcer and is reported in 22 states, it is considered as a health problem. For its treatment, pentavalent antimonial drugs are administered. These drugs cause severe side effects, are costly. Drug-resistant cases have been reported and have been developing for over 70 years. One alternative to the drugs that are currently available is to find active molecules in medicinal plants. Dihydrocorynantheine, corynantheine and corynantheidine are active against Leishmania major,while harmane, pleiocarpin, buchtienin, luteolin and quercetin are active against Leishmania donovani. In Mexico, about 20 medicinal plants have been evaluated against Leishmania mexicana, among which the most active are Tridax procumbens, Lonchocarpus xuul and Pentalinon andrieuxii. From these plants, active compounds with IC_(50)≤30 mg/mL or m M have been isolated, such as 3(S)-16,17-didehydrofalcarinol or Oxylipin, cholestra-4,20,24-trien-3-one or pentalinosterol, 24-methylcholest-4-24(28)-dien-3-one, cholest-4-en-3-one, 6,7-dihydroneridie-none, neridienone, cholest-5,20,24-trien-3β-ol, and isocordoin. Today, only pentalinonsterol has been synthesized and assayed in the visceral leishmaniasis experimental model using BALB/c mice infected with Leishmania donovani. Liposome formulation of this compound administered by intravenous route at 2.5 mg/kg showed a significant reduction of parasite load in mouse liver and spleen.

Has Stewart approach improved our ability to diagnose acid-base disorders in critically ill patients?

The Stewart approach-the application of basic physicalchemical principles of aqueous solutions to blood-is an appealing method for analyzing acid-base disorders. These principles mainly dictate that p H is determined by three independent variables, which change primarily and independently of one other. In blood plasma in vivo these variables are:(1) the PCO2;(2) the strong ion difference(SID)-the difference between the sums of all the strong(i.e., fully dissociated, chemically nonreacting) cations and all the strong anions; and(3) the nonvolatile weak acids(Atot). Accordingly, the p H and the bicarbonate levels(dependent variables) are only altered when one or more of the independent variables change. Moreover, the source of H+ is the dissociation of water to maintain electroneutrality when the independent variables are modified. The basic principles of the Stewart approach in blood, however, have been challenged in different ways. First, the presumed independent variables are actually interdependent as occurs in situations such as:(1) the Hamburger effect(a chloride shift when CO2 is added to venous blood from the tissues);(2) the loss of Donnan equilibrium(a chloride shift from the interstitium to the intravascular compartment to balance the decrease of Atot secondary to capillary leak; and(3) the compensatory response to a primary disturbance in either independent variable. Second, the concept of water dissociation in response to changes in SID is controversial and lacks experimental evidence. In addition, the Stewart approach is not better than the conventional method for understanding acid-base disorders such as hyperchloremic metabolic acidosis secondary to a chloride-rich-fluid load. Finally, several attempts were performed to demonstrate the clinical superiority of the Stewart approach. These studies, however, have severe methodological drawbacks. In contrast, the largest study on this issue indicated the interchangeability of the Stewart and conventional methods. Although the introduction of the Stewart approach was a new insight into acid-base physiology, the method has not significantly improved our ability to understand, diagnose, and treat acid-base alterations in critically ill patients.

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

The field of neuroimmunology has expanded in recent years providing new insights and therapies into pathologies like stroke, autism, and depression. However, few works explore the relationship between inflammatory stimuli and motivation. Thus, the aim of this study was to determine how non-painful inflammatory stimuli affect reward. To test reward-response, we used the morphine and the nicotine induced conditioned place-preference and place-aversion model in rats with non-painful inflammation. The following inflammatory models were used: non-painful infectious inflammation: 24 hrs prior to conditioning sessions, an injection with Calmette-Guerin bacillus (CGB) 1 × 107 cfu, ip, was administered. Non-painful non-infectious inflammation: 24 hrs prior to conditioning sessions, rats’ sciatic nerve was blocked and cut, followed by the injection of carrageenan (750 μl) in the paw. We then measured the cytokine concentration to determine the inflammatory profile of each of our models. Finally, we administered ibuprofen to determine if it could prevent the effect of inflammation over conditioned place-preference. We show that carrageenan significantly reduced the morphine-induced reward. Non-painful inflammatory stimulus, CGB and denervation + carrageenan, inhibit the conditioned place-preference to morphine and nicotine, CGB also block conditioned place-aversion to nicotine;carrageenan has no effect on CPA. The administration of ibuprofen reinstates conditioned place-preference to morphine and nicotine in the carrageenan model, but has no effect in the CGB model;finally ibuprofen has no effect on CPA. Our data suggest that non-painful-inflammatory stimuli inhibit the reward system, independent of cytokine concentration. Furthermore, the administration of a PGE 2 inhibitor can importantly modulate this phenomenon.

Arsenic Removal from Zimapan Contaminated Water Monitored by the Tyndall Effect

In Zimapan Valley, Mexico, up to 1.1 mg·L-1 of arsenic concentrations have been detected in deep wells that are used as drinking water supply for almost 39,000 people, which could have been exposed to levels higher than 10 μg·L-1 of arsenic, the maximum level recommended by the World Health Organization. Chronic consumption of water contaminated with arsenic can cause several diseases, including cancer. For it, the implementation of practical and economical methods to remove arsenic from drinking water is crucial to protect the population health. In this work, an electrochemical method to remove arsenic from drinking water is described. The process, monitored by Tyndall effect, utilizes Cu2+ and Zn2+ ions from a brass electrode in an electrochemical cell with water as electrolyte. Results show that the EC process reduces the concentration of the arsenic diluted in Zimapan water to a level below the limit of detection of the atomic absorption spectrophotometer employed. Arsenic was removed through the formation of Cu and Zn arsenic compounds. Cu2+ and Zn2+ ions form a hydroxide and eventually polycrystalline precipitation of kottigite and cornubite complexes (identified by energy-dispersive X-ray spectroscopy and X-ray diffraction), which are then filtered to eliminate the precipitated arsenic compounds.

Safety and Efficacy of Oral Mirodenafil in Mexican with Erectile Dysfunction

Erectile dysfunction is treated with 5-phospodiesterase inhibitors as Mirodenafil, which has shown its efficacy and safety in Koreans, however;no information in other populations is available. An open clinical trial study was designed to evaluate the efficacy and safety in real life of a fixed-dose of Mirodenafil in Mexican patients with erectile dysfunction. Forty-seven male patients received a 100 mg tablet of Mirodenafil, during 12 weeks. Primary outcome efficacy measure was the percentage of male patients with successful intercourse. Secondary outcomes measures included patient satisfaction, mood and self-esteem level. Safety assessments included laboratory tests, vital signs, physical examination, 12-lead electrocardiogram recordings, and incidence of adverse events by patients. Oral administration of Mirodenafil improved in an 80% - 90% the number of successful intercourses from 7 to 84 days of treatment. Moreover, patients reported a significant increment in their sexual satisfaction, mood and self-esteem. Mirodenafil treatment did not modify vital signs nor anthropometric parameters during 84 days. Mild headache was the most frequent adverse event (17.0%) and there were no severe adverse events during pharmacological treatment. Data suggest that oral Mirodenafil is safety, well tolerated and effective in the Mexican population with erectile dysfunction.

Serum Adiponectin levels in Different Phenotypes of Polycystic Ovary Syndrome

Objectives: to evaluate and compare serum adiponectin levels in different phenotypes of polycystic ovary syndrome (PCOS) and to investigate their correlation with endocrine and metabolic parameters. Material and methods: we studied 5 groups of patients: A (n = 20): H (hyperandrogenism) + O (oligoanovulation) + P (polycystic ovary) [classic phenotype];B (n = 17): H + O [classic phenotype but normal ovaries];C (n = 15): H + P [Ovulatory phenotype];D (n = 17): O + P [Normoandrogenic phenotype];and E (n = 16) control group. Body mass index, waist circumference, waist/hip ratio, blood pressure and hirsutism were evaluated. Serum concentrations of adiponectin, insulin, Creactive protein, SHBG, androgens and lipids were measured. Oral glucose tolerance test was performed. Results: there were no differences between the groups in terms of age and BMI. Total cholesterol, LDL-C and triglyceride levels were higher in phenotype A than in C (P P = 0.03). HOMA-IR, insulin and glucose/insulin ratio were significantly higher in phenotypes A and D vs C and E (P P P < 0.05). Conclusions: adiponectin serum concentrations vary according to the phenotypic expression of PCOS. Our results suggest that adiponectin could be used as a biochemical marker to identify phenotypes at increased metabolic risk.

Adenosine 5'triphosphate transport and accumulation during the cold preservation of rat hepatocytes in University of Wisconsin solution

AIM: We used isolated hepatocytes to investigate how different concentrations of ATP in the University of Wisconsin (UW) solution affected both cellular ATP content and cell viability during the cold storage and the rewarming step. The mechanism involved in ATP transport and accumulation in hypothermia was also determined. METHODS: The cells were preserved up to 72 h in different conditions: UW solution without ATP (a-group), UW+5 mmol/L ATP (b-group), and UW+10 mmol/L ATP (c-group). The ATP content and the cell viability (LDH release) were determined during the cold storage and the rewarming step. In the groups a and c, the respiratory function of the cells at rewarming was studied. In addition, the cell volume of hepatocytes and the mechanism involved in ATP transport and accumulation were assessed. The extracellular degradation of exogenous nucleotides during transport experiments was investigated by a HPLC technique. RESULTS: After three days of cold storage a loss of cellular ATP content was observed in hepatocytes preserved either without nucleotides (a-group) or with 5 mmol/L ATP (b-group). In contrast, 10 mmol/L ATP (c-group) was able to maintain a normal ATP cellular content, with only a 6% diminution after 72 h of cold storage. The respiratory function was significantly different in hepatocytes preserved with 10 mmol/L ATP than without ATP. No significant change was detected For the three groups in cellular volume during the cold storage. We also report that the time course accumulation of [3H]-ATP by cold stored hepatocytes is a rapid process that is completed after 180 s with linear dependence on the extracellular ATP concentration (linear fitting results in a slope of 0.5624±0.1179 mmol/L ATP intracell/mmcl/L ATP extracell). CONCLUSION: Our results show that, during hypothermic storage in UW solution, hepatocytes are permeable to ATP by a diffusive mechanism. Also, we found that it is ATP the main extracellular nucleotide available for transport and it is not the breakdown products.

Brain angiotensin Ⅱ in dopaminergic imbalance-derived pathologies:neuroinflammation and vascular responses

Brain angiotensinⅡ(ANGⅡ)as a pleiotropic player:Mental disorders have been commonly associated with an imbalance in many neurotransmitter systems,such as dopamine,glutamate,and gamma-aminobutyric acid.Considering the complexity of brain functioning,all components of the neurovascular unit should be considered in studies for a better comprehension of the physiopathology and possible therapeutics.

Gut microbiota in a population highly affected by obesity and type 2 diabetes and susceptibility to COVID-19

Coronavirus disease 2019(COVID-19)is a disease produced by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and it is currently causing a catastrophic pandemic affecting humans worldwide.This disease has been lethal for approximately 3.12 million people around the world since January 2020.Globally,among the most affected countries,Mexico ranks third in deaths after the United States of America and Brazil.Although the high number of deceased people might also be explained by social aspects and lifestyle customs in Mexico,there is a relationship between this high proportion of deaths and comorbidities such as high blood pressure(HBP),type 2 diabetes,obesity,and metabolic syndrome.The official epidemiological figures reported by the Mexican government have indicated that 18.4%of the population suffers from HBP,close to 10.3%of adults suffer from type 2 diabetes,and approximately 36.1%of the population suffers from obesity.Disbalances in the gut microbiota(GM)have been associated with these diseases and with COVID-19 severity,presumably due to inflammatory dysfunction.Recent data about the association between GM dysbiosis and metabolic diseases could suggest that the high levels of susceptibility to SARSCoV-2 infection and COVID-19 morbidity in the Mexican population are primarily due to the prevalence of type 2 diabetes,obesity,and metabolic syndrome.

Effect of dichloromethylene diphosphonate on liver regeneration following thioacetamide-induced necrosis in rats

AIM: To study the effect of dichloromethylene diphos-phonate (DMDP), a selective Kupffer cell toxicant in reference to liver damage and postnecrotic liver regeneration in rats induced by sublethal dose thioacetamide (TA). METHODS: Rats, intravenously (iv ) pre-treated with a single dose of DMDP (10 mg/kg), were intraperitoneally (ip ) injected with TA 6.6 mmol/kg (per 500 mg/kg body weight). Hepatocytes were isolated from rats at 0, 24, 48 and 72 h following TA intoxication and blood and liver samples were obtained. To evaluate the mecha-nisms involved in the postnecrotic regenerative state, DNA distribution and ploidy time course were assayed in isolated hepatocytes. Circulating cytokine tumor necrosis factor-alpha (TNF-α) was assayed in serum and determined by reverse transcriptase-polymerase chain reaction in liver extract. RESULTS: The effect of DMDP induced noticeable changes in postnecrotic regeneration, causing an increased percentage of hepatocytes in the cell cycle S phase. The increase at 24 h in S1 population in rats pretreated with DMDP + TA was significantly (P < 0.05) different compared with that of the TA group (18.07% vs 8.57%). Hepatocytes increased their proliferation as a result of these changes. Also, TNF-α expression and serum level were increased in rats pre-treated with DMDP. Thus, DMDP pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. CONCLUSION: These results demonstrate that Kupffer cells are involved in TA-induced liver, as well as in post-necrotic proliferative liver states.

Anti-inflammatory evaluation and acute toxicity of three food supplements that contain Moussonia deppeana

Objective:To identify the anti-inflammatory activity through two murine models and in the median Lethal Dose(LD_(50)) of three dietary supplements that contain Moussonia deppeana.Methods:The anti-inflammatory activity of three dietary supplements(Cicatrisan/Gastricus^(R),Gastinol^(R),and Gastrovita^(R)) EtOH extracts was evaluated by TPA and by carrageenan murine models;also,median Lethal Dose(LD_(50)) was determined.Verbascoside was quantified by High-Performance Liquid Chromatography.β-sitosterol,stigmasterol and the mixture of ursolic and oleanolic acids were identified in all supplements by TLC;however,none of these dietary supplements contain verbascoside.Results:For the TPA model,Cicatrisan/Gastricus^(R)generated a notable effect with 38.24%inhibition.While in the carrageenan model,it also exhibited noteworthy anti-inflammatory activity of ear edema with 66.39%of paw edema inhibition at 150 mg/kg,followed by Gastinol^(R) and Gastrovita^(R) with 50%at 300 mg/kg.Finally,LD_(50) was >2 g/kg for all supplements,when was administered intragastrically and Body Weight(BW) gain in mice was not altered after 14 days.Conclusions:Of the three food supplements containing M.deppeana,only the EtOH extract from the Cicatrisan/Gastricus^(R)formulation(tablets) showed significant anti-inflammatory activity in both experimental models and the LD_(50) was > 2 g/kg.

Noise-induced hippocampal damage:potential mechanisms

Exposure to noise of high intensities(> 80 dB) is considered a stressful event and might produce both auditory and extra-auditory damage,including different central nervous system(CNS) injuries.Within the CNS,the hippocampus(HC),a structure related to several cognitive functions,has shown to be particularly susceptible to the effects of noise.

Ayahuasca:Uses,Phytochemical and Biological Activities

Ayahuasca(caapi,yajé),is a psychoactive brew from the Amazon Basin region of South America traditionally considered a“master plant.”It is prepared as a decoction from Banisteriopsis caapi and Psychotria viridis,which it is thought that it stimulates creative thinking and visual creativity.Native healers of the Orinoco and Amazon basins have used traditionally ayahuasca as a healing tool for multiple purposes,particularly to treat psychological disorders in the patients,with some beneficial effects experimentally and clinically validated.Recently,several syncretic religions,as the“Uniao de Vegetal”(UDV)group in Brazil,have been spread around the world.The use of ayahuasca has been popularized by internet and smart-shops,bringing the psychoactive substance to new highs,emerging new“ayahuasqueros.”Ayahuasca has alkaloids asβ-carbolines and dimethyltryptamines,which inhibit the monoamine oxidase and active the 5-HT_(2A)(5-hydroxytryptamine)receptor,respectively,resulting in hallucinations in the users.Ayahuasca induces a psychedelic change in the anteroposterior coupling of the electrophysiological brain oscillations in humans.Traditional ayahuasca beverage is generating pharmacological,commercial and spiritual interest among the scientific community,government people,and different populations worldwide.The goal of this article is to report about the uses,chemistry and biological activities of ayahuasca.