Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.

Bamboo Fibers Elaborating Cellulose Hydrogel Films for Medical Applications

Bamboo fibers were used as source to prepare cellulose hydrogel films for cell cultivation scaffold. The preparation of cellulose solutions was carried out by three different dissolving methods with NaOH-based and NaOH/urea aqueous solutions and DMAc/LiCl solution. Several hydrogel films were elaborated and their properties were compared to evaluate the effect of the dissolving method. It was found that tensile strength of the resultant hydrogel films increased from 21 to 66 N/mm2 when DMAc/LiCl was used instead of the NaOH/urea solution. The same tendency was observed in the obtained elongation values. Moreover, a remarkable difference in fibroblast cell cultivation was observed in higher cell density, when DMAc/LiCl method was used. The obtained results with DMAc/LiCl also were seen to be higher than the results for PS dish used as control. However, low cytocompatibility was observed when NaOH and NaOH/urea methods were used. The obtained results showed that hydrogel films elaborated with cellulose solution prepared with DMAc/LiCl method exhibited good cytocompatibility for the cell cultivation scaffold.

IL28B polymorphisms associated with therapy response in Chilean chronic hepatitis C patients

AIM:To analyze the association of three IL28B single nucleotide polymorphisms with response to therapy in Chilean patients infected with hepatitis C virus CV.METHODS:We studied two groups of patients with chronic CV infection genotype 1,under standard combined treatment with pegylated interferon plus ribavirin.One group consisted of 50 patients with sustained virological response,whereas the second group consisted of 49 null responders.In order to analyze the IL28B single nucleotide polymorphisms rs12979860,rs12980275 and rs8099917,samples were used for polymerase chain reaction amplification,and the genotyping was performed by restriction fragment lengthpolymorphism.RESULTS:The IL28B rs12979860 CC,rs12980275 AA and rs8099917 TT genotypes were much more frequently found in patients with sustained virological response compared to null responders 38%,44% and 50% vs 2%,8.2% and 8.2%,respectively.These differences were highly significant in all three cases(P < 0.0001.CONCLUSION:The three IL28B polymorphisms studied are strongly associated with sustained virological response to therapy in Chilean patients with chronic CV genotype 1.

Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic diseases that includes ulcerative colitis,Crohn’s disease,and indeterminate colitis.Patients with IBD require prolonged treatment and high utilization of healthcare resources for proper management.The treatment of patients with IBD is focused on achieving therapeutic goals including clinical,biochemical,and endoscopic variables that result in improvement of the quality of life and prevention of disability.Advanced IBD treatment includes tumor necrosis factor inhibitors,integrin antagonist,antagonist of the p40 subunit of interleukin 12/23,and small molecule drugs.However,despite the multiple treatments available,about 40%of patients are refractory to therapy and present with persistent symptoms that have a great impact on their quality of life,with hospitalization and surgery being necessary in many cases.Dual therapy,a strategy sometimes applicable to refractory IBD patients,includes the combination of two biologics or a biologic in combination with a small molecule drug.There are two distinct scenarios in IBD patients in which this approach can be used:(1)Refractory active luminal disease without extraintestinal manifestations;and(2)patients with IBD in remission,but with active extraintestinal manifestations or immune-mediated inflammatory diseases.This review provides a summary of the results(clinical response and remission)of different combinations of advanced drugs in patients with IBD,both in adults and in the pediatric population.In addition,the safety profile of different combinations of dual therapy is analyzed.The use of newer combinations,including recently approved treatments,the application of new biomarkers and artificial intelligence,and clinical trials to establish effectiveness during long-term followup,are needed to establish new strategies for the use of advanced treatments in patients with refractory IBD.

Association between EGF +61A/G polymorphism and gastric cancer in Caucasians

AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study. METHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian. RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021). CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men.

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma(HCC)worldwide,and this association is likely to remain during the next decade.Moreover,viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years.In order to reduce such a burden,some major challenges must be faced.Universal vaccination against hepatitis B virus,especially in the neonatal period,is probably the most relevant primary preventive measure against the development of HCC.Moreover,considering the large adult population already infected with hepatitis B and C viruses,it is also imperative to identify these individuals to ensure their access to treatment.Both hepatitis B and C currently have highly effective therapies,which are able to diminish the risk of development of liver cancer.Finally,it is essential for individuals at high-risk of HCC to be included in surveillance programs,so that tumors are detected at an early stage.Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program.As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis,other high-risk groups of patients with hepatitis B are also candidates for surveillance.Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.

Microbiological Quality of Asadero Cheese Manufactured with a Plant Based Coagulant from <i>Solanum elaeagnifolium</i>

In Chihuahua, north Mexico, the berries of Solanum elaeagnifolium (trompillo or silverleaf nightshade) have been used in the manufacture of artisanal filata-type asadero cheese. Solanum elaeagnifolium is a wild plant that possesses proteases in its fruit;those enzymes exhibit general proteolytic activities, which are useful in traditional asadero cheesemaking as a rennet substitute. These type of cheese is softer than those made with rennin or chymosin due to their water content and proteolysis. Thus, the aim of this work was to explore microbiological susceptibility of asadero cheese made with an extract from ripe berries and compared with those elaborated with commercial rennet. Crude extract of such fruit was obtained by salting out with ammonium sulfate (40%). Cheeses were obtained by a standardized process only changing the enzyme, packaged in plastic bag or vacuum bag and storage at 4℃ -?6℃. The study included the analysis of spoilage bacteria (total aerobic count, yeasts and molds), indicators of hygiene (total coliforms and E. coli) and fecal contamination (fecal coliforms) after 1, 7, 14, 21 and 28 days of production. Although cheese made with S. elaeagnifolium had lower microbial growth, the aerobic count and yeasts and molds count of all cheese samples showing a 28 days shelf life. Total coliforms, in limits beyond the established ones by the Mexican legislation for human consumption with no effect of the enzyme type used for production, as well as for fecal coliforms. Differences were detected just for packaged method, suggesting that good manufacturing practices take place not the plant coagulant.

Glial-derived transforming growth factor β1(TGF-β1):a key factor in multiple sclerosis neuroinflammation

Glial cell activation and neuroinflammation in multiple sclerosis(MS):MS is an irreversible and progressive central nervous system(CNS)disease which originates in the autoimmune attack of lymphocytes against CNS myelin.This specialized membrane,synthesized by oligodendrocytes(OL)in the CNS,provides metabolic support to axons and allows for saltatory conduction in neurons.The lack of myelin(i.e.,demyelination)leads to axonal degeneration,neuronal death,and the consequent neurological disabilities(Franklin and Ffrench-Constant,2017).

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PDAC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer detection.Endoscopic ultrasound(EUS)is a premium image modality for PDAC screening and precursor lesion characterization.While no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases.AIM To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by EUS.METHODS This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,Portugal.All patients provided written informed consent.EUS and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all subjects.EUS-guided tissue acquisition was done whenever necessary.For statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was used.All graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(82.0%,IQR:28.9%-98.2%),NLOD(12.6%,IQR:5.2%-63.4%),and CG(16.2%,IQR:6.6%-20.1%)(P<0.0001).Median levels of CA 19-9 were within the normal range in all groups(standard clinical cut-off of 37 U/mL).Within HR,individuals with a positive history of cancer had higher median levels of GPC1+crExos(97.9%;IQR:61.7%-99.5%),compared to those without(59.7%;IQR:26.3%-96.4%),despite no statistical significance(P=0.21).Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+crExos(99.6%;IQR:97.6%-99.8%)compared to those without(96.5%;IQR:81.3%-99.5%)(P=0.011),presenting an area under the receiver operating characteristic curve value of 0.723(sensitivity 75.0%and specificity 67.7%,using a cutoff of 98.5%;P=0.012).CONCLUSION GPC1+crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions,and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.

Administering Copper Blocks CA1 Neuron Hyper-Excitability in Rat Hippocampal Slices

The aim of this study was to determine the capacity of copper to modify synaptic hyperexcitability generated by penicillin G. This epileptogenic drug was studied with CA1 neurons of the rat hippocampus. Hippocampal slices were extracted from adult male Wistar rats (n = 16). The field potentials (FP) were registered in CA1 neurons after electrical stimulation from the stratum radiatum. The mean voltage and duration of FP were measured during control, penicillin G, copper and washout stages. Copper (100 μM) significantly decreased mean FP voltage compared to the control and penicillin stages. However, during the washout stage, the mean FP voltage was significantly higher than in the penicillin stage. Regarding the FP duration, 100 μM of copper significantly decreased the mean FP during the penicillin stage. After the washing stage, the mean FP lasted significantly longer. Thus, administering copper modified CA1 synapses by blocking hippocampal neuronal excitability was generated by the epileptic agent.

Antioxidant Capacity and Bioaccessibility of Synergic Mango (cv. Ataulfo) Peel Phenolic Compounds in Edible Coatings Applied to Fresh-Cut Papaya

Edible coatings (EC) applied to fresh-cut fruits are used to increase their shelf-life and to deliver antioxidant bioactives such as phenolic compounds (PC) that reduce their oxidative damage while enhance their functional value. However, the combination of different PC may have synergetic, additive or antagonic effects on the final antioxidant capacity (AOXC). The aim of this study was to examine the AOXC of binary combinations of selected PC from mango peel and their bioaccessibility from 6% alginate-based EC applied to fresh-cut papaya, under simulated gastrointestinal conditions. Among equimolar (0.1 mM) combinations, gallic + protocatechuic acids (AB) were synergic in radical scavenging activity (RSA) as assayed by DPPH (90% RSA) and FRAP (0.39 mg TE/mL) methods;when assayed in 6% alginate-based EC, their RSA increased (117.85% RSA, 0.88 mg TE/mL). The application of EC + AB to papaya cubes and further in vitro digestion decreased their AOXC probably due to interactions between EC and papaya’s matrix. Therefore, further studies are needed in order to evaluate the effect of combination of phenolic and EC applied in other fruits matrix on antioxidants bioaccessibility.

Oxidative stress in brickmakers of Juárez City, Chihuahua, México: Case-control study

A case-control study was conducted in a brickmaker’s community in Juarez City, Chihuahua in Mexico. This population has been chronically exposed to a wide spectrum of potentially health-damaging pollutants that include coarse, fine and ultrafine particles, carbon monoxide (CO), oxides of nitrogen and sulphur, transitional metals, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds and bioaerosols. Lipid peroxidation level (LPX) and protein carbonyl content (PCC) help to evaluate oxidized protein content and activity of the antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were evaluated in blood samples of study participants. The group of occupationally exposed (OE) workers consisted of 30 individuals ranging in age from 25 to 55 years, with a mean of 15 years in a brick production-related job. The control group included 30 volunteers who were neither environmentally nor occupationally exposed to brick production activities and whose sociodemo-graphic characteristics were similar to the OE group. Results indicate that none of workers used any type of protective equipment (respirator or face mask, gloves, coveralls) during brick manufacturing. LPX and PCC significantly increased (p < 0.5) in the OE group compared to the control group. SOD, CAT and GPx activity was significantly increased (p < 0.5) in the OE group compared to the control group. Therefore, evaluation of stress oxidative biomarkers is advisable in order to assay chronic exposure to workers in brick manufacturing.

Development of Chitosan/Poly(L-Lactide)/Multiwalled Carbon Nanotubes Scaffolds for Bone Tissue Engineering

This work focuses to improve the mechanical properties and investigates the growth of osteoblasts on a degradable chitosan/poly(L-lactide)/carbon nanotubes composite for tissue engineering. The morphological and mechanical properties characterizations were performed using scanning electronic microscopy (SEM) and rheometrics analysis system (RSA). Osteoblasts differentiation was determined by alkaline phosphatase activity, total number cells by an Alamar Blue assay, cell attachment and proliferation were visualized qualitatively using SEM, mineralization was characterized by transformed infrared spectroscopy, energy dispersive spectroscopy, and X-ray diffraction. The results suggest that the chitosan/poly(L-lactide)/multiwalled carbon nanotubes composites exhibit the ability to promote cell adhesion, proliferation, and differentiation on their surface.

Current Knowledge on Hepatitis E

Although only a single serotype of hepatitis E virus (HEV),the causative agent of hepatitis E,has been identified,there is great genetic variation among the different HEV isolates reported.There are at least four major recognized genotypes of HEV:genotypes 1 and 2 are mainly restricted to humans and linked to epidemic outbreaks in nonindustrialized countries,whereas genotypes 3 and 4 are zoonotic in both developing and industrialized countries.Besides human strains,genotype 3 and 4 strains of HEV have been genetically characterized from swine,sika deer,mongooses,sheep,and rabbits.Currently,there are approximately 11,000 human and animal sequences of HEV available at the International Nucleotide Sequence Database Collaboration.HEV is the major cause of waterborne outbreaks of hepatitis in areas of poor sanitation.Additionally,it is responsible for sporadic cases of viral hepatitis in not only endemic but industrialized countries as well.Transmission of HEV occurs predominantly by the fecal-oral route,although parenteral and perinatal routes have been reported.HEV infection develops in most individuals as a self-limiting,acute,icteric hepatitis;with mortality rates around 1%.However,some affected individuals will develop fulminant hepatic failure,a serious condition that is frequently fatal without a liver transplant.This complication is particularly common when the infection occurs in pregnant women,where mortality rates rise dramatically to up to 25%.Among the preventive measures available to avoid HEV infection,two separate subunit vaccines containing recombinant truncated capsid proteins of HEV have been shown to be highly effective in the prevention of disease.One of them,HEV 239,was approved in China,and its commercialization by Innovax began in November 2012 under the name Hecolin(R).

Intranasal rapamycin ameliorates Alzheimerlike cognitive decline in a mouse model of Down syndrome

Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain,prior and after the development of Alzheimer Disease(AD).The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways,including insulin signaling and autophagy,involved in pathology onset and progression.Within this context,the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena.By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol(InRapa)that maximizes brain delivery and reduce systemic side effects.Methods:Ts65Dn mice were administered with InRapa for 12 weeks,starting at 6 months of age demonstrating,at the end of the treatment by radial arms maze and novel object recognition testing,rescued cognition.Results:The analysis of mTOR signalling,after InRapa,demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR(reduced to physiological levels),which led,through the rescue of autophagy and insulin signalling,to reduced APP levels,APP processing and APP metabolites production,as well as,to reduced tau hyperphosphorylation.In addition,a reduction of oxidative stress markers was also observed.Discussion:These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis,thus ultimately resulting in improved cognition.Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

Neurological disorders(NDs)are characterized by progressive neuronal dysfunction leading to synaptic failure,cognitive impairment,and motor injury.Among these diseases,Alzheimer’s disease(AD),Parkinson’s disease(PD),Huntington’s disease(HD),and amyotrophic lateral sclerosis(ALS)have raised a significant research interest.These disorders present common neuropathological signs,including neuronal dysfunction,protein accumulation,oxidative damage,and mitochondrial abnormalities.In this context,mitochondrial impairment is characterized by a deficiency in ATP production,excessive production of reactive oxygen species,calcium dysregulation,mitochondrial transport failure,and mitochondrial dynamics deficiencies.These defects in mitochondrial health could compromise the synaptic process,leading to early cognitive dysfunction observed in these NDs.Interestingly,skin fibroblasts from AD,PD,HD,and ALS patients have been suggested as a useful strategy to investigate and detect early mitochondrial abnormalities in these NDs.In this context,fibroblasts are considered a viable model for studying neurodegenerative changes due to their metabolic and biochemical relationships with neurons.Also,studies of our group and others have shown impairment of mitochondrial bioenergetics in fibroblasts from patients diagnosed with sporadic and genetic forms of AD,PD,HD,and ALS.Interestingly,these mitochondrial abnormalities have been observed in the brain tissues of patients suffering from the same pathologies.Therefore,fibroblasts represent a novel strategy to study the genesis and progression of mitochondrial dysfunction in AD,PD,HD,and ALS.This review discusses recent evidence that proposes fibroblasts as a potential target to study mitochondrial bioenergetics impairment in neurological disorders and consequently to search for new biomarkers of neurodegeneration.