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1.
J Nanobiotechnology ; 22(1): 249, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745193

ABSTRACT

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Cell Survival , Mitoxantrone , Organosilicon Compounds , Humans , Breast Neoplasms/drug therapy , Female , Cell Survival/drug effects , Organosilicon Compounds/chemistry , Organosilicon Compounds/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Mitoxantrone/pharmacology , Mitoxantrone/chemistry , Mitoxantrone/therapeutic use , Cell Line, Tumor , Drug Carriers/chemistry , Silicon Dioxide/chemistry , Porosity , Drug Liberation , Nanoparticles/chemistry , MCF-7 Cells , Nanomedicine/methods , Reactive Oxygen Species/metabolism
2.
J Med Chem ; 67(8): 6410-6424, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38592014

ABSTRACT

We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.


Subject(s)
Antineoplastic Agents , Organoplatinum Compounds , Prodrugs , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesis , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Animals , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/chemical synthesis , Ligands , Mice , Cell Line, Tumor , Silanes/chemistry , Silanes/pharmacology , Structure-Activity Relationship , Drug Screening Assays, Antitumor , HT29 Cells
3.
J Clin Nurs ; 33(6): 2226-2236, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38476057

ABSTRACT

AIMS: To assess the effects of COVID-19 pandemic on clinical variables as part of the routine clinical monitoring of patients with chronic diseases in primary care. DESIGN: A prospective longitudinal study was conducted in primary care centres of the Andalusian Health Service. METHODS: Data were recorded before the pandemic (T1), during the declaration of the state of emergency (T2) and in the transition phase (T3). The Barthel index and the Short Portable Mental Status Questionnaire (SPMSQ) were used to analyse functional and cognitive changes at the three time points. HbA1c, systolic and diastolic blood pressure, heart rate, BMI and lipid levels were assessed as clinical variables. Descriptive statistics and non-parametric chi-square test were used for analysis. STROBE checklist was used for the preparation of this paper. RESULTS: A total fo148 patients with chronic conditions were included in the analysis. Data analysis revealed in T2 only significant reductions in BMI, total levels of cholesterol and HDL during the onset of the pandemic. Barthel Index, SPMSQ, blood pressure and triglycerides and LDL levels worsened in T2, and the negative effects were maintained in T3. Compared to pre-pandemic values, HbA1c levels improved in T3, but HDL levels worsened. CONCLUSIONS: COVID-19 has drastically disrupted several functional, cognitive and biological variables. These results may be useful in identifying clinical parameters that deserve closer attention in the case of a new health crisis. Further studies are needed to assess the potential impacts of each specific chronic condition. IMPACT: Cognitive and functional status, blood pressure and triglycerides and LDL levels worsen in short term, maintaining the negative effects in medium-term.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Longitudinal Studies , Prospective Studies , Male , Chronic Disease , Female , Middle Aged , Aged , Pandemics , SARS-CoV-2 , Spain/epidemiology , Adult , Primary Health Care
4.
Neurol Int ; 15(4): 1253-1272, 2023 Oct 10.
Article in English | MEDLINE | ID: mdl-37873836

ABSTRACT

Type 2 diabetes mellitus (T2D) is a metabolic disease reaching pandemic levels worldwide. In parallel, Alzheimer's disease (AD) and vascular dementia (VaD) are the two leading causes of dementia in an increasingly long-living Western society. Numerous epidemiological studies support the role of T2D as a risk factor for the development of dementia. However, few basic science studies have focused on the possible mechanisms involved in this relationship. On the other hand, this review of the literature also aims to explore the relationship between T2D, AD and VaD. The data found show that there are several alterations in the central nervous system that may be promoting the development of T2D. In addition, there are some mechanisms by which T2D may contribute to the development of neurodegenerative diseases such as AD or VaD.

5.
Article in English | MEDLINE | ID: mdl-37297528

ABSTRACT

The development of the personality of university students can determine their affinities for certain disciplines; therefore, it is important to know their specific socio-demographic and motivational profile, what motivates them to start a certain university degree and what encourages them to continue with it, which can help to adapt the teaching methodology. A total of 292 university students from the University of Granada (Ceuta and Melilla campuses) participated in this quantitative study with a descriptive, cross-sectional design, in which motivation and social skills were analysed. Among the results, it can be highlighted that the student population is mainly female, with a higher level of motivation. Sociability, communication, thinking (optimistic or pessimistic), empathy and self-confidence are skills that affect university students' motivation levels. This study highlights the importance and impact of students' motivation on their learning and the development of their social competence, so it is essential to carry out educational interventions that promote these types of skills, especially in cross-border contexts, which can be demotivating environments.


Subject(s)
Learning , Motivation , Humans , Female , Male , Universities , Cross-Sectional Studies , Students
6.
Int J Mol Sci ; 24(10)2023 May 12.
Article in English | MEDLINE | ID: mdl-37240018

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. The aim of this study is to analyze the possible relationship between the rate of disease progression (functional rating scale (ALS-FRS)) and the plasma lipid levels at the early stage of ALS. A systematic review was carried out in July 2022. The search equation was "Triglycerides AND amyotrophic lateral sclerosis" and its variants. Four meta-analyses were performed. Four studies were included in the meta-analysis. No significant differences were observed between the lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol) and the ALS-FRS score at the onset of the disease. Although the number of studies included in this research was low, the results of this meta-analytic study suggest that there is no clear relationship between the symptoms observed in ALS patients and the plasma lipid levels. An increase in research, as well as an expansion of the geographical area, would be of interest.


Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Humans , Triglycerides , Cholesterol, HDL , Cholesterol, LDL
7.
Int J Mol Sci ; 24(9)2023 Apr 28.
Article in English | MEDLINE | ID: mdl-37175748

ABSTRACT

Aging continues to be the main cause of the development of Alzheimer's, although it has been described that certain chronic inflammatory pathologies can negatively influence the progress of dementia, including obesity and hyperlipidemia. In this sense, previous studies have shown a relationship between low-density lipoprotein receptor (LDLR) and the amyloid-beta (Aß) binding activity, one of the main neuropathological features of Alzheimer's disease (AD). LDLR is involved in several processes, including lipid transport, regulation of inflammatory response and lipid metabolism. From this perspective, LDLR-/- mice are a widely accepted animal model for the study of pathologies associated with alterations in lipid metabolism, such as familial hypercholesterolemia, cardiovascular diseases, metabolic syndrome, or early cognitive decline. In this context, we induced hyperlipidemia in LDLR-/- mice after feeding with a high-saturated fatty acid diet (HFD) for 44 weeks. LDLR-/--HFD mice exhibited obesity, hypertriglyceridemia, higher glucose levels, and early hepatic steatosis. In addition, HFD increased plasmatic APOE and ubiquitin 60S levels. These proteins are related to neuronal integrity and health maintenance. In agreement, we detected mild cognitive dysfunctions in mice fed with HFD, whereas LDLR-/--HFD mice showed a more severe and evident affectation. Our data suggest central nervous system dysfunction is associated with a well-established metabolic syndrome. As a late consequence, metabolic syndrome boots many behavioral and pathological alterations recognized in dementia, supporting that the control of metabolic parameters could improve cognitive preservation and prognosis.


Subject(s)
Alzheimer Disease , Hyperlipidemias , Metabolic Syndrome , Mice , Animals , Metabolic Syndrome/genetics , Metabolic Syndrome/complications , Diet, High-Fat , Alzheimer Disease/pathology , Obesity/complications , Hyperlipidemias/complications , Cognition , Fatty Acids , Receptors, LDL/genetics , Receptors, LDL/metabolism , Disease Models, Animal
8.
Pharmaceutics ; 15(3)2023 Feb 25.
Article in English | MEDLINE | ID: mdl-36986631

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative pathology, the origin of which is associated with the death of neuronal cells involved in the production of dopamine. The prevalence of PD has increased exponentially. The aim of this review was to describe the novel treatments for PD that are currently under investigation and study and the possible therapeutic targets. The pathophysiology of this disease is based on the formation of alpha-synuclein folds that generate Lewy bodies, which are cytotoxic and reduce dopamine levels. Most pharmacological treatments for PD target alpha-synuclein to reduce the symptoms. These include treatments aimed at reducing the accumulation of alpha-synuclein (epigallocatechin), reducing its clearance via immunotherapy, inhibiting LRRK2, and upregulating cerebrosidase (ambroxol). Parkinson's disease continues to be a pathology of unknown origin that generates a significant social cost for the patients who suffer from it. Although there is still no definitive cure for this disease at present, there are numerous treatments available aimed at reducing the symptomatology of PD in addition to other therapeutic alternatives that are still under investigation. However, the therapeutic approach to this pathology should include a combination of pharmacological and non-pharmacological strategies to maximise outcomes and improve symptomatological control in these patients. It is therefore necessary to delve deeper into the pathophysiology of the disease in order to improve these treatments and therefore the quality of life of the patients.

9.
Biomedicines ; 11(1)2023 Jan 05.
Article in English | MEDLINE | ID: mdl-36672646

ABSTRACT

Life expectancy has been boosted in recent decades at expenses of increasing the age-associated diseases. Dementia, for its incidence, stands out among the pathologies associated with aging. The exacerbated cognitive deterioration disables people from carrying out their daily lives autonomously and this incidence increases exponentially after 65 years of age. The etiology of dementia is a miscellaneous combination of risk factors that restrain the quality of life of our elderly. In this sense, it has been established that some metabolic pathologies such as obesity and diabetes act as a risk factor for dementia development. In contrast, a high educational level, as well as moderate physical activity, have been shown to be protective factors against cognitive impairment and the development of dementia. In the present study, we have evaluated the metabolic composition of a population between 60-90 years old, mentally healthy and with high academic degrees. After assessing agility in mental state, we have established relationships between their cognitive abilities and their body composition. Our data support that excess body fat is associated with poorer maintenance of cognition, while higher percentages of muscle mass are associated with the best results in the cognitive tests.

10.
J Nanobiotechnology ; 20(1): 502, 2022 Dec 01.
Article in English | MEDLINE | ID: mdl-36457046

ABSTRACT

Dental caries is the major biofilm-mediated oral disease in the world. The main treatment to restore caries lesions consists of the use of adhesive resin composites due to their good properties. However, the progressive degradation of the adhesive in the medium term makes possible the proliferation of cariogenic bacteria allowing secondary caries to emerge. In this study, a dental adhesive incorporating a drug delivery system based on L-arginine-containing mesoporous silica nanoparticles (MSNs) was used to release this essential amino acid as a source of basicity to neutralize the harmful acidic conditions that mediate the development of dental secondary caries. The in vitro and bacterial culture experiments proved that L-arginine was released in a sustained way from MSNs and diffused out from the dental adhesive, effectively contributing to the reduction of the bacterial strains Streptococcus mutans and Lactobacillus casei. Furthermore, the mechanical and bonding properties of the dental adhesive did not change significantly after the incorporation of L-arginine-containing MSNs. These results are yielding glimmers of promise for the cost-effective prevention of secondary caries.


Subject(s)
Dental Caries , Nanoparticles , Humans , Silicon Dioxide , Dental Caries/prevention & control , Arginine , Streptococcus mutans , Dental Cements/pharmacology
11.
Diagnostics (Basel) ; 12(12)2022 Dec 08.
Article in English | MEDLINE | ID: mdl-36553100

ABSTRACT

The management of chronic diseases in the midst of the COVID-19 pandemic is especially challenging, and reducing potential psychological harm is essential. This review aims to determine the prevalence of depression during the COVID-19 pandemic in patients with chronic disease, and to characterize the impacts of related factors. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The meta-analysis was performed using StatsDirect software. The review identified 33 articles with a total of 50,905 patients with chronic diseases. Four meta-analyses were performed to estimate the prevalence of depression. In diabetic patients, the prevalence ranged from 17% (95% CI = 7-31) (PHQ-9) to 33% (95% CI = 16-51) (PHQ-8); in obese patients, the prevalence was 48% (95% CI = 26-71); and in hypertensive patients, the prevalence was 18% (95% CI = 13-24). The factors significantly associated with depression were female sex, being single, deterioration in the clinical parameters of diabetes, a decrease in self-care behavior, reduced physical activity and sleep time and fear of contagion. The COVID-19 pandemic has significantly increased levels of depression among persons with chronic disease. Pandemics and other emergency events have a major impact on mental health, so early psychological interventions and health management policies are needed to reinforce chronic patients' physical and mental health.

12.
Pharmaceutics ; 14(6)2022 May 24.
Article in English | MEDLINE | ID: mdl-35745693

ABSTRACT

Alzheimer's disease (AD) is the most common cause of dementia. The pathophysiology of this disease is characterized by the accumulation of amyloid-ß, leading to the formation of senile plaques, and by the intracellular presence of neurofibrillary tangles based on hyperphosphorylated tau protein. In the therapeutic approach to AD, we can identify three important fronts: the approved drugs currently available for the treatment of the disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, and a combination of memantine and donepezil; therapies under investigation that work mainly on Aß pathology and tau pathology, and which include γ-secretase inhibitors, ß-secretase inhibitors, α-secretase modulators, aggregation inhibitors, metal interfering drugs, drugs that enhance Aß clearance, inhibitors of tau protein hyperphosphorylation, tau protein aggregation inhibitors, and drugs that promote the clearance of tau, and finally, other alternative therapies designed to improve lifestyle, thus contributing to the prevention of the disease. Therefore, the aim of this review was to analyze and describe current treatments and possible future alternatives in the therapeutic approach to AD.

14.
Front Mol Neurosci ; 14: 788039, 2021.
Article in English | MEDLINE | ID: mdl-34938160

ABSTRACT

Intrinsic membrane excitability (IME) sets up neuronal responsiveness to synaptic drive. Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+ channels TASK1. However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment of MN IME via TASK1. Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal rats, neonatal knockout mice for TASK1 (task1 -/-) and TASK3 (task3 -/-, the another highly expressed TASK subunit in MNs), and primary cultures of embryonic spinal cord MNs (SMNs). Small-interfering RNA (siRNA) technology was also used to knockdown either ROCK1 or ROCK2. Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR ligands to stimulate ROCK. Microiontophoretically applied H1152, a ROCK inhibitor, and siRNA-induced ROCK2 knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo, which mainly express the ROCK2 isoform. In brainstem slices, intracellular constitutively active ROCK2 (aROCK2) led to H1152-sensitive HMN hyper-excitability. The aROCK2 inhibited pH-sensitive and TASK1-mediated currents in SMNs. Conclusively, aROCK2 increased IME in task3 -/-, but not in task1 -/- HMNs. MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism entailing Gαi/o-protein stimulation, ROCK2, but not ROCK1, activity and TASK1 inhibition. Finally, two neurotransmitters, TRH, and 5-HT, which are both known to increase MN IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling. These outcomes suggest that LPA and several neurotransmitters impact MN IME via Gαi/o/Gαq-protein-coupled receptors, downstream ROCK2 activation, and subsequent inhibition of TASK1 channels.

15.
Biomedicines ; 9(12)2021 Dec 14.
Article in English | MEDLINE | ID: mdl-34944723

ABSTRACT

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by cognitive decline and progressive memory loss. The aim of this review was to update the state of knowledge on the pathophysiological mechanisms, diagnostic methods and therapeutic approach to AD. Currently, the amyloid cascade hypothesis remains the leading theory in the pathophysiology of AD. This hypothesis states that amyloid-ß (Aß) deposition triggers a chemical cascade of events leading to the development of AD dementia. The antemortem diagnosis of AD is still based on clinical parameters. Diagnostic procedures in AD include fluid-based biomarkers such as those present in cerebrospinal fluid and plasma or diagnostic imaging methods. Currently, the therapeutic armory available focuses on symptom control and is based on four pillars: pharmacological treatment where acetylcholinesterase inhibitors stand out; pharmacological treatment under investigation which includes drugs focused on the control of Aß pathology and tau hyperphosphorylation; treatment focusing on risk factors such as diabetes; or nonpharmacological treatments aimed at preventing development of the disease or treating symptoms through occupational therapy or psychological help. AD remains a largely unknown disease. Further research is needed to identify new biomarkers and therapies that can prevent progression of the pathology.

16.
Nanomaterials (Basel) ; 11(9)2021 Sep 21.
Article in English | MEDLINE | ID: mdl-34578771

ABSTRACT

Among the different types of nanoparticles used in biomedical applications, Fe nanoparticles and mesoporous siliceous materials have been extensively investigated because of their possible theranostic applications. Here, we present hollow-shell mesoporous silica nanoparticles that encapsulate iron oxide and that are prepared using a drug-structure-directing agent concept (DSDA), composed of the model drug tryptophan modified by carbon aliphatic hydrocarbon chains. The modified tryptophan can behave as an organic template that allows directing the hollow-shell mesoporous silica framework, as a result of its micellisation and subsequent assembly of the silica around it. The one-pot synthesis procedure facilitates the incorporation of hydrophobically stabilised iron oxide nanoparticles into the hollow internal silica cavities, with the model drug tryptophan in the shell pores, thus enabling the incorporation of different functionalities into the all-in-one nanoparticles named mesoporous silica nanoparticles containing magnetic iron oxide (Fe3O4@MSNs). Additionally, the drug loading capability and the release of tryptophan from the silica nanoparticles were examined, as well as the cytostaticity and cytotoxicity of the Fe3O4@MSNs in different colon cancer cell lines. The results indicate that Fe3O4@MSNs have great potential for drug loading and drug delivery into specific target cells, thereby overcoming the limitations associated with conventional drug formulations, which are unable to selectively reach the sites of interest.

17.
Int J Mol Sci ; 22(15)2021 Jul 26.
Article in English | MEDLINE | ID: mdl-34360733

ABSTRACT

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.


Subject(s)
Cilastatin , Drug Delivery Systems , Lipids , Nanoparticles/chemistry , Cilastatin/chemistry , Cilastatin/pharmacokinetics , Cilastatin/pharmacology , Humans , Kidney , Lipids/chemistry , Lipids/pharmacokinetics , Lipids/pharmacology , Silicon Dioxide
18.
Neuropathol Appl Neurobiol ; 47(7): 1004-1018, 2021 12.
Article in English | MEDLINE | ID: mdl-33508894

ABSTRACT

AIMS: Alterations in excitability represent an early hallmark in Amyotrophic Lateral Sclerosis (ALS). Therefore, deciphering the factors that impact motor neuron (MN) excitability offers an opportunity to uncover further aetiopathogenic mechanisms, neuroprotective agents, therapeutic targets, and/or biomarkers in ALS. Here, we hypothesised that the lipokine lysophosphatidic acid (lpa) regulates MN excitability via the G-protein-coupled receptor lpa1 . Then, modulating lpa1 -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model. METHODS: The influence of lpa-lpa1 signalling on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro. Expression of lpa1 in cultured MNs and in the spinal cord of SOD1-G93A mice was analysed. ALS mice were chronically treated with a small-interfering RNA against lpa1 (siRNAlpa1 ) or with the lpa1 inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated. RESULTS: AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa1 . Lpa-lpa1 signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels. Cultured SOD1-G93A MNs displayed lpa1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNAlpa1 or AM095 reduced lpa1 expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice. CONCLUSIONS: These results suggest that stressed lpa-lpa1 signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa1 slows down disease progression. This highlights LPA1 signalling as a potential target and/or biomarker in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Motor Neurons/pathology , Receptors, Lysophosphatidic Acid/metabolism , Superoxide Dismutase-1/genetics , Amyotrophic Lateral Sclerosis/genetics , Animals , Disease Models, Animal , Disease Progression , Mice, Transgenic , Microglia/pathology , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Spinal Cord/pathology
19.
Archiv. med. fam. gen. (En línea) ; 17(2): 16-24, no. 2020. tab
Article in Spanish | LILACS, InstitutionalDB, BINACIS, UNISALUD | ID: biblio-1292940

ABSTRACT

Introducción. La prevalencia general de la automedicación en la población general fluctúa de 27.3% a 61.3%. En trabajadores de la salud está menos documentado (Definido como auto prescripción), así como su frecuencia y las características del personal médico. Material y métodos. Se trata de un estudio comparativo transversal de 3 países, México (178), Bolivia (250) y Ecuador (130) en población de Médicos Familiares y Médicos Generales de Primer nivel de atención en salud; sexo y edad indistintos, activos en consulta pública o institucional. El muestreo fue por conveniencia calculado por fórmula. Se usó una encuesta con datos demográficos, Frecuencia de automedicación y auto prescripción, patologías donde se usaron, y razones de uso y fuentes de información. Se capturaron y analizaron en SPSS versión 20. Se utilizaron estadísticas descriptivas e inferenciales como ji-cuadrada y Kruskal Wallis. Aprobado por el comité de ética de dos países. Resultados. De los participantes 58.0% son médicos familiares, la mayoría femeninas (p<.05), con pareja, y con promedio de edad de 39.3. Laboran en el sistema público 42.2%. Se automedicaron y auto prescribieron más medicamentos los médicos en México y menos en Ecuador (p<.0001). En general, en el último mes, 61.5% de los profesionales estudiados se auto medicó (media 2.99 veces), y menor porcentaje se auto prescribió 35.8%, (media 1.28 veces) principalmente analgésicos y antibióticos (p<.0001) y por patologías respiratorias (p<.05). Las variables numéricas no cumplieron los supuestos de normalidad. Conclusión. Más de la mitad de los profesionales estudiados se auto medicó y más de un tercio se auto prescribió (antibióticos y analgésicos), esto más en México (AU)


Introduction. The general prevalence of selfmedication in the general population fluctuates from 27.3% to 61.3%. It is less documented in health workers (denominated as selfprescription), as well as its frequency and the characteristics of medical personnel. Material and methods. This is a cross- sectional, comparative study of 3 countries, Mexico (178), Bolivia (250) and, Ecuador (130) in the population of Family Physicians and General Practitioners of the first level of care; indistinct sex and age, active practice in public or institutional consultation. Sampling was for convenience calculated by a formula. A survey with demographic data, II Frequency of self-medication and self-prescription, pathologies where they were used, reasons for use and, sources of information were used. They were captured and analyzed in SPSS version 20. Descriptive and inferential statistics such as chi-square and Kruskal Wallis were used. It was approved by the ethic committee from two countries. Results. Of the participants, 58.0% are family doctors, the majority female (p <.05), with a partner, and with an average age of 39.3 years; 42.2% work in the public system. More physicians in Mexico and fewer in Ecuador used self-medicated and self- prescribed medications (p <.0001). In general in the last month, 61.5% of the professionals self-medicated (average 2.99 times), and a lower percentage (35.8%,)self-prescribed (average 1.28 times) mainly pain relievers and antibiotics (p <.0001) and for respiratory pathologies (p <.05). The numerical variables did not meet the assumptions of normality. Conclusion. More than half of the professionals studied practice self-medication and more than third antibiotics and analgesics as self-prescription this more in Mexico (AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Primary Health Care , Self Medication , Bolivia , Attitude of Health Personnel , Ecuador , Mexico
20.
Molecules ; 25(12)2020 Jun 19.
Article in English | MEDLINE | ID: mdl-32575444

ABSTRACT

The purpose of this work is to define optimal growth conditions to maximise biomass for batch culture of the cyanobacterium Arthrospira maxima and the microalgae Chlorella vulgaris, Isochrysis galbana and Nannochloropsis gaditana. Thus, we study the effect of three variables on cell growth: i.e., inoculum:culture medium volume ratio (5:45, 10:40, 15:35 and 20:30 mL:mL), light:dark photoperiod (8:16, 12:12 and 16:8 h) and type of culture medium, including both synthetic media (Guillard's F/2 and Walne's) and wastewaters. The results showed that the initial inoculum:culture medium volume ratio, within the range 5:45 to 20:30, did not affect the amount of biomass at the end of the growth (14 days), whereas high (18 h) or low (6 h) number of hours of daily light was important for cell growth. The contribution of nutrients from different culture media could increase the growth rate of the different species. A. maxima was favoured in seawater enriched with Guillard's F/2 as well as C. vulgaris and N. gaditana, but in freshwater medium. I. galbana had the greatest growth in the marine environment enriched with Walne's media. Nitrogen was the limiting nutrient for growth at the end of the exponential phase of growth for C. vulgaris and N. gaditana, while iron was for A. maxima and I. galbana. The growth in different synthetic culture media also determines the biochemical composition of each of the microalgae. All species demonstrated their capability to grow in effluents from a wastewater treatment plant and they efficiently consume nitrogen, especially the three microalga species.


Subject(s)
Batch Cell Culture Techniques , Biomass , Chlorella vulgaris/growth & development , Cyanobacteria/growth & development , Microalgae/growth & development , Stramenopiles/growth & development
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