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1.
J Family Med Prim Care ; 13(1): 157-162, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38482332

RESUMEN

Background: The present study was carried out to assess the awareness of the adverse consequences of tobacco use in the semi-urban school population in Wardha district because tobacco use in schools is a significant concern and is rising at an alarming rate. The purpose of the current study was to assess the prevalence of tobacco use among students and teachers as well as their knowledge of the negative effects of tobacco use. It also aimed to educate students and teachers about these effects and assess the effectiveness of the intervention. Methodology: A total of 350 students from a semi-urban school in the Wardha area participated in this study. Pre-tests were administered to a group of chosen kids and instructors to gauge their familiarity with tobacco. After the pre-test data were analyzed, teachers were offered intervention. PowerPoint presentations, posters, and models were used to educate them about the dangers of tobacco usage for dental health. There were discussions, role plays, and skits done. After the instruction, the students took a post-test to gauge how well they understood what they had learned. Results: The recent study is a significant step toward the semi-urban school population quitting smoking. Overall, the study involves testing participants' knowledge, teaching them about tobacco's negative consequences, and inspiring habitual smokers to completely kick the habit. The majority of the NTCP questionnaire's elements were significant when compared to knowledge of tobacco use and its components (*p0.05; significant). Conclusion: The suggested study is a significant step toward the semi-urban school population quitting smoking. The research will provide a genuine and dependable change and help promote optimal dental health.

2.
Cureus ; 15(10): e46812, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37954784

RESUMEN

Introduction Pediatric dentists support children's dental health while also providing parents with health education and information. Parents are guardians of their children's oral health, as their knowledge, beliefs, also attitude about oral health can influence early childhood oral health directly or indirectly. Recognizing parenting practices on early childhood oral health is essential for developing effective prevention and treatment strategies for the child, because parents' health attitudes, behavior, and their children's dental health are usually influenced directly or indirectly by their practice. Objectives of this study were to find out what factors parents prefer while choosing a pediatric dentist for their kids, to assess parent attitudes towards management of a symptomatic primary tooth, to analyze parental understanding of the importance of deciduous teeth, and to assess parent knowledge and perception regarding their child. Methodology A cross-sectional study conducted at Sharad Pawar Dental College and Hospital was done, where 20 questions were posed to the parents who came with their children for dental treatment. Questions were divided into two parts, knowledge-based assessment scale and perception-based assessment scale. The questions were formulated to assess the knowledge of parents regarding dental care, their perception, and their attitude toward the decision-making while selecting a pediatric dentist for their kids. The questions also included information about the child's habits and associated problems with it. Three hundred parents of children under 14 years of age were chosen randomly where all parents were adequately informed beforehand, and their written consent was taken before proceeding with the questions. All the questions were formulated in the native language that they could easily understand. A convenient method was applied as per the respondent from an offline questionnaire survey.  Results By evaluating the parental knowledge as well as perception towards children's oral health and dental treatment we are able to determine which aspects parents prefer while selecting a pediatric dentist for their child. The study found that parents had limited knowledge about the causes, treatment, prevention, and consequences of oral health problems in children. Many parents neglect oral health problems and lack correct knowledge. Conclusion  Hence this study assesses the parental knowledge as well as perception towards children's oral health. This study concludes that it is crucial to raise awareness about oral health among parents and inform them about available treatments, consequences of negligence and future problems to aid them in decision-making.

3.
Cureus ; 15(9): e45944, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37885509

RESUMEN

Background The most frequent reason involving failure of root canal treatment in molar teeth is the inability to locate additional canals. While much research has been conducted on the morphology of mandibular molars, little is known about isthmuses and middle mesial (MM) canals in the Indian population. The primary aim of the present research was to determine the prevalence of MM canals and isthmuses of mandibular first molars in the Central India population using cone-beam computed tomography (CBCT) images. Methodology CBCT of 140 mandibular first molar teeth was analyzed from the institutional database images in the coronal, sagittal, and axial planes. Data concerning the number of root canals, the presence of middle mesial canals, and the presence of isthmus were noted. Information collected was transferred into an Excel sheet and analyzed using the Statistical Package for Social Sciences (IBM Corp., Armonk, NY, USA). Results Eight images (5.71%) revealed the presence of middle mesial canals with no statistically significant occurrence. The incidence of isthmi in the mandibular first molar was 84.3%, and the presence of isthmi in the coronal third was about 38.6%. This showed a considerable presence. Conclusion There is incidence of the middle mesial canal, which emphasizes the need to locate extra canals in patients undergoing root canal endodontic treatment. The implementation of CBCT will help identify the extra canal before the treatment. This will help ultimately in providing better patient care.

4.
Pan Afr Med J ; 44: 153, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37455892

RESUMEN

Introduction: over one third of total Disability-Adjusted-Life-Years lost in Kenya are due to non-communicable diseases (NCD). In response, the Government declared significant commitment towards improving NCD care. The COVID-19 pandemic increased the burden on the already overstretched health systems in Kenya. The aims of this study are to assess whether health care providers perceived NCD care to be optimal during the pandemic and explore how to improve responses to future emergencies. Methods: this cross-sectional online survey included healthcare personnel with non-clinical roles (public health workers and policy-makers) and those delivering health care (doctors and nurses). Respondents were recruited between May and September 2021 by random sampling, completed by snowball sampling. Results: among 236 participants (42% in clinical, 58% in non-clinical roles) there was an overall consensus between respondents on NCD care being disrupted and compromised during the pandemic in Kenya. Detracted supplies, funding, and technical resources affected the continuity of NCDs' response, despite government efforts. Respondents agreed that the enhanced personnel capacity and competencies to manage COVID-19 patients were positive, but noted a lack of guidance for redirecting care for chronic diseases, and advocated for digital innovation as a solution. Conclusion: this paper explores the perceptions of key stakeholders involved in the management of NCDs in Kenya to improve planning for future emergency responses. Gaps were identified in health system response and preparedness capacity during the pandemic including the perceived need to strengthen NCD services, with solutions offered to guide resilience efforts to protect the health system from disruption.


Asunto(s)
COVID-19 , Enfermedades no Transmisibles , Humanos , Enfermedades no Transmisibles/epidemiología , Enfermedades no Transmisibles/terapia , Pandemias , Kenia , Estudios Transversales
5.
Int J Public Health ; 68: 1605861, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37304500

RESUMEN

Objectives: This study assesses the opinions of health professionals in Malaysia on the disruption of non-communicable disease (NCD) services during the COVID-19 pandemic from March 2020 to January 2022. Methods: We conducted a cross-sectional online survey with 191 non-clinical public health workers and clinical health service workers in Malaysia from November 2021 to January 2022. Participants were recruited by the Malaysian Ministry of Health using major networks including key experts and practitioners. Secondary respondents were subsequently enrolled through snowballing. Results: The most notable issues raised by the survey participants relate to NCD service disruption, the redirection of NCD care resources, and NCD care being overburdened post-pandemic. Respondents also reported accounts of resilience and prompt reaction from the healthcare system, as well as calls for innovation. Conclusion: Most respondents perceived that the challenges arising from COVID-19 were mostly managed well by the healthcare system, which was able to provide the necessary services to NCD patients during this health emergency. However, the study identifies gaps in the health system response and preparedness capacity, and highlights solutions for strengthening NCD services.


Asunto(s)
COVID-19 , Enfermedades no Transmisibles , Humanos , Malasia/epidemiología , Enfermedades no Transmisibles/epidemiología , Pandemias , Estudios Transversales , COVID-19/epidemiología , Fuerza Laboral en Salud
6.
J Family Med Prim Care ; 12(1): 90-95, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37025229

RESUMEN

Background: Awareness in semi-urban school population about harmful effects of tobacco use. Hence, the objectives of the present research protocol are to evaluate the incidence of tobacco usage amongst school children and educators, to evaluate the knowledge of students and teachers regarding the harmful effects of tobacco, to educate students and teachers regarding the deleterious effects of tobacco and to evaluate the success of the intervention. Material and Methods: This study will be conducted at a semi-urban school located in the Wardha district. A cluster of students and teachers will be selected and will be given a pre-test to assess their knowledge regarding tobacco. The questionnaire will also help in evaluating the total number of participants consuming tobacco. Teachers will be given intervention when the data from the pre-test has been analysed. They will be educated regarding tobacco and its effects on oral health with the use of PowerPoint presentations, posters and models. Activities such as skits, role plays and discussions will be performed. Teachers will be asked to educate the students regarding the same. After the students are educated, they will be given a post-test to evaluate their understanding after the teachers have educated them. Tobacco users will be motivated to complete the cessation of tobacco. A questionnaire comprises 20 questions that are taken from National Tobacco Control Programme (NTPC) guidelines. Expected Results: The proposed study represents a major step towards tobacco cessation amongst semi-urban school population. Overall, the study includes evaluating the knowledge of participants, educating them regarding the harmful effects of tobacco and motivating the participants who are tobacco chewers to complete stoppage of habit. The study will develop a valid and reliable change and would contribute in the development of good oral health. This research will provide in the Indian context, evidence that will underpin better selection in semi-urban schools of the Wardha district. Conclusion: The proposed study represents a major step towards tobacco cessation amongst semi-urban school population. The study will develop a valid and reliable change and would contribute in the development of good oral health.

7.
Int J Clin Pediatr Dent ; 16(Suppl 3): 278-282, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38268625

RESUMEN

Background: Cleft lip and palate (CLP) is considered to be a congenital defect involving the orofacial region. This defect affects the esthetics, speech as well and psychological well-being of a person. The study was performed to analyze the prevalence of different types of cleft deformity reported in a tertiary care hospital which would aid in spreading awareness and thereby reducing the prevalence of this congenital defect. Aim: To study the demographic profile of patients with CLP in the Wardha region. Materials and methods: A single-center retrospective cross-sectional study was performed. The patients with cleft deformity report under the "Smile Train Project" under the Department of Orthodontics and Dentofacial Orthopedics along with the Department of Oral and Maxillofacial Surgery. The data retrieved included the name of the patient, age, gender, residential address, contact details, and type of cleft. This data was segregated focusing on the gender and type of cleft as per the concern of this study. The datasets were then entered in the Microsoft Excel sheet and the statistical graphical representation was done using Microsoft PowerPoint. Results: In the present study we tried to find out the profile of CLP in the local population. We reported the high prevalence of this orofacial deformity among the population of this area. Conclusion: The data from the present study will help to provide a deeper insight into the burden of CLP anomaly. Based on the data obtained from the present study, future research can be conducted, and cleft-care improvement outcomes can be measured. Clinical significance: There are several etiological factors that are responsible for the development of CLP. Also, due to a lack of awareness regarding this, there is an increased prevalence of this defect. In India, due to a lack of knowledge regarding cleft anomaly, poverty, and social stigma, many patients do not report to the hospitals, and hence, there is a need to spread awareness which would encourage people to access the healthcare facilities at an early age and would reduce the complications in later stages. How to cite this article: Shivlani VI, Niranjane PP, Diagavane PS, et al. Demographic Profile of Patients with Cleft Lip and Palate Anomaly: 15-year Experience from a Tertiary Care Hospital and Teaching Institute in Wardha District of Maharashtra, India. Int J Clin Pediatr Dent 2023;16(S-3):S278-S282.

8.
Essays Biochem ; 2022 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-36504386

RESUMEN

Viruses are the obligate intracellular parasites that exploit the host cellular machinery to replicate their genome. During the viral life cycle viruses manipulate the host cell through interactions with host proteins. Many of these protein-protein interactions are mediated through the recognition of host globular domains by short linear motifs (SLiMs), or longer intrinsically disordered domains (IDD), in the disordered regions of viral proteins. However, viruses also employ their own globular domains for binding to SLiMs and IDDs present in host proteins or virus proteins. In this review, we focus on the different strategies adopted by viruses to utilize proteins or protein domains for binding to the disordered regions of human or/and viral ligands. With a set of examples, we describe viral domains that bind human SLiMs. We also provide examples of viral proteins that bind to SLiMs, or IDDs, of viral proteins as a part of complex assembly and regulation of protein functions. The protein-protein interactions are often crucial for viral replication, and may thus offer possibilities for innovative inhibitor design.

9.
J Family Med Prim Care ; 11(8): 4263-4266, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36352913

RESUMEN

Smoking is still a major public health issue that causes morbidity and mortality all over the world. The percentage of deaths caused by tobacco smoking has escalated from 1.4% in 1990 to 13.3% by 2020. There are numerous evidence-based tobacco control strategies available, and newer ones are always being developed. However, on ceasing the habit, cigarettes users go through a period of withdrawal with an increased percentage of relapse before entering to a more stable condition of sobriety in the long run. In this review, Endnote software was used as resource material to collect literature, which was then carefully arranged in a synchronised way. The Markov model captures the dynamic character of the quitting/relapse process, allowing for more accurate figures of abstinence rate, treatment outcomes and evaluating the performance of newer cessation initiatives during tobacco cessation counselling, as well as suggesting pathways for survivability.

10.
Cureus ; 14(8): e27956, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36120261

RESUMEN

Dental plaque is a biofilm of microorganisms that present naturally on the exposed tooth surface; it is the main etiological factor for many periodontal conditions and other oral health issues and its regular removal from the oral cavity can prevent many periodontal problems. Despite several experiments using herbal oral care products to reduce dental plaque or gingivitis, the findings remain inconclusive. We performed a systematic literature search on PubMed and Cochrane Library for randomized controlled trials (RCTs) dating from 2001 up to and including the year 2021. The keywords and Medical Subject Headings (MeSH) terms comprised combinations of the following: herbal, clove oil, peppermint oil, ginger, basil, ajwain, betel leaf extract, neem, lavender, non-herbal, chlorhexidine, fluorides, hydrogen fluoride, hydrogen fluoride, stannous fluoride, and mouthwashes. Each of the titles that the search elicited was screened and duplicates were removed from the gathered results. The full-text versions of the remaining articles were downloaded and examined by title and abstract. Handsearching was not carried out. We initially identified 21 studies; 14 studies, which did not fulfill the selection criteria, were excluded. All the included studies reported a reduction in plaque index (PI) and gingival index (GI) scores in both herbal and non-herbal groups. Two studies reported the superiority of the non-herbal mouthwash over the herbal one while five of the studies showed no significant difference in PI and GI scores between herbal and non-herbal mouthwash, implying equal efficacy of both, i.e., Triphala, aloe vera, tea tree, and polyherbal groups like Zingiber officinale, Rosmarinus officinalis, and Calendula officinalis, and chlorhexidine. Current research suggests that herbal mouthwashes are as effective as non-herbal mouthwashes for reducing dental plaque in the short term; however, the evidence is based on low-quality trials.

11.
J Biol Chem ; 298(8): 102143, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35714774

RESUMEN

Prion-like self-perpetuating conformational conversion of proteins is involved in both transmissible neurodegenerative diseases in mammals and non-Mendelian inheritance in yeast. The transmissibility of amyloid-like aggregates is dependent on the stoichiometry of chaperones such as heat shock proteins (Hsps), including disaggregases. To provide the mechanistic underpinnings of the formation and persistence of prefibrillar amyloid seeds, we investigated the role of substoichiometric Hsp104 on the in vitro amyloid aggregation of the prion domain (NM-domain) of Saccharomyces cerevisiae Sup35. At low substoichiometric concentrations, we show Hsp104 exhibits a dual role: it considerably accelerates the formation of prefibrillar species by shortening the lag phase but also prolongs their persistence by introducing unusual kinetic halts and delaying their conversion into mature amyloid fibers. Additionally, Hsp104-modulated amyloid species displayed a better seeding capability compared to NM-only amyloids. Using biochemical and biophysical tools coupled with site-specific dynamic readouts, we characterized the distinct structural and dynamical signatures of these amyloids. We reveal that Hsp104-remodeled amyloidogenic species are compositionally diverse in prefibrillar aggregates and are packed in a more ordered fashion compared to NM-only amyloids. Finally, we show these Hsp104-remodeled, conformationally distinct NM aggregates display an enhanced autocatalytic self-templating ability that might be crucial for phenotypic outcomes. Taken together, our results demonstrate that substoichiometric Hsp104 promotes compositional diversity and conformational modulations during amyloid formation, yielding effective prefibrillar seeds that are capable of driving prion-like Sup35 propagation. Our findings underscore the key functional and pathological roles of substoichiometric chaperones in prion-like propagation.


Asunto(s)
Proteínas de Choque Térmico , Factores de Terminación de Péptidos , Priones , Proteínas de Saccharomyces cerevisiae , Amiloide/química , Proteínas Amiloidogénicas/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Factores de Terminación de Péptidos/genética , Factores de Terminación de Péptidos/metabolismo , Priones/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
J Family Med Prim Care ; 11(11): 6778-6782, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36992999

RESUMEN

The use of salivary biomarkers in diagnosis, treatment, and overall prognosis of coronavirus disease 2019 (COVID-19) has been developed recently. Salivary biomarkers are extremely promising as they are fast to obtain and involve noninvasive collection of specimens. Monitoring patients in real time is necessary in this pandemic. Saliva is another biofluid with major advantages at the molecular level. Methods that detect viral presence in the host secretions measure the current infection by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), whereas the detection of human antibodies against SARS-CoV-2 evaluates the past exposure to the virus. There is an urgent need to increase the active research for the detection of SARS-CoV-2 in saliva because diagnostics may provide a reliable and cost-effective method and is suitable for the fast and early detection of COVID-19 infection. Salivary biomarkers have a potential to be a vital guide in determining coronavirus disease. Many people still do not get results of COVID-19 tests due to imbalance between supply and demand at large testing centers. The use of saliva has various advantages compared to collection of nasopharyngeal swabs. New techniques should be developed for detecting salivary biomarkers that help in diagnosis of COVID-19.

13.
J Cell Biochem ; 122(11): 1594-1608, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34494298

RESUMEN

Soluble oligomers of amyloid-ß (Aß) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aß oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aß oligomers based on their morphology, size, and structural reactivity toward the conformation-specific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aß oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aß oligomers such as N-methyl- d-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aß oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aß by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Inmunoterapia/métodos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/química , Encéfalo/metabolismo , Encéfalo/fisiopatología , Humanos , Imagen Molecular , Proteínas del Tejido Nervioso/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Priones/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo
14.
Phys Chem Chem Phys ; 23(16): 9686-9694, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33908427

RESUMEN

The accumulation of toxic soluble oligomers of the amyloid-ß peptide (Aß) is a key step in the pathogenesis of Alzheimer's disease. There are mainly two conformationally distinct oligomers, namely, prefibrillar and fibrillar oligomers, that are recognized by conformation-specific antibodies, anti-amyloid oligomer antibody (A11) and anti-amyloid fibrillar antibody (OC), respectively. Previous studies have shown that the interaction of Aß oligomers with the lipid membrane is one of the key mechanisms of toxicity produced by Aß oligomers. However, the mechanism by which structurally distinct Aß oligomers interact with the lipid membrane remains elusive. In this work, we dissect the molecular mechanism underlying the interaction of structurally distinct Aß42 oligomers with the lipid membrane derived from the brain total lipid extract. Using picosecond time-resolved fluorescence spectroscopy, we show that the A11-positive Aß42 oligomers undergo a membrane-induced conformational change that promotes the deeper immersion of these oligomers into the lipid hydrocarbon region and results in an increase in the membrane micro-viscosity. In sharp contrast, OC-positive Aß42 oligomers interact with the lipid membrane via electrostatic interactions between the negatively-charged lipid headgroup and positively-charged residues of Aß42 without perturbing the membrane dynamics. We show that the two structurally distinct Aß42 oligomers demonstrating different interaction mechanisms with the lipid membrane eventually lead to the formation of typical amyloid fibrils. Our findings provide the mechanistic underpinning of the perturbation of lipid membranes by two conformationally distinct Aß42 oligomers and can be of prime importance in designing anti-Alzheimer's therapeutic agents targeting Aß-membrane interactions.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Liposomas Unilamelares/metabolismo , Secuencia de Aminoácidos , Péptidos beta-Amiloides/química , Polarización de Fluorescencia , Fluidez de la Membrana/efectos de los fármacos , Fragmentos de Péptidos/química , Unión Proteica , Conformación Proteica , Multimerización de Proteína , Liposomas Unilamelares/química
15.
J Family Med Prim Care ; 10(11): 3951-3955, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35136751

RESUMEN

Antimicrobial resistance (AMR) is assigned as a menace by the WHO (World Health Organization) where diseases resulting from multidrug-resistant bacteria are refractory to treatment as a result of a scarcity of new antibiotics in the queue. Antibiotic stewardship program is one of the worldwide strategies to advertise responsible use of antibiotics to halt AMR. The world has started facing a postantibiotic era without immediate and integrated action. Common infections which were treatable for decades can once again kill. The dentistry contributions towards antibiotic resistance are substantial. Approximately 10% of all common antibiotics are prescribed by dentists. Antimicrobial stewardship is a policy that can assist us in addressing the problems of antibiotic resistance. It is a framework that promotes the truly sustainable use of antimicrobials in dentistry. It refers to the approach which is multifaceted and incorporates policies, and guidelines along with surveillance, reports of prevalence and education, and audit of practice for reducing prescribing, adopted by health care organizations. The prime strategy is to improve clinical results while mitigating unintended consequences such as toxicity, pathogenic organism selection, and resistance emergence. Such issues should be centralized and the ongoing need to identify and convert "responsible usage" into context-specific and time-specific behavior. The importance of the antibiotic stewardship program, its team, and their action has become a challenge for the dental hospital but along with it, there are numerous opportunities to achieve the goal.

16.
J Phys Chem Lett ; 11(21): 9012-9018, 2020 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-33040538

RESUMEN

Soluble oligomers of amyloidogenic proteins like an amyloid-ß (Aß) peptide are believed to exhibit toxic effects in neurodegenerative diseases. The structural classification of oligomers indicates two fundamentally distinct oligomers, namely, fibrillar and prefibrillar oligomers that are recognized by OC and A11 conformation-specific antibodies, respectively. Previous studies have indicated that the interaction of Aß oligomers with the lipid membrane is one of the mechanisms by which these oligomers exert their toxic effects in Alzheimer's disease. Here, we report that the orientational ordering of liquid crystals (LC) can be used to study the membrane-induced aggregation of Aß oligomers at nanomolar concentrations. Our results demonstrate a faster fibrillation kinetics of OC-positive fibrillar Aß oligomers with the lipid monolayer in comparison to that of the A11-positive prefibrillar Aß oligomers. Our findings suggest a general strategy for distinguishing conformationally distinct soluble oligomers that are formed by a number of amyloidogenic proteins on lipid-decorated aqueous-LC interfaces.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/química , Amiloide/química , Cristales Líquidos/química , Fragmentos de Péptidos/química , Humanos , Cinética , Microscopía , Fosfolípidos/química , Agregado de Proteínas , Conformación Proteica , Relación Estructura-Actividad , Propiedades de Superficie
17.
Biophys J ; 118(11): 2621-2626, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32402242

RESUMEN

Amyloid fibrils are highly ordered nanoscopic protein aggregates comprising a cross-ß amyloid core and are associated with deadly human diseases. Structural studies have revealed the supramolecular architecture of a variety of disease-associated amyloids. However, the critical role of transient intermolecular interactions between the disordered polypeptide segments of protofilaments in directing the supramolecular structure and nanoscale morphology remains elusive. Here, we present a unique case to demonstrate that interchain excitation energy migration via intermolecular homo-Förster resonance energy transfer can decipher the architecture of amyloid fibrils of human α-synuclein. Site-specific homo-Förster resonance energy transfer efficiencies measured by fluorescence depolarization allowed us to construct a two-dimensional proximity correlation map that defines the supramolecular packing of α-synuclein within the fibrils. These studies captured unique heteroterminal cross talks between the fuzzy interprotofilament interfaces of the parallel-in-register amyloid spines. Our results will find applications in discerning the broader role of protein disorder and fuzziness in steering the distinct polymorphic amyloids that exhibit strain-specific disease phenotypes.


Asunto(s)
Amiloide , alfa-Sinucleína , Péptidos beta-Amiloides , Humanos
18.
ACS Chem Neurosci ; 11(1): 86-98, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31808343

RESUMEN

Soluble oligomeric species of the amyloid-ß (Aß) peptide exhibit pronounced neurotoxic effects in Alzheimer's disease. Recent studies have indicated that the prion protein (PrP) is one of the cell-surface receptors, so-called a bad receptor, of Aß oligomers that mediates downstream cellular toxicity. A rational classification of Aß oligomers on the basis of conformation indicates that there are two distinct types of oligomers, namely, prefibrillar and fibrillar oligomers that are positive to A11 and OC conformation-dependent antibodies, respectively. The mechanism of heterotypic assembly of conformationally distinct oligomers and PrP is poorly understood. In this work, using an array of biophysical and biochemical tools, we dissect the molecular mechanism of the interaction of A11- and OC-positive Aß42 oligomers with human PrP. Using site-specific binding titrations, we show that the recruitment of Aß oligomers primarily occurs via the electrostatic interaction between the N-terminal intrinsically disordered region of PrP and Aß oligomers. Our results demonstrate that OC-positive fibrillar oligomers possessing in-register parallel ß-sheet packing displayed ∼30 times stronger binding with PrP compared to A11-positive oligomers. We also show that these OC-positive oligomers exacerbate their toxic effects on mammalian cells upon binding to PrP. On the contrary, the addition of PrP does not alter the toxicity exhibited by A11-positive oligomers. Our findings suggest that strategies targeting the interaction between PrP and OC-positive oligomers, which have been shown to be highly concentrated in the vicinity of amyloid plaques, may have therapeutic potential against Alzheimer's disease.


Asunto(s)
Péptidos beta-Amiloides/química , Proteínas Priónicas/química , Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Supervivencia Celular/fisiología , Células HeLa , Humanos , Conformación Molecular , Proteínas Priónicas/metabolismo , Unión Proteica
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