Differential Expression of Caveolin-3, Suppression of Tumorigenicity 2, and Growth Differentiation Factor-15 Genes and Their Association with Acute Myocardial Infarction: A Cross-Sectional Study in a Multi-Specialty Hospital in Tamil Nadu.

Background: Acute myocardial infarction (AMI) is one of the world's leading causes of cardiovascular death. Recent studies have reported the influence of the genes caveolin-3 (CAV3), suppression of tumorigenicity 2, and growth differentiating factor-15 in cardiovascular diseases, especially myocardial infarction, but their role and function remain unclear. Hence, this study was designed to evaluate the expression levels of these three genes in AMI and understanding the role of CAV-3 in the pathogenesis of AMI. Methods and Results: Blood samples were collected from 50 AMI patients and 50 non-AMI controls in this cross-sectional study. Relative expression levels of the three genes were performed using real-time PCR. Bioinformatics tools were used for functional gene enrichment and protein-protein interactions. CAV-3 was significantly upregulated among AMI patients compared to controls. In silico analyses identified CAV-3 as playing critical roles in smooth muscle contraction, cardiac conduction, and calcium-mediated transport via binding with essential proteins including dysferlin and annexins Conclusion: This study is a first of its kind, reporting an upregulation of CAV-3 in AMI patients. The expression of all three genes significantly influenced the systolic function of the heart in AMI patients. A more in-depth understanding of CAV-3 in the pathophysiology of AMI is essential and it may prove to be a novel.

In Vitro Antioxidant, Anti-inflammatory, Antimicrobial, and Antidiabetic Activities of Synthesized Chitosan-loaded p-Coumaric Acid Nanoparticles.

BACKGROUND: p-Coumaric acid is a phenolic compound widely distributed in fruits and vegetables that displays an array of therapeutic properties, including antidiabetic effects. Prominent application in diabetes is limited due to its suboptimal pharmacokinetics, poor aqueous solubility, and poor bioavailability. Nanotechnology-based delivery methods have been developed to address these limitations and improve the therapeutic uses of p-coumaric acid, and the nanoencapsulation method is emerging as a feasible alternative. OBJECTIVE: The objective of this study is to synthesize p-coumaric acid nanoparticles (PCNPs) and to evaluate their In Vitro activities. METHODS: The PCNPs were synthesized by the nanoprecipitation method and characterized by UV-visible spectroscopy, zeta potential, Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM) with dispersive energy X-ray (EDX) analysis. In addition, the PCNPs were analyzed for In Vitro antioxidant activity using six different free radical scavenging assays and were also analyzed for antimicrobial, anti-inflammatory, antithrombotic, and antidiabetic effects. RESULTS: The formation of PCNPs was confirmed by UV-visible spectra at 283 nm, and FTIR analysis revealed the reduction and capping of the chitosan nanoparticles. SEM was used to assess the size and shape of the PCNPs, and the high absorption property of the PCNPs was investigated using EDX analysis. The PCNPs had significant antioxidant, hydrogen peroxide (H2O2), lipid peroxidation (LPO), superoxide and nitric oxide (NO) radical scavenging power activities, and showed potent antimicrobial, anti-inflammatory, antithrombotic, and antidiabetic activities. CONCLUSION: The present study suggests that PCNPs can be used as a potential medication delivery approach to provide a greater nephroprotective effect in the treatment of diabetic nephropathy. To the best of our knowledge, this is the first attempt at the synthesis of chitosan-loaded PCNPs.

Prioritization of microRNA biomarkers for a prospective evaluation in a cohort of myocardial infarction patients based on their mechanistic role using public datasets.

Background: MicroRNAs (miR) have proven to be promising biomarkers for several diseases due to their diverse functions, stability and tissue/organ-specific nature. Identification of new markers with high sensitivity and specificity will help in risk reduction in acute myocardial infarction (AMI) patients with chest pain and also prevent future adverse outcomes. Hence the aim of this study was to perform a detailed in silico analysis for identifying the mechanistic role of miRs involved in the pathogenesis/prognosis of AMI for prospective evaluation in AMI patients. Methods: miR profiling data was extracted from GSE148153 and GSE24591 datasets using the GEO2R gene expression omnibus repository and analyzed using limma algorithm. Differentially expressed miRs were obtained by comparing MI patients with corresponding controls after multiple testing corrections. Data mining for identifying candidate miRs from published literature was also performed. Target prediction and gene enrichment was done using standard bioinformatics tools. Disease specific analysis was performed to identify target genes specific for AMI using open targets platform. Protein-protein interaction and pathway analysis was done using STRING database and Cytoscape platform. Results and conclusion: The analysis revealed significant miRs like let-7b-5p, let-7c-5p, miR-4505, and miR-342-3p in important functions/pathways including phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin, advanced glycation end products and its receptor and renin-angiotensin-aldosterone system by directly targeting angiotensin II receptor type 1, forkhead box protein O1, etc. With this approach we were able to prioritize the miR candidates for a prospective clinical association study in AMI patients of south Indian origin.

Seeding, maturation and propagation of amyloid ß-peptide aggregates in Alzheimer's disease.

Alzheimer's disease is neuropathologically characterized by the deposition of the amyloid ß-peptide (Aß) as amyloid plaques. Aß plaque pathology starts in the neocortex before it propagates into further brain regions. Moreover, Aß aggregates undergo maturation indicated by the occurrence of post-translational modifications. Here, we show that propagation of Aß plaques is led by presumably non-modified Aß followed by Aß aggregate maturation. This sequence was seen neuropathologically in human brains and in amyloid precursor protein transgenic mice receiving intracerebral injections of human brain homogenates from cases varying in Aß phase, Aß load and Aß maturation stage. The speed of propagation after seeding in mice was best related to the Aß phase of the donor, the progression speed of maturation to the stage of Aß aggregate maturation. Thus, different forms of Aß can trigger propagation/maturation of Aß aggregates, which may explain the lack of success when therapeutically targeting only specific forms of Aß.

Usefullness of MicroRNAs in Predicting the Clinical Outcome of Patients with Acute Myocardial Infarction During Follow-Up: A Systematic Review.

Background: Myocardial infarction (MI) is reported as the leading cause of mortality and morbidity worldwide. It is associated with a 30% mortality rate. Echocardiography, coronary angiography, and biomarkers like cardiac troponins are employed as prognostic tests. Although these biomarkers are the gold standard for the diagnosis of MI, they are not accurate as prognostic markers due to their lack of specificity. Studies have suggested that dysregulation of specific microRNAs (miRNAs) influences post-MI complications during follow-up. However, the findings of these studies have several inconsistencies. This systematic review was performed to investigate the potential of miRNAs to predict clinical outcomes post-MI. Methodology: Pubmed and Google Scholar databases were used for identifying research articles published from inception till August 2021; the search terms included "microRNAs" AND "prognosis" AND "myocardial infarction" or "acute coronary syndrome." All the articles included were critically analyzed using STROBE guidelines. Results and Conclusion: Several miRNAs were elevated in MI patients, including miR-208b, miR-499, and miR-375. Association of these miRNA levels with the outcome of MI, such as all-cause mortality and major adverse cardiovascular events during follow-up, were also reported. However, none of the studies included in this systematic review exhibited promising evidence that these miRNAs can be utilized as ideal biomarkers for prognosis post-MI. Understanding the molecular mechanisms involved in the pathogenesis and progression of MI is crucial. Hence, these findings can be used as a guide when performing further experimental studies to identify useful post-MI prognostic markers.

Correction to: Different aspects of Alzheimer's disease-related amyloid ß-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

An amendment to this paper has been published and can be accessed via the original article.

Different aspects of Alzheimer's disease-related amyloid ß-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

Alzheimer's disease (AD)-related amyloid ß-peptide (Aß) pathology in the form of amyloid plaques and cerebral amyloid angiopathy (CAA) spreads in its topographical distribution, increases in quantity, and undergoes qualitative changes in its composition of modified Aß species throughout the pathogenesis of AD. It is not clear which of these aspects of Aß pathology contribute to AD progression and to what extent amyloid positron emission tomography (PET) reflects each of these aspects. To address these questions three cohorts of human autopsy cases (in total n = 271) were neuropathologically and biochemically examined for the topographical distribution of Aß pathology (plaques and CAA), its quantity and its composition. These parameters were compared with neurofibrillary tangle (NFT) and neuritic plaque pathology, the degree of dementia and the results from [18F]flutemetamol amyloid PET imaging in cohort 3. All three aspects of Aß pathology correlated with one another, the estimation of Aß pathology by [18F]flutemetamol PET, AD-related NFT pathology, neuritic plaques, and with the degree of dementia. These results show that one aspect of Aß pathology can be used to predict the other two, and correlates well with the development of dementia, advancing NFT and neuritic plaque pathology. Moreover, amyloid PET estimates all three aspects of Aß pathology in-vivo. Accordingly, amyloid PET-based estimates for staging of amyloid pathology indicate the progression status of amyloid pathology in general and, in doing so, also of AD pathology. Only 7.75% of our cases deviated from this general association.

Aß-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein.

Extracellular deposition of amyloid ß-protein (Aß) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aß and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM → NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human Aß42 (APP48) with τ-transgenic mice overexpressing human mutant 4-repeat τ-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble Aß was associated with the aggravation of p-τ pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-τ pathology in the CA1/subiculum region nor displayed significant levels of soluble Aß in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-τ propagation, Aß and p-τ were co-immunoprecipitated with cellular prion protein (PrPC). A similar interaction between PrPC, p-τ and Aß was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrPC may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrPC is capable of interacting with Aß and p-τ. Using a proximity ligation assay, we could demonstrate proximity (less than ~ 30-40 nm distance) between PrPC and Aß and between PrPC and p-τ in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrPC and p-τ was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrPC is a critical player in the interplay between Aß and p-τ propagation at least in a large group of AD cases. Preexisting p-τ pathology interacting with PrPC, thereby, appears to be a prerequisite for Aß to function as a p-τ pathology accelerator via PrPC.

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis.

Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, δ- or η-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPδ/η) or shorter fragments of sAPPη. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPδ/η fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid ß-protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions.

Knowledge, awareness, and practice among gynecologists, medical practitioners and dentists in Madurai regarding association between periodontitis and pregnancy outcomes.

BACKGROUND: The prevalence of oral disease during pregnancy affects the health of the fetus and mother. The interdisciplinary protocol between general dentists (GDs), gynecologists, and general medical practitioners (GMPs) is proved to reduce the incidence of maternal and neonatal complications. AIM: The aim of the present survey is to assess the knowledge, awareness, and attitude of practicing gynecologists, GMPs, and GDs regarding the association of periodontitis and adverse pregnancy outcomes. MATERIALS AND METHODS: This cross-sectional study was conducted among 150 health-care professionals in Madurai. A well-structured pretested questionnaire consisted of 12 questions which were used to assess the awareness of association regarding maintaining oral health during pregnancy among GMPs, GDs, and gynecologists. The knowledge, awareness, and practice scores were calculated for the correct answers to the questions. A software program (SPSS 12) was used for statistical analysis. RESULTS: The mean age of participants was of 33.14 ± 1.5, 32.58 ± 2.80, and 37.7 ± 9.7, respectively. Majority of the participants agreed the importance of dental examination and maintaining oral health during pregnancy GMPs (96%), GDs (100%), and gynecologists (92%). About 92% of gynecologists and GMPs supported that providing dental treatment during pregnancy improved pregnancy outcomes. About 64%, 76%, and 68% of GMPs, GDs, and gynecologists, respectively, confirmed the association between periodontal disease and adverse pregnancy outcomes. CONCLUSION: In this study, knowledge and awareness of gynecologists and GMPs are appreciable; however, their attitude toward bringing the facts into clinical practice needs to be improved through integrated programs.

Impact of amyloid ß aggregate maturation on antibody treatment in APP23 mice.

INTRODUCTION: The deposition of the amyloid ß protein (Aß) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aß by Aß-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aß aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aß stages). To test the impact of the B-Aß stage on Aß immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aß-antibody ß1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aß plaque deposition and dendrite degeneration. RESULTS: At 5 months of age, first Aß aggregates in APP23 brain consisted of non-modified Aß (representing B-Aß stage 1) whereas mature Aß-aggregates containing N-terminal truncated, pyroglutamate-modified AßN3pE and phosphorylated Aß (representing B-Aß stage 3) were found at 11 months of age in both ß1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old ß1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between ß1- and PBS-treated APP23 mice sacrificed with 11 months. CONCLUSIONS: Aß antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aß aggregation was absent or represented B-Aß stage 1 but had no protective or curative effect in later stages with mature Aß aggregates (B-Aß stage 3). These data indicate that the maturation stage of Aß aggregates has impact on potential treatment effects in APP23 mice.

Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against ß-amyloid (Aß) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against Aß (NAbs-Aß) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs-Aß recognized the mid-/C-terminal end of Aß and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs-Aß were able to interfere with Aß peptide toxicity, but NAbs-Aß did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs-Aß in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs-Aß to dispose of proteins or peptides that are prone to forming toxic aggregates.

Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against amyloid-beta.

Intravenous immunoglobulins (IVIG) are currently used for therapeutic purposes in autoimmune disorders. Recently, we demonstrated the presence of naturally occurring antibodies against amyloid-beta (nAbs-Abeta) within the pool of IVIG. In this study, we compared different brands of IVIG for nAbs-Abeta and have found differences in the specificity of the nAbs-Abeta towards Abeta(1-40) and Abeta(1-42). We analyzed the influence of a pH-shift over the course of antibody storage using ELISA and investigated antibody dimerization at acidic and neutral pH as well as differences in the IgG subclass distributions among the IVIG using both HPLC and a nephelometric assay. Furthermore, we investigated the epitope region of purified nAbs-Abeta. The differences found in Abeta specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer's disease.

Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown.

BACKGROUND: Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. RESULTS: Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. CONCLUSION: Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.