Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models.

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest challenges facing cardiovascular medicine today. Despite being the most common form of heart failure worldwide, there has been limited success in developing therapeutics for this syndrome. This is largely due to our incomplete understanding of the biology driving its systemic pathophysiology and the heterogeneity of clinical phenotypes, which are increasingly being recognized as distinct HFpEF phenogroups. Development of efficacious therapeutics fundamentally relies on robust preclinical models that not only faithfully recapitulate key features of the clinical syndrome but also enable rigorous investigation of putative mechanisms of disease in the context of clinically relevant phenotypes. In this review, we propose a preclinical research strategy that is conceptually grounded in model diversification and aims to better align with our evolving understanding of the heterogeneity of clinical HFpEF. Although heterogeneity is often viewed as a major obstacle in preclinical HFpEF research, we challenge this notion and argue that embracing it may be the key to demystifying its pathobiology. Here, we first provide an overarching guideline for developing HFpEF models through a stepwise approach of comprehensive cardiac and extra-cardiac phenotyping. We then present an overview of currently available models, focused on the 3 leading phenogroups, which are primarily based on aging, cardiometabolic stress, and chronic hypertension. We discuss how well these models reflect their clinically relevant phenogroup and highlight some of the more recent mechanistic insights they are providing into the complex pathophysiology underlying HFpEF.

Best Practices: Indications and Procedural Controversies of Adrenal Vein Sampling for Primary Aldosteronism.

Primary hyperaldosteronism (PA) is the most common secondary form of hyper-tension in middle-aged adults. Its harmful effects exceed those of essential hyper-tension. Once PA is diagnosed, treatment hinges on whether aldosterone secretion is unilateral or bilateral, as the former can be effectively treated with adrenalectomy but the latter is treated medically with mineralocorticoid receptor antagonists such as spironolactone or eplerenone. Adrenal vein sampling (AVS) is critical in this determination. There is wide variation in how AVS is performed, including whether to use synthetic adrenocorticotropic hormone stimulation and where the catheter tip should be placed during left adrenal gland sampling. In addition, some institutions and guidelines omit AVS in young patients (i.e., those younger than an age threshold ranging from 35 to 40 years old) who have unilateral adrenal findings on cross-sectional imaging. In this article, we provide background on PA and performance of AVS and then summarize the evidence supporting best practices for these three areas of controversy regarding how and when to perform AVS.

Extra-nuclear histones: origin, significance and perspectives.

Histones are classically known to organize the eukaryotic DNA into chromatin. They are one of the key players in regulating transcriptionally permissive and non-permissive states of the chromatin. Nevertheless, their context-dependent appearance within the cytoplasm and systemic circulation has also been observed. The past decade has also witnessed few scientific communications on the existence of vesicle-associated histones. Diverse groups have attempted to determine the significance of these extra-nuclear histones so far, with many of those studies still underway. Of note amongst these are interactions of extra-nuclear or free histones with cellular membranes, mediated by mutual cationic and anionic natures, respectively. It is here aimed to consolidate the mechanism of formation of extra-nuclear histones; implications of histone-induced membrane destabilization and explore the mechanisms of their association/release with extracellular vesicles, along with the functional aspects of these extra-nuclear histones in cell and systemic physiology.

A systemic review on liquid crystals, nanoformulations and its application for detection and treatment of SARS - CoV- 2 (COVID - 19).

The COVID-19 is a pandemic caused by the SARS-CoV-2 virus, has instigated major health problems and prompted WHO to proclaim a worldwide medical emergency. The knowledge of SARS-CoV-2 fundamental structure, aetiology, its entrance mechanism, membrane hijacking and immune response against the virus, are important parameters to develop effective vaccines and medicines. Liquid crystals integrated nano-techniques and various nanoformulations were applied to tackle the severity of the virus. It was reported that nanoformulations have helped to enhance the effectiveness of presently accessible antiviral medicines or to elicit a fast immunological response against COVID-19 virus. Applications of liquid crystals, nanostructures, nanoformulations and nanotechnology in diagnosis, prevention, treatment and tailored vaccine administration against COVID-19 which will help in establishing the framework for a successful pandemic combat are reviewed. This review also focuses on limitations associated with liquid crystal-nanotechnology based systems and suggests the possible ways to address these limitations. Also, topical advancements in the ground of liquid crystals and nanostructures established diagnostics (nanosensor/biosensor) are discussed in detail.

Influence of processing parameters and formulation factors on the bioadhesive, temperature stability and drug release properties of hot-melt extruded films containing miconazole.

This study investigated the processing parameters and formulation factors on the bioadhesive properties, temperature stability properties, and drug release properties of miconazole in PolyOx® and Klucel® matrix systems produced by Hot-melt Extrusion (HME) technology. Miconazole incorporated into these matrix systems were found to be stable for 8 months by X-ray diffraction (XRD). The addition of miconazole increased area under the curve (AUC) at contact time intervals of 30 and 60 sec, while the bioadhesion decreased with an increase in processing temperatures. The release profiles suggest that a sustained release of miconazole was observed from all of the tested HME film formulations for approximately 10 h. The release from the optimal HME film extruded at 205°C was found to be significantly different than that extruded at 190°C. Therefore, this matrix system may address the present shortcomings of currently available therapy for oral and pharyngeal candidiasis.

Incongruent Treatment Recommendations Between Left and Right Hip Bone Mineral Densities.

Objective The official position of the International Society for Clinical Densitometry (ISCD) is that either hip site can be scanned with dual-energy X-ray absorptiometry (DXA) imaging. Whether there is a difference in guideline-based treatment recommendations between hip sites has not previously been assessed. Methods We conducted a retrospective analysis of all individuals who underwent DXA imaging at a single center from September 1, 2018, to October 31, 2019. Women aged ≥ 40 years old and men aged ≥ 50 years old were included. Individuals without bilateral hip measurements or who were on osteoporosis treatment were excluded. The 10-year probability of fracture using the fracture risk assessment tool (FRAX) was calculated for each hip when the worst T-score was in the osteopenia range. Results Of the included participants, 10% (n = 151/1505) had incongruent treatment recommendations (ITR) between the left and right hips. In the ITR group, 70% (n = 106) had osteopenia and 30% (n = 45) had osteoporosis. Age was the only significant risk factor for ITR overall (OR: 1.06, 95% CI: 1.04-1.09). In the osteopenia group, however, age (OR: 1.17, 95% CI: 1.13-1.21), history of parental hip fracture (OR: 3.16, 95% CI: 1.65-6.05), and glucocorticoid use (OR: 4.18, 95% CI: 1.6-11.0) were associated with ITR. In the osteoporosis group, the right hip (femoral neck and total) T-scores were significantly lower compared to the left. Conclusion Measuring bone mineral density on both hips changes treatment recommendations in 10% of people. This was more likely in those with osteopenia who were older, had a parental history of hip fracture, or were on glucocorticoids. Measuring both hips did not add time or cost to patient care. Given the minimal disadvantages to measuring both hips, there should be a strong consideration to change the current guidance of only measuring one hip.

Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion.

The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH.

SWI/SNF Chromatin Remodelers: Structural, Functional and Mechanistic Implications.

The nuclear events of a eukaryotic cell, such as replication, transcription, recombination and repair etc. require the transition of the compactly arranged chromatin into an uncompacted state and vice-versa. This is mediated by post-translational modification of the histones, exchange of histone variants and ATP-dependent chromatin remodeling. The SWI/SNF chromatin remodeling complexes are one of the most well characterized families of chromatin remodelers. In addition to their role in modulating chromatin, they have also been assigned roles in cancer and health-related anomalies such as developmental, neurocognitive, and intellectual disabilities. Owing to their vital cellular and medical connotations, developing an understanding of the structural and functional aspects of the complex becomes imperative. However, due to the intricate nature of higher-order chromatin as well as compositional heterogeneity of the SWI/SNF complex, intra-species isoforms and inter-species homologs, this often becomes challenging. To this end, the present review attempts to present an amalgamated perspective on the discovery, structure, function, and regulation of the SWI/SNF complex.

A Comparative Analysis of Heavy Metal Effects on Medicinal Plants.

Popularity of herbal drugs has always been in high demand, but recently it has been increasing all over the world, especially in India, because of the lower range of adverse health effects as compared to synthetic or man-made drugs. Not only this but their cost-effectiveness and easy availability to the poor people and the masses, particularly in developing countries, are major causes for their demand. But there lies a huge problem during the process of plant collection that affects their medicinal properties to certain degrees. This is caused by heavy metal toxicity in soil in different locations of the Indian subcontinent. This was correlated with their potential to cause health damage. Exposure of humans to heavy metals includes diverse pathways from food to water to consumption and inhalation of polluted air to permanent damage to exposed skin and even by occupational exposure at workplaces. As we can understand, the main mechanisms of heavy metal toxicity include the production of free radicals to affect the host by oxidative stress, damaging biological molecules such as enzymes, proteins, lipids, and even nucleic acids and finally damaging DNA which is the fastest way to carcinogenesis and in addition, neurotoxicity. Therefore, in this paper, we have researched how the plants/herbs are affected due to heavy metal deposition in their habitat and how it can lead to serious clinical complications.

Endothelial cell CD36 mediates stroke-induced brain injury via BBB dysfunction and monocyte infiltration in normal and obese conditions.

CD36 expressed in multiple cell types regulates inflammation, vascular function, and innate immunity. Specifically, CD36 in microvascular endothelial cells (ECs) signals to elicit inflammation and causes EC death. This study investigated roles for EC-CD36 on acute stroke pathology in normal and obese conditions. Obesity induced by a high-fat diet (HD) selectively increased CD36 expression in ECs, not in monocytes/macrophages, in the post-ischemic brain. Mice deficient CD36 in ECs (ECCD36-/-) showed reduced injury size and vascular permeability in normal conditions. While control mice fed a HD developed obesity and aggravated stroke injury, ECCD36-/- mice were resistant to develop an obesity phenotype. Subjecting ECCD36-/- mice to stroke resulted in reduced injury size and BBB disruption. Moreover, the mice had reduced MCP-1 and CCR2 gene expression, resulting in reduced monocyte trafficking with improved survival and acute motor function. Reduced MCP-1 and CCR2 expression was still evident in ECCD36-/- mice subjected to severe stroke, suggesting that monocyte trafficking is an infarct-independent metabolic effect associated with specific EC-CD36 deletion. Our findings demonstrate the importance of EC-CD36 in developing vascular comorbidities and suggest that targeting EC-CD36 is a potential preventative strategy to normalize vascular risk factors, leading to improved acute stroke outcomes.

Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology.

The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.

Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFß signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Molar Pregnancy Complicated by Impending Thyroid Storm.

Gestational trophoblastic diseases, which include molar pregnancy, have an increased risk of complications associated with the thyroid gland. This condition is mainly caused by elevated levels of beta-human chorionic gonadotropin produced during pregnancy, which is exaggerated in molar pregnancy and can lead to thyrotoxicosis. Hence, it is important to recognize the signs and symptoms of hyperthyroidism among women of childbearing age to prevent complications such as thyroid storm. Medical management of thyroid storm before surgery is critical to prevent adverse maternal outcomes. Here, we report a rare case of impending thyroid storm induced by molar pregnancy.

Targeting the Nrf2/ARE Signalling Pathway to Mitigate Isoproterenol-Induced Cardiac Hypertrophy: Plausible Role of Hesperetin in Redox Homeostasis.

Cardiac hypertrophy is the underlying cause of heart failure and is characterized by excessive oxidative stress leading to collagen deposition. Therefore, understanding the signalling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodelling and heart failure. In this study, we hypothesized that hesperetin, a flavanone that elicits the activation of Nrf2 signalling and thereby suppresses oxidative stress, mediated pathological cardiac hypertrophy progression. A cardiac hypertrophy model was established with subcutaneous injection of isoproterenol in male Wistar rats. Oxidative stress markers, antioxidant defense status, and its upstream signalling molecules were evaluated to discover the impacts of hesperetin in ameliorating cardiac hypertrophy. Our results implicate that hesperetin pretreatment resulted in the mitigation of oxidative stress by upregulating antioxidant capacity of the heart. This curative effect might be owing to the activation of the master regulator of antioxidant defense system, known as Nrf2. Further, analysis of Nrf2 revealed that hesperetin enhances its nuclear translocation as well as the expression of its downstream targets (GCLC, NQO1, and HO-1) to boost the antioxidative status of the cells. To support this notion, in vitro studies were carried out in isoproterenol-treated H9c2 cells. Immunocytochemical analysis showed augmented nuclear localization of Nrf2 implicating the action of hesperetin at the molecular level to maintain the cellular redox homeostasis. Thus, it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby ameliorates pathological cardiac remodelling.

LOX-1, the Common Therapeutic Target in Hypercholesterolemia: A New Perspective of Antiatherosclerotic Action of Aegeline.

BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized low-density lipoprotein (Ox-LDL) in the aorta of aged rats. Ox-LDL initiates LOX-1 activation in the endothelium of lipid-accumulating sites of both animal and human subjects of hypercholesterolemia. Targeting LOX-1 may provide a novel diagnostic strategy towards hypercholesterolemia and vascular diseases. HYPOTHESIS: This study was planned to address whether aegeline (AG) could bind to LOX-1 with a higher affinity and modulate the uptake of Ox-LDL in hypercholesterolemia. STUDY DESIGN: Thirty-six Wistar rats were divided into six groups. The pathology group rats were fed with high-cholesterol diet (HCD) for 45 days, and the treatment group rats were fed with HCD and aegeline/atorvastatin (AV) for the last 30 days. In vivo and in vitro experiments were carried out to assay the markers of atherosclerosis like Ox-LDL and LOX-1 levels. Histopathological examination was performed. Oil Red O staining was carried out in the IC-21 cell line. Docking studies were performed. RESULTS: AG administration effectively brought down the lipid levels induced by HCD. The lowered levels of Ox-LDL and LOX-1 in AG-administered rats deem it to be a potent antihypercholesterolemic agent. Compared to AV, AG had a pronounced effect in downregulating the expression of lipids evidenced by Oil Red O staining. AG binds with LOX-1 at a higher affinity validated by docking. CONCLUSION: This study validates AG to be an effective stratagem in bringing down the lipid stress induced by HCD and can be deemed as an antihypercholesterolemic agent.

Simulation of the response of an ionization chamber to 214Bi emission. Application to the measurement of 222Rn.

PENELOPE simulations of a Vinten ionization chamber (IC) were performed to investigate the influence of the thickness of glass-ampoules used in 222Rn standardization. The simulation reveals a non-negligible variation of the energy deposited in the chamber gas region (which may induce a proportional variation of the measured current) when considering the ß transition emissions of the daughters of 222Rn. This reinforces the idea of using a specialist container (made of metal to preserve the integrity of the container) that would circulate between the metrology laboratories in the context of international comparison exercises using the BIPM international reference system (SIR).

Evaluation of Turmeric Chip Compared with Chlorhexidine Chip as a Local Drug Delivery Agent in the Treatment of Chronic Periodontitis: A Split Mouth Randomized Controlled Clinical Trial.

AIMS AND OBJECTIVE: The aim of this study was to evaluate and compare the effect of chlorhexidine (CHX) chip and turmeric chip as a local drug delivery (LDD) agent in the treatment of patients with chronic periodontitis. MATERIALS AND METHODS: A total of 120 sites with pocket depths 5-8 mm were chosen as a split mouth design at 3 sites in the same patient. Selected sites were randomly divided into three groups to receive CHX chip in addition to scaling and root planing (SRP) in group A, turmeric chip in addition to SRP in group B, and SRP only in group C. Clinical parameters, that is, plaque index (PI), gingival index (GI), probing pocket depth (PPD), and relative attachment level (RAL) were recorded at baseline, 1 month, and 3 months interval. RESULT: On applying statistical analysis, results revealed that there was a significant reduction in all the clinical parameters, that is, PI, GI, PPD, and gain in RAL from baseline to 1 month and 3 months in all the three groups. These results were found to be significantly high in the CHX group and turmeric group than in the SRP group. Also, the results in both the test groups were maintained till the end of the study periods, but SRP group showed a significant deterioration after 1 month as was seen by increase in PPD and decrease in RAL scores after 3 months in the SRP group. CONCLUSION: Both the treatment modalities with the application of LDD as an adjunct to SRP proved to be equally beneficial in the treatment of chronic periodontitis.

Influence of solubilization and AD-mutations on stability and structure of human presenilins.

Presenilin (PS1 or PS2) functions as the catalytic subunit of γ-secretase, which produces the toxic amyloid beta peptides in Alzheimer's disease (AD). The dependence of folding and structural stability of PSs on the lipophilic environment and mutation were investigated by far UV CD spectroscopy. The secondary structure content and stability of PS2 depended on the lipophilic environment. PS2 undergoes a temperature-dependent structural transition from α-helical to ß-structure at 331 K. The restructured protein formed structures which tested positive in spectroscopic amyloid fibrils assays. The AD mutant PS1L266F, PS1L424V and PS1ΔE9 displayed reduced stability which supports a proposed 'loss of function' mechanism of AD based on protein instability. The exon 9 coded sequence in the inhibitory loop of the zymogen was found to be required for the modulation of the thermal stability of PS1 by the lipophilic environment.

Impact of EGCG Supplementation on the Progression of Diabetic Nephropathy in Rats: An Insight into Fibrosis and Apoptosis.

Apoptosis is an active response of cells to altered microenvironments, which is characterized by cell shrinkage, chromatin condensation, and DNA fragmentation, in a variety of cell types such as renal epithelial cells, endothelial cells, mesangial cells, and podocytes. Hyperglycemia is among the microenvironmental factors that may facilitate apoptosis, which plays a decisive role in the initiation of diabetic nephropathy. Transforming growth factor-ß emerges as a powerful fibrogenic factor in the development of renal hypertrophy. Although, a number of potential treatment strategies exist for diabetic nephropathy, considering the ease of use and bioavailability, phytochemicals stands distinct as the preeminent option. EGCG, a green tea catechin is one such phytochemical which possesses hypoglycemic and antifibrotic activity. The present study aims to explore the potential of EGCG to prevent apoptosis in a high-fat diet and STZ induced diabetic nephropathy rats by assessing renal function, pro-fibrotic marker, and the expression of apoptotic and antiapoptotic proteins. Our results validate EGCG as a potential antiapoptotic agent evidently by improving renal function via down regulating TGF-ß, consequently ameliorating diabetic nephropathy. In accordance with this, EGCG might be regarded as a prospective therapeutic candidate in modulating diabetic nephropathy, thus being a promising treatment.