Diabetic Cardiomyopathy: From Mechanism to Management in a Nutshell.

Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus characterized by gradually failing heart with detrimental cardiac remodelings, such as fibrosis and diastolic and systolic dysfunction, which is not directly attributable to coronary artery disease. Insulin resistance and resulting hyperglycemia is the main trigger involved in the initiation of diabetic cardiomyopathy. There is a constellation of many pathophysiological events, such as lipotoxicity, oxidative stress, inflammation, inappropriate activation of the renin-angiotensin-aldosterone system, dysfunctional immune modulation promoting increased rate of cardiac cell injury, apoptosis, and necrosis, which ultimately culminates into interstitial fibrosis, cardiac stiffness, diastolic dysfunction, initially, and later systolic dysfunction too. These events finally lead to clinical heart failure of DCM. Herein, The pathophysiology of DCM is briefly discussed. Furthermore, potential therapeutic strategies currently used for DCM are also briefly mentioned.

The Language Development Via FOXP2 in Autism Spectrum Disorder: A Review.

BACKGROUND: An increasing number of newborn children in numerous nations are enrolled in early childhood education programs, and instructors, in this way, assume a focal job in invigorating language improvement in these youthful kids. Kids with language issues are found to have a higher risk for future scholarly challenges and learning inabilities. Language advancement among kids is an intricate procedure and vital for correspondence. The shortcomings in the utilization of grammatical structures may lessen the useful utilization of language for verbally expressive kids with autism spectrum disorder and exacerbate troubles with academic and social expertise advancement. RESULTS: FOXP2, the single principal gene connected to a speech and language issue, is significant for the right execution of complex motor behaviors used for speech. In any case, changes in FOXP2 lead to a speech/language issue portrayed by childhood apraxia of speech. These days, language learning is fundamentally required for kids who need to move to different nations to pursue the instructive frameworks and be helpful individuals or residents of those nations. CONCLUSION: The purpose of this study was to explore the role of FOXP2 in language disorder and its management for children's language and communication development.

Ajmalicine and its Analogues Against AChE and BuChE for the Management of Alzheimer's Disease: An In-silico Study.

BACKGROUND: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions. OBJECTIVE: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. METHODS: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using 'Autodock4.2'. RESULTS: Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. CONCLUSION: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

Comparative study of outcomes between locking plates and three-dimensional plates in mandibular fractures.

OBJECTIVES: The objective was to compare the efficiency and assess postoperative complications of 2.00 mm unicortical locking plates and three-dimensional (3D) plates in surgical correction of uncomplicated mandibular fracture. MATERIALS AND METHODS: A prospective cohort study of twenty patients of uncomplicated mandibular fractures, who were operated either by noncompression unicortical 2-mm locking mini-plate or by noncompression unicortical 2-mm 3D mini-plate, were enrolled and followed up for the study outcomes such as operative time, postoperative infection, and postoperative occlusion. RESULTS: Majority of the patients (90%) were male who had road traffic accident. In 80% of cases, mandibular fracture site was parasymphysis. The mean operating time for 3D plates (43.20 min) was significantly lower than that for locking plates (54.82 min), P < 0.001. All cases operated by 3D plates compared to 60% by locking mini-plates did not need intermaxillary fixation, P = 0.025. The 80% of cases operated by 3D plates did not require postoperative occlusion correction compared to 30% in another group, P = 0.01. For other parameters such as postoperative sensory disturbance, postoperative infection, incidence tooth damage, vertical displacement of mandible, feeling of plate after platting, and chewing efficiency after 1 week, there were no statistical significant differences between the two groups. CONCLUSIONS: The outcome of 2.0mm 3D mini-plate is better in terms of operating time required, post-operative need of intermaxillary fixation and occlusal correction. While the outcome is similar to the use of non-compression unicortical 2.00mm locking miniplate in parameters like infection rate and incidence of tooth damage etc.

Coenzyme Q and its role in glaucoma.

Presently the management of glaucoma is limited to lowering of intra-ocular pressure (IOP). Since this modality does not appear to be successful in all cases there is increasing focus on non-IOP lowering medications. Coenzyme Q is a naturally occurring compound similar to vitamins. There are a few reports suggesting the neuroprotective efficacy of this agent in glaucoma models. The present systematic review was undertaken to study the pharmacology, physiology, metabolism and role of Coenzyme Q in glaucoma. An English-language search for relevant items was undertaken using PubMed, Google Scholar, Scopus and other databases. The present review found a positive outcome of Coenzyme Q as a neuroprotectant being reported in all studies. However, the review also found that the majority of studies on Coenzyme Q have been reported by a single group of researchers. In order to have a more wide-ranging impact regarding the efficacy of Coenzyme Q in glaucoma, it would be useful to undertake further multi- center trials.

NMR: From Molecular Mechanism to its Application in Medical Care.

BACKGROUND: Nuclear Magnetic Resonance (NMR) spectroscopy is a systematic science strategy utilized in pharmaceutical research, development, quality control, and research to decide the content and purity of a sample as well as its sub-atomic structure. There are several parameters working for better execution of NMR which can include chemical shifts, spin multiplicity, pH dependence, heteronuclear and homonuclear covalent network, and the atomic overhauser impact. NMR imaging offers an extensive scope of potential outcomes for the portrayal of skeletal muscle structure, function and metabolism. 1H additionally has the most noteworthy NMR affectability of any nucleus. The principle of NMR depends on the spins of atomic nuclei. The magnetic estimations rely on an unpaired electron, while NMR estimates attractive impact brought about by the turn of protons and neutrons. The nucleons have intrinsic angular momenta or spins, which is considered as basic magnet. CONCLUSION: The presence of atomic attraction was uncovered in the hyperfine structure of spectral lines. If the nucleus magnetic moment is put in the magnetic field, the phenomenon of space quantization can be observed and each allowed direction will have a marginally unique energy level. Invitro, high-resolution NMR spectroscopy helps to assess tumor metabolism by the investigation of body liquids like urine, blood and removed tissue specimens. In-cell NMR is a powerful technique to assess strong compounds in medication improvement to spare exploratory expenses.

The Structure and Function of α, ß and γ-Secretase as Therapeutic Target Enzymes in the Development of Alzheimer's Disease: A Review.

Alzheimer's disease is a progressive neurodegenerative disorder that affects the central nervous system. There are several factors that cause AD, like, intracellular hyperphosphorylated Tau tangles, collection of extracellular Amyloid-ß42 and generation of reactive oxygen species due to mitochondrial dysfunction. This review analyses the most active target of AD and both types of AD-like early-onset AD and late-onset AD. BACE1 is a ß-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease. The presenilin proteins play a critical role in the pathogenesis of Alzheimer malady by intervening the intramembranous cleavage of amyloid precursor protein and the generation of amyloid ß. The two homologous proteins PS1 and PS2 speak to the reactant subunits of particular γ-secretase edifices that intercede an assortment of cellular processes. Natural products are common molecular platforms in drug development in AD. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target in AD. Presently, there are a few theories clarifying the early mechanisms of AD pathogenesis. Recently, research advancements in the field of nanotechnology, which utilize macromolecular strategies to make drugs in nanoscale measurements, offer nanotechnology-based diagnostic tools and drug carriers which are highly sensitive for effective drug targeting in the treatment of Alzheimer's disease.

What is Blockchain Technology and its Significance in the Current Healthcare System? A Brief Insight.

BACKGROUND: The promising eventual fate of blockchain in healthcare has a lot more extensive prospect. Blockchain is a novel structure that gives another design to storage and trade of data among different members of a particular network. In case of a hospital, blockchain takes into consideration the creation of a better treatment structure by the expert doctor in order to arrange the meeting based on the symptoms of patients throughout the world by the electronic system. Blockchain technology is crucial for biomedical and human services applications as social insurance has turned out to be a standout among the most essential rising application areas of the blockchain distributed ledger technology. RESULT: By and large, blockchain is treated as a conveyed record to store social insurance related information for allocation, trading, dissecting, footage, and affirming purposes among accomplices. The advantage of blockchain databases versus traditional dispersed databases is that they are decentralized, permanent, and perfected with advanced digital payment frameworks and hash chain occasion structure. The blockchain code is an unlocked resource and can be utilized, altered, and customized by its clients. CONCLUSION: Nowadays, blockchain is expected to be almost universally adopted across medical organizations around the world. The purpose of this review article is to comprehend the current explored subjects, difficulties, and future headings in regards to blockchain innovation from the specialized perspective in the health care system.

Current acetylcholinesterase-inhibitors: a neuroinformatics perspective.

This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on 'hybrid of pre-existing drugs' has been incorporated. Furthermore, current status of therapeutic applications of AChEinhibitors has also been summarized.

Molecular interaction of human brain acetylcholinesterase with a natural inhibitor huperzine-B: an enzoinformatics approach.

The present study emphasizes the molecular interactions between human brain acetylcholinesterase (AChE) and the natural ligand Huperzine-B and its comparison to 'AChE-Tolserine interactions'. Docking between Huperzine-B and AChE was performed using 'Autodock4.2'. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Huperzine-B within the 'catalytic site' of AChE to permit docking. However, docking of Tolserine to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Huperzine-B. Scope still remains in the determination of the three-dimensional structure of AChE-Huperzine-B complex by X-ray crystallography to validate the described data. Furthermore, this study confirms that Huperzine-B is a more efficient inhibitor of human brain AChE compared to tolserine with reference to Ki and ΔG values.

Prediction of comparative inhibition efficiency for a novel natural ligand, galangin against human brain acetylcholinesterase, butyrylcholinesterase and 5-lipoxygenase: a neuroinformatics study.

The present study elucidates molecular interactions of human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 5-lipoxygenase (5-LPO) with a novel natural ligand Galangin (GAL); and also with the well-known ligands Bisnorcymserine (BNC) and Cymserine for comparison. Docking between these ligands and enzymes were performed using 'Autodock4.2'. It was found that hydrophobic interactions play an important role in the correct positioning of BNC within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking while hydrogen bonds are significant in case of cymserine for the same. However, only polar interactions are significant in the correct positioning of GAL within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking. Such information may aid in the design of versatile AChE, BuChE and 5 LPO-inhibitors, and is expected to aid in safe clinical use of above ligands. Scope still remains in the determination of the three-dimensional structure of AChE-GAL, BuChE-GAL and 5-LPO-GAL complex by X-ray crystallography to certify the described data. Moreover, the present study confirms that GAL is a more efficient inhibitor of human brain AChE compared to BNC and cymserine, while in case of 5-LPO and human brain BuChE, BNC is a more efficient inhibitor compared to GAL and cymserine with reference to ΔG and Ki values.

Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbß3 integrin.

The platelet protein disulfide isomerase called ERp57 mediates platelet aggregation, but its role in thrombus formation is unknown. To determine the specific role of platelet-derived ERp57 in hemostasis and thrombosis, we generated a megakaryocyte/platelet-specific knockout. Despite normal platelet counts and platelet glycoprotein expression, mice with ERp57-deficient platelets had prolonged tail-bleeding times and thrombus occlusion times with FeCl3-induced carotid artery injury. Using a mesenteric artery thrombosis model, we found decreased incorporation of ERp57-deficient platelets into a growing thrombus. Platelets lacking ERp57 have defective activation of the αIIbß3 integrin and platelet aggregation. The defect in aggregation was corrected by the addition of exogenous ERp57, implicating surface ERp57 in platelet aggregation. Using mutants of ERp57, we demonstrate the second active site targets a platelet surface substrate to potentiate platelet aggregation. Binding of Alexa 488-labeled ERp57 to thrombin-activated and Mn(2+)-treated platelets lacking ß3 was decreased substantially, suggesting a direct interaction of ERp57 with αIIbß3. Surface expression of ERp57 protein and activity in human platelets increased with platelet activation, with protein expression occurring in a physiologically relevant time frame. In conclusion, platelet-derived ERp57 directly interacts with αIIbß3 during activation of this receptor and is required for incorporation of platelets into a growing thrombus.

Kearns-Sayre syndrome: An unusual ophthalmic presentation.

Kearns-Sayre syndrome (KSS) belongs to the group of neuromuscular disorders known as mitochondrial encephalomyopathies. It has characteristic syndromal features, which include: chronic progressive external ophthalmoplegia, bilateral atypical pigmentary retinopathy, and cardiac conduction abnormalities. So far, only a single case has been reported where a patient with KSS had a normal retina. Herein, we report this extremely rare variant of KSS, which not only presented later than the normal age of presentation, but also had minimal pigmentary retinopathy.

The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis.

A close homologue to protein disulfide isomerase (PDI) called ERp57 forms disulfide bonds in glycoproteins in the endoplasmic reticulum and is expressed on the platelet surface. We generated 2 rabbit Abs to ERp57. One Ab strongly inhibited ERp57 in a functional assay and strongly inhibited platelet aggregation. There was minimal cross-reactivity of this Ab with PDI by Western blot or in the functional assay. This Ab substantially inhibited activation of the αIIbß3 fibrinogen receptor and P-selectin expression. Furthermore, adding ERp57 to platelets potentiated aggregation. In contrast, adding a catalytically inactive ERp57 inhibited platelet aggregation. When infused into mice the inactive ERp57 prolonged the tail bleeding times. We generated 2 IgG2a mAbs that reacted with ERp57 by immunoblot. One of these Abs inhibited both ERp57 activity and platelet aggregation. The other Ab did not inhibit ERp57 activity or platelet aggregation. The inhibitory Ab inhibited activation of αIIbß3 and P-selectin expression, prolonged tail bleeding times, and inhibited FeCl(3)-induced thrombosis in mice. Finally, we found that a commonly used mAb to PDI also inhibited ERp57 activity. We conclude that a glycoprotein-specific member of the PDI family, ERp57, is required for platelet aggregation, hemostasis, and thrombosis.

Dactinomycin impairs cellular respiration and reduces accompanying ATP formation.

The effect of dactinomycin on cellular respiration and accompanying ATP formation was investigated in Jurkat and HL-60 cells. Cellular mitochondrial oxygen consumption (measured by a homemade phosphorescence analyzer) and ATP content (measured by the luciferin-luciferase bioluminescence system) were determined as functions of time t during continuous exposure to the drug. The rate of respiration, k, was the negative of the slope of [O2] versus t. Oxygen consumption and ATP content were diminished by cyanide, confirming that both processes involved oxidations in the mitochondrial respiratory chain. In the presence of dactinomycin, k decreased gradually with t, the decrease being more pronounced at higher drug concentrations. Cellular ATP remained constant for 5 h in untreated cells, but in the presence of 20 microM dactinomycin it decreased gradually (to one-tenth the value at 5 h for untreated cells). The drug-induced inhibition of respiration and decrease in ATP were blocked by the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethyl ketone (zVAD-fmk). A rapid but temporary decrease in cellular ATP observed on the addition of zVAD-fmk was shown to be due to DMSO (added with zVAD-fmk). The effect of dactinomycin on respiration differed from that of doxorubicin. Plots of [O2] versus t were curved for dactinomycin so that k decreased gradually with t. The corresponding plots for doxorubicin were well fit by two straight lines; so k was constant for approximately 150 min, at which time k decreased, remaining constant at a lower level thereafter. The results for cells treated with mixtures of the two drugs indicated that the drugs acted synergistically. These results show the onset and severity of mitochondrial dysfunction in cells undergoing apoptosis induced by dactinomycin.

Role of the C2 domain of factor VIIIa in the assembly of factor-X activating complex on the platelet membrane.

Optimal rates of factor X (FX) activation require binding of factor IXa (FIXa), factor VIII(a) [FVIII(a)], and FX to activated platelet receptors. To define the FVIIIa domains that mediate platelet interactions, albumin density gradient washed, gel-filtered platelets (3.5 x 10(8)/mL) activated by the thrombin receptor peptide, SFLLRN (25 microM), were incubated with 125I-labeled FVIII C2 domain, or 125I-FVIIIa, or 125I-FVIII((LC)), or peptides from the C2 domain region, with or without anti-C2 domain monoclonal antibodies (MoAb), ESH4 or ESH8. FVIIIa (Kd approximately 1.7 nM), FVIII((LC)) (Kd approximately 3 nM), and the C2 domain (Kd approximately 16 nM) all interacted with approximately 700-800 binding sites/platelet. Unlike FVIIIa, the C2 domain did not respond to the presence of excess EGR-FIXa (45 nM) and FX (1.5 microM) with enhanced binding stoichiometry and affinity. Both the MoAb ESH4 and a synthetic peptide corresponding to FVIII residues 2303-2332 (epitope for FVIII MoAb, ESH4) inhibited FVIIIa binding to platelets, whereas MoAb ESH8 and a C2 domain peptide corresponding to residues 2248-2285 (epitope for the FVIII MoAb, ESH8) failed to inhibit FVIIIa binding. Thus, a major platelet-binding site resides within residues 2303-2332 in the C2 domain of FVIIIa, and an additional site within residues 2248-2285 increases the stoichiometry and affinity of FVIIIa binding to activated platelets only in the presence of FIXa and FX but does not directly mediate FVIIIa binding to the platelet surface.

A Glu113Ala mutation within a factor VIII Ca2+-binding site enhances cofactor interactions in factor Xase.

We recently identified an acidic-rich segment in the A1 domain of factor VIII (residues 110-126) that functions in the coordination of Ca(2+), an ion necessary for cofactor activity [Wakabayashi et al. (2004) J. Biol. Chem. 279, 12677-12684]. Mutagenesis studies showed that replacement of residue Glu113 with Ala (E113A) yielded a factor VIII point mutant possessing increased specific activity as determined by a one-stage clotting assay. Mutagenesis at this site suggested that substitution with relatively small, nonpolar residues was well tolerated, whereas replacement with a number of polar or charged residues appeared detrimental to activity. Ala substitution resulted in the greatest enhancement, yielding an approximately 2-fold increased specific activity. Time course experiments following reaction with thrombin revealed similar rates of activation and inactivation of E113A as observed for the wild type. Results from factor Xa generation assays showed minimal differences in kinetic parameters and factor IXa affinity for E113A and wild-type factor VIIIa when run in the presence of synthetic phospholipid vesicles, whereas factor VIIIa E113A displayed an approximately 4-fold greater affinity for factor IXa compared with factor VIIIa wild type in reactions run on the platelet membrane surface. This latter effect may be attributed, in part, to a 2-fold increased affinity of factor VIIIa E113A for the platelet membrane. Considering that low levels of factors VIIIa and IXa are generated during clotting in plasma, the increased cofactor specific activity observed for E113A factor VIII may result from its enhanced affinity for factor IXa on the physiological membrane.

Proteases in blood clotting.

The serine proteases, cofactors and cell-receptor molecules that comprise the haemostatic mechanism are highly conserved modular proteins that have evolved to participate in biochemical reactions in blood coagulation, anticoagulation and fibrinolysis. Blood coagulation is initiated by exposure of tissue factor, which forms a complex with factor VIIa and factor X, which results in the generation of small quantities of thrombin and is rapidly shutdown by the tissue factor pathway inhibitor. The generation of these small quantities of thrombin then activates factor XI, resulting in a sequence of events that lead to the activation of factor IX, factor X and prothrombin. Sufficient thrombin is generated to effect normal haemostasis by converting fibrinogen into fibrin. The anticoagulant pathways that regulate blood coagulation include the protein C anticoagulant mechanism, the serine protease inhibitors in plasma, and the Kunitz-like inhibitors, tissue factor pathway inhibitor and protease nexin 2. Finally, the fibrinolytic mechanism that comprises the activation of plasminogen into plasmin prevents excessive fibrin accumulation by promoting local dissolution of thrombi and promoting wound healing by reestablishment of blood flow.