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Deposition of toxic protein inclusions is a common hallmark of many neurodegenerative disorders including Alzheimer's disease, Parkinson disease etc. N-acetylaspartate (NAA) is an important brain metabolite whose levels got altered under various neurodegenerative conditions. Indeed, NAA has been a widely accepted biological marker for various neurological disorders. We have also reported that NAA is a protein stabilizer. In the present communication, we investigated the role of NAA in modulating the aggregation propensity on two model proteins (carbonic anhydrase and catalase). We discovered that NAA suppresses protein aggregation and could solubilize preformed aggregates.

Cancer: Links with homocysteine Cancer can be added to the wide range of diseases known to be associated with elevated blood levels of the small amino acid homocysteine. Abnormally high levels of this compound are already known to contribute to conditions including cardiovascular problems, neurodegenerative diseases, neural tube defects, Down’s syndrome, diabetes and megaloblastic anemia. This review, by Laishram R. Singh and colleagues at the University of Delhi, India, concludes that disturbed homocysteine metabolism is associated with many forms of human cancer. The authors discuss a range of genetic, epigenetic and environmental factors that may be involved in the cause and effect relationships between homocysteine metabolism and cancer. It is particularly interesting that low folate (vitamin B9) levels result in high homocysteine levels, and vice versa. Further research may yield insights leading to new forms of cancer treatment and diagnosis.

Small molecule osmolytes, responsible for protecting stresses have long been known to rescue proteins and enzymes from loss of function. In addition to protecting macromolecules integrity, many osmolytes also act as potential antioxidant and also help to prevent protein aggregation, amyloid formation or misfolding, and therefore are considered promising molecules for neurodegenerative and many other genetic diseases. Osmolytes are also known to be involved in the regulation of several key immunological processes. In the present review we discuss in detail the effect of these compounds on important aspects of vaccines i.e., increasing the efficiency, production and purification steps. The present review therefore will help researchers to make a better strategy in vaccine production to formulation by incorporating specific and appropriate osmolytes in the processes.

We are reporting a simple, efficient and green protocol for the synthesis of chromenes and dihydropyrimidines (products of Knoevenagel and Biginelli reaction, respectively) by the use of silica-supported perchloric acid (HClO4–SiO2) as an effective heterogeneous catalyst. Short reaction times, high product yields, simple procedure and reusability of the catalyst are the superior characteristics of this protocol.

Abstract Osmolytes (small molecules that help in circumventing stresses) are known to promote protein folding and prevent aggregation in the case of globular proteins. However, the effect of such osmolytes on the structure and function of intrinsically disordered proteins (IDPs) has not been clearly understood. Here we have investigated the effect of methylamine osmolytes on α-casein (an IDP present in mammalian milk) and discovered that TMAO (Trimethylamine-N-oxide) but not other methylamines renders α-casein functionless. We observed that the loss of chaperone activity of α-casein in presence of TMAO was due to the induction of an unstable aggregation-prone intermediate. The results indicate that different osmolytes may have different structural and functional consequences on IDPs, and therefore might have clinical implications for a large number of human diseases (e.g., amyloidosis, cancer, diabetes, and neurodegeneration) where IDPs are involved.

The extracellular protein, transthyretin is responsible for the transport of thyroxin and retinol binding protein complex to the various parts of the body. In addition to this transport function, transthyretin has also been involved in cardiovascular malfunctions, polyneuropathy, psychological disorders, obesity and diabetes, etc. Recent developments have evidenced that transthyretin has been associated with many other biological functions that are directly or indirectly associated with the oxidative stress, the common hallmark for many human diseases. In this review, we have attempted to address that transthyretin is associated with oxidative stress and could be an important biomarker. Potential future perspectives have also been discussed.

Most of the human diseases related to various proteopathies are confined to the brain, which leads to the development of various forms of neurological disorders. The human brain consists of several osmolytic compounds, such as N-Acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), glutamine (Gln), creatine (Cr), and choline-containing compounds (Cho). Among these osmolytes, the level of NAA drastically decreases under neurological conditions, and, hence, NAA is considered to be one of the most widely accepted neuronal biomarkers in several human brain disorders. To date, no data are available regarding the effect of NAA on protein stability, and, therefore, the possible effect of NAA under proteopathic conditions has not been fully uncovered. To gain an insight into the effect of NAA on protein stability, thermal denaturation and structural measurements were carried out using two model proteins at different pH values. The results indicate that NAA increases the protein stability with an enhancement of structure formation. We also observed that the stabilizing ability of NAA decreases in a pH-dependent manner. Our study indicates that NAA is an efficient protein stabilizer at a physiological pH.

Peroxiredoxins(Prdx), the family of non-selenium glutathione peroxidases, are important antioxidant enzymes that defend our system from the toxic reactive oxygen species (ROS). They are thiol-based peroxidases that utilize self-oxidation of their peroxidatic cysteine (Cp) group to reduce peroxides and peroxidized biomolecules. However, because of its high affinity for hydrogen peroxide this peroxidatic cysteine moiety is extremely susceptible to hyperoxidation, forming peroxidase inactive sulfinic acid (Cys-SO2H) and sulfonic acid (Cys-SO3H) derivatives. With the exception of peroxiredoxin 6 (Prdx6), hyperoxidized sulfinic forms of Prdx can be reversed to restore peroxidase activity by the ATP-dependent enzyme sulfiredoxin. Interestingly, hyperoxidized Prdx6 protein seems to have physiological significance as hyperoxidation has been reported to dramatically upregulate its calcium independent phospholipase A2 activity. Using biochemical studies and molecular dynamic (MD) simulation, we investigated the roles of thermodynamic, structural and internal flexibility of Prdx6 to comprehend the structural alteration of the protein in the oxidized state. We observed the loosening of the hydrophobic core of the enzyme in its secondary and tertiary structures. These changes do not affect the internal dynamics of the protein (as indicated by root-mean-square deviation, RMSD and root mean square fluctuation, RMSF plots). Native-PAGE and dynamic light scattering experiments revealed the formation of higher oligomers of Prdx6 under hyperoxidation. Our study demonstrates that post translational modification (like hyperoxidation) in Prdx6 can result in major alterations of its multimeric status.

Macromolecular crowding has been shown to have an exacerbating effect on the aggregation propensity of amyloidogenic proteins; while having an inhibitory effect on the non-amyloidogenic proteins. However, the results concerning aggregation propensity of non-amyloidogenic proteins have not been convincing due to the contrasting effect on holo-LA, which despite being a non-amyloidogenic protein was observed to aggregate under crowded conditions. In the present study, we have extensively characterized the crowding-induced holo-LA aggregates and investigated the possible mechanism responsible for the aggregation process. We discovered that macromolecular crowding reduces the calcium binding affinity of holo-LA resulting in the formation of apo-LA (the calcium-depleted form of holo-LA) leading to aggregate formation. Another finding is that calcium acts as a chaperone capable of inhibiting and dissociating crowding-induced holo-LA aggregates. The study has a direct implication to Alzheimer Disease as the results invoke a new mechanism to prevent Aβ fibrillation.

One of the proposed mechanisms of homocysteine toxicity in human is the modification of proteins by the metabolite of Hcy, homocysteine thilolactone (HTL). Incubation of proteins with HTL has earlier been shown to form covalent adducts with ε-amino group of lysine residues of protein (called N-homocysteinylation). It has been believed that protein N-homocysteinylation is the pathological hallmark of cardiovascular and neurodegenerative disorders as homocysteinylation induces structural and functional alterations in proteins. In the present study, reactivity of HTL towards proteins with different physico-chemical properties and hence their structural and functional alterations were studied using different spectroscopic approaches. We found that N-homocysteinylation has opposite consequences on acidic and basic proteins suggesting that pI of the protein determines the extent of homocysteinylation, and the structural and functional consequences due to homocysteinylation. Mechanistically, pI of protein determines the extent of N-homocysteinylation and the associated structural and functional alterations. The study suggests the role of HTL primarily targeting acidic proteins in eliciting its toxicity that could yield mechanistic insights for the associated neurodegeneration.

Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state--an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity.

Osmolytes are low molecular weight organic molecules accumulated by organisms to assist proper protein folding, and to provide protection to the structural integrity of proteins under denaturing stress conditions. It is known that osmolyte-induced protein folding is brought by unfavorable interaction of osmolytes with the denatured/unfolded states. The interaction of osmolyte with the native state does not significantly contribute to the osmolyte-induced protein folding. We have therefore investigated if different denatured states of a protein (generated by different denaturing agents) interact differently with the osmolytes to induce protein folding. We observed that osmolyte-assisted refolding of protein obtained from heat-induced denatured state produces native molecules with higher enzyme activity than those initiated from GdmCl- or urea-induced denatured state indicating that the structural property of the initial denatured state during refolding by osmolytes determines the catalytic efficiency of the folded protein molecule. These conclusions have been reached from the systematic measurements of enzymatic kinetic parameters (Km and kcat), thermodynamic stability (Tm and ΔHm) and secondary and tertiary structures of the folded native proteins obtained from refolding of various denatured states (due to heat-, urea- and GdmCl-induced denaturation) of RNase-A in the presence of various osmolytes.

Understanding of protein structure and stability gained to date has been acquired through investigations made under dilute conditions where total macromolecular concentration never surpasses 10 g l(-1). However, biological macromolecules are known to evolve and function under crowded intracellular environments that comprises of proteins, nucleic acids, ribosomes and carbohydrates etc. Crowded environment is known to result in altered biological properties including thermodynamic, structural and functional aspect of macromolecules as compared to the macromolecules present in our commonly used experimental dilute buffers (for example, Tris HCl or phosphate buffer). In this study, we have investigated the thermodynamic and structural consequences of synthetic crowding agent (Ficoll 70) on three different proteins (Ribonuclease-A, lysozyme and holo α-lactalbumin) at different pH values. We report here that the effect of crowding is protein dependent in terms of protein thermal stability and structure. We also observed that the structural characteristics of the denatured state determines if crowding will have an effect or not on the protein stability.

Lanthanide-containing complexes have been widely developed as ratiometric luminescence thermometers, which are non-invasive, contactless and accurate. The synthesis of these Ln complexes generally requires high temperatures, multiple steps and other harsh conditions. Moreover, bimetallic lanthanide complexes, which have been reported to be better thermometers, are even more challenging to synthesize. This complexity can be simplified by preparing a host-guest complex of lanthanides. In this work, Tb or both Tb and Eu are encapsulated in an MOF host, making them emissive. The ratio of Tb/Eu was also easily tuned by simply changing their ratio in the solution, resulting in a tunable emission. Accordingly, we were able to synthesise both the emissive Tb complex and Tb/Eu complexes at different ratios using a single host. The complexes were found to be suitable as ratiometric luminescent thermometers in the temperature range of 160-380 K, with reasonably good sensitivity and uncertainty. The thermometer's sensitivity and uncertainty were significantly improved using bimetallic Tb and Eu host-guest complexes. Calculations using the host and Eu emission ratio were found to provide better thermometer parameters than the commonly reported Tb and Eu emission ratio. Thus, using a single host, we were able to synthesise different lanthanide complexes that can sense temperature, and we improved the thermometer parameters by incorporating multiple lanthanides in a single host. This research will enable the scientific community to reexamine the applicability of unexplored host-guest lanthanide complexes.

Background: Population-based cancer survival is a key indicator for assessing the effectiveness of cancer control by a health care system in a specific geographic area. Breast cancer is the most common cancer among women in India, accounting for over one quarter of all female cancers. The objective of this study was to estimate the 5-year survival of female patients who were diagnosed with breast cancer between 2012 and 2015 from the existing Population-Based Cancer Registries (PBCRs) in India., Methods: In total, 17,331 patients who had breast cancer diagnosed between 2012 and 2015 from 11 PBCRs were followed until June 30, 2021. Active methods were used to track the vital status of registered breast cancer cases. The study conducted survival analysis by calculating the difference between the date of first diagnosis and the date of death or censoring to estimate observed survival and relative survival using the actuarial survival approach and the Ederer-II approach, respectively., Results: The 5-year age-standardized relative survival (95% confidence interval [CI]) of patients with breast cancer was 66.4% (95% CI, 65.5%-67.3%). Mizoram (74.9%; 95% CI, 68.1%-80.8%), Ahmedabad urban (72.7%; 95% CI, 70.3%-74.9%), Kollam (71.5%; 95% CI, 69.2%-73.6%), and Thiruvananthapuram (69.1%; 95% CI, 67.0%-71.2%) had higher survival rates than the national average. Conversely, Pasighat had the lowest survival rate (41.9%; 95% CI, 14.7%-68.6%). The 5-year observed survival rates for localized, regional, and distant metastasis in the pooled PBCRs were 81.0%, 65.5%, and 18.3%, respectively., Conclusions: The overall disparity in survival rates was observed across 11 PBCRs, with lower survival rates reported in Manipur, Tripura, and Pasighat. Therefore, it is imperative to implement comprehensive cancer control strategies widely throughout the country., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Cancer survival data from Population Based Cancer Registries (PBCR) reflect the average outcome of patients in the population, which is critical for cancer control efforts. Despite decreasing incidence rates, cervical cancer is the second most common female cancer in India, accounting for 10% of all female cancers. The objective of the study is to estimate the five-year survival of patients with cervical cancer diagnosed between 2012 and 2015 from the PBCRs in India., Methods: A single primary incidence of cervical cancer cases of 11 PBCRs (2012-2015) was followed till June 30, 2021 (n = 5591). Active follow-ups were conducted through hospital visits, telephone calls, home or field visits, and public databases. Five-year Observed Survival (OS) and Age Standardised Relative Survival (ASRS) was calculated. OS was measured by age and clinical extent of disease for cervical cancers., Findings: The five-year ASRS (95% CI) of cervical cancer was 51.7% (50.2%-53.3%). Ahmedabad urban (61.5%; 57.4%-65.4%) had a higher survival followed by Thiruvananthapuram (58.8%; 53.1%-64.3%) and Kollam (56.1%; 50.7%-61.3%). Tripura had the lowest overall survival rate (31.6%; 27.2%-36.1%). The five-year OS% for pooled PBCRs was 65.9%, 53.5%, and 18.0% for localised, regional, and distant metastasis, respectively., Interpretation: We observed a wide variation in cervical cancer survival within India. The findings of this study would help the policymakers to identify and address inequities in the health system. We re-emphasise the importance of awareness, early detection, and increase the improvement of the health care system., Funding: The National Cancer Registry Programme is funded through intra-mural funding by Indian Council of Medical Research, Department of Health Research, India, Ministry of Health & Family Welfare., Competing Interests: None. The National Cancer Registry Programme is funded through intra-mural funding by Indian Council of Medical Research, Department of Health Research, Ministry of Health & Family Welfare., (© 2023 The Author(s).)

Dynamic supramolecular polymers, with their functional similarities to classical covalent polymers and their adaptive and self-repairing nature reminiscent of biological assemblies, have emerged as highly promising systems for the design of smart soft materials. Recent advancements in mechanistic investigations and novel synthetic strategies, such as living supramolecular polymerization, have significantly enhanced our ability to control the primary structure of these supramolecular polymers. However, realizing their full functional potential requires expanding their topological diversity in a manner akin to classical polymers as well as achieving precise molecular organization at higher hierarchical levels of self-assembly. In this paper, we present a remarkable advancement in this field, introducing an unprecedented and controlled synthesis of secondary supramolecular polymers. Our innovative strategy combines chirality-controlled surface-catalyzed secondary nucleation and a bioinspired peptide design, effectively stabilizing higher-order assembly. Furthermore, by harnessing this stereoselective nucleation process, we demonstrate the successful synthesis of racemic supramolecular polymers featuring parallelly stacked conglomerate microstructures─a previously unreported topology in synthetic self-assembled systems. Additionally, we elucidate that the extent of secondary supramolecular polymers can be regulated by modulating the enantiomeric excess of the chiral monomers. Consequently, our study unveils new topologies that exhibit enhanced higher-order structural complexity in the realm of supramolecular polymers.

Two-dimensional materials are trending nowadays because of their atomic thickness, layer-dependent properties, and their fascinating application in the semiconducting industry. In this work, we have synthesized MoSe 2 and WSe 2 nanosheets (NSs) via a liquid-phase exfoliation method and investigated these NSs as channel materials in field-effect transistors (FET). The x-ray diffraction (XRD) pattern revealed that the synthesized NSs have a 2H phase with 0.65 nm d -spacing which belongs to the (002) Miller plane. Transmission electron microscopy (TEM) studies revealed that MoSe 2 and WSe 2 have a nanosheet-like structure, and the average lateral dimensions of these NSs are ~ 25 nm and ~ 63 nm, respectively. From Raman spectra, we found that the intensity of the A 1g vibrational mode decreases with the reduction in the number of layers. UV-visible spectroscopy revealed that the bandgap values of MoSe 2 and WSe 2 NSs are 1.55 eV and 1.50 eV, respectively, calculated using the Tauc equation. The output and transfer characteristics of the FET devices reveals that the fabricated FETs have good ohmic contact with the channel material and an ON/OFF current ratio of about 10 2 for both devices. This approach for the fabrication of FET devices can be achieved even without sophisticated fabrication facilities, and they can be applied as gas sensors and phototransistors, among other applications., Competing Interests: Conflict of interestThere are no conflicts to declare., (© The Minerals, Metals & Materials Society 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Mechanistic understanding and the control of molecular self-assembly at all hierarchical levels remain grand challenges in supramolecular chemistry. Functional realization of dynamic supramolecular materials especially requires programmed assembly at higher levels of molecular organization. Herein, we report an unprecedented molecular control on the fibrous network topology of supramolecular hydrogels and their resulting macroscopic properties by biasing assembly pathways of higher-order structures. The surface-catalyzed secondary nucleation process, a well-known mechanism in amyloid fibrilization and chiral crystallization of small molecules, is introduced as a non-covalent strategy to induce physical cross-links and bundling of supramolecular fibers, which influences the microstructure of gel networks and subsequent mechanical properties of hydrogels. In addition, seed-induced instantaneous gelation is realized in the kinetically controlled self-assembled system under this study, and more importantly, the extent of secondary nucleation events and network topology is manipulated by the concentration of seeds.

Competing Interests: Competing interests: None declared.

Fluorescence resonance energy transfer (FRET) in pairs of chromophores has mostly been achieved using covalently bound chromophores. In this study, we have demonstrated energy transfer in FRET pairs by taking advantage of the self-assembly of the chromophores on metal cholate hydrogel fibers.

Competing Interests: There are no conflicts of interest.

A detailed understanding of gelation mechanism can enable the properties of gels to be tuned for various applications, and may possibly help in understanding the aggregation of different biomolecules. We report a detailed study of the morphological and physio-chemical changes, dynamics (of a probe), and kinetics during the gelation of europium and calcium cholate hydrogels, leading to the development of a growth model. AFM images showed the transition of aggregated particles (100-150 nm) in the sol phase growing to a fibrous network in the gel through the entanglement of fibres, and not by dendritic growth (height analysis). The dynamic changes during this phase transformation were studied using a fluorescence probe (change in intensity and lifetime). We have been able to delineate the growth mechanism by using a combination of Eu(III) luminescence and a polarity sensitive fluorescence probe. The growth was found to follow the nucleation-elongation model, and these two phases responded in distinctly different fashions in rheological and luminescence measurements., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Silver(I) forms a hydrogel in the presence of cholate with unusual properties, which are not observed with other cations. Polarity-sensitive probes have shown that the spherical aggregates observed in the gel have 'pockets' with hydrophobicity comparable to that of degassed cyclohexane. The gel exhibited thermo- and mechanoresponsive properties. Color tunability from blue to cyan and green was observed with prodan. The two sol phases of the gel formed by applying stress and temperature showed very different properties., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Withania somnifera is an important medicinal herb that has been widely used for the treatment of different clinical conditions. The overall medicinal properties of Withania somnifera make it a viable therapeutic agent for addressing anxiety, cancer, microbial infection, immunomodulation, and neurodegenerative disorders. Biochemical constituents of Withania somnifera like withanolideA, withanolide D, withaferin A and withaniamides play an important role in its pharmacological properties. Proteins like Withania somnifera glycoprotein and withania lectin like-protein possess potent therapeutic properties like antimicrobial, anti-snake venom poison and antimicrobial. In this review, we have tried to present different pharmacological properties associated with different extract preparations, phytochemical constituents and protein component of Withania somnifera. Future insights in this direction have also been highlighted.

Background: It is generally believed that organisms use and accumulate methylamine osmolytes to prevent urea's damaging effect on protein stability and activity. However, urea-rich cells not only accumulate methylamines but also many other methylated and non-methylated compounds as well. But, so far it is not known whether osmolytes that are not accumulated in urea-rich cells could also confer urea-counteracting properties., Objective: We investigated the behavior of a non-methylamine osmolyte, alanine for its counteracting effect against urea denaturation of a model protein, ribonuclease A (RNase-A)., Methods: We have measured structure and thermodynamic parameters (Tm, ΔHm, and ΔGD°) of RNase-A in the presence of alanine, urea and their combination. The results were also compared with the ability of glycine (osmolyte lacking one methyl group when compared with alanine) to counter urea's effect on protein stability., Results: We observed that alanine but not glycine counteracts urea's harmful effect on RNase-A stability., Discussion: The results indicated that alanine (in addition to methylamine osmolytes) may serve as an alternate urea-counteractant. Since glycine fails to protect RNase-A from urea's destabilizing effect, it seems that methylation to glycine might have some evolutionary significance to protect proteins against harmful effects of urea.

We present a case of pancytopenia and cutaneous cryptococcosis in a young girl with no complaints of fever, headache and vomiting. Fine-needle aspiration cytology and further investigation for pancytopenia revealed presence of Cryptococcus in skin and bone marrow aspirates. Fungal cultures of the skin aspirates, blood and bone marrow confirmed cryptococcal infection. Counselling and human immunodeficiency virus (HIV) test revealed the status of the patient to be retropositive. Although meningitis is the commonest manifestation of cryptococcosis among HIV-infected patients, rare cutaneous manifestation with pancytopenia but with no meningeal signs indicate the HIV status in an endemic area of penicilliosis, Manipur.

A new thermostable caseinolytic serine protease was purified from the latex of Euphorbia heterophylla L. to electrophoretic homogeneity by a procedure involving successive steps of pretreatment of the latex, PEG fractionation, CM-cellulose chromatography and DEAE-cellulose chromatography. The purified protease was found to be a monomeric protein of molecular weight 77.2 kDa. It exhibited caseinolytic activity with hyperbolic azocasein saturation with Vmax and Km values of 0.11 units.mL(-1) and 0.55 mg.mL(-1) respectively. Specific inhibitory studies revealed the enzyme to be a serine protease. The protease was characterized by pH optimum of 8.0 and high thermostability with T1/2 of 75°C. Based on the results of peptide mass fingerprinting analysis, the protease was shown to be a new protein not characterized earlier.

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer's disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of β-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and β-amyloid peptide (Aβ) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Alpha-Synuclein (αSyn) is a 14 kDa pre-synaptic protein predominantly expressed in various regions of brain comprising neocortex, hippocampus, striatum, thalamus and cerebellum. αSyn aggregates have special neuropathologic relevance for comprehending Parkinson's disease (PD) and other synucleopathies due to the presence of αSyn aggregates in brain of patients suffering from these diseases. Direct relationship between PD and various single nuclear polymorphisms of αSyn further displays an inherent significance of mutated αSyn in increasing the risk for developing PD. So far, various theories have been emerged to explain αSyn mediated neuronal cell toxicity seen in patients with PD, including interaction of αSyn aggregates with biomolecules, vesicle dystrafficking, augmented oxidative stress, mitochondrial dysfunction, and disruption of synaptic function. Despite the advances in understanding of PD pathophysiology, current available treatments are still aiming at giving symptomatic relief. Lately, PD vaccines against αSyn aggregates are also being considered. However, various other avenues for e.g. post-translational and conformational modifications of αSyn, effect of cellular small molecules such as polyamines and osmolytes on αSyn aggregation, still remain unexplored and we believe that therapeutics directed at these ignored targets will surface as a successful combinational therapy for PD. Additionally, understanding mechanisms behind the interplay between PD and other health conditions, such as Gaucher's disease, Cardiovascular disorders, Hypertension, Homocystinuria, Type-II Diabetes, and Cancer are also speculated to provide great insight for novel therapeutic interventions. In the current review, we have precisely discussed all these ignored avenues with their possible clinical implications. Link between PD and other associated diseases has also been extensively reviewed.

Kidney cells of animals including human and marine invertebrates contain high amount of the protein denaturant, urea. Methylamine osmolytes are generally believed to offset the harmful effects of urea on proteins in vitro and in vivo. In this study we have investigated the possibility of glycine to counteract the effects of urea on three proteins by measuring thermodynamic stability, ΔGD° and functional activity parameters (K(m) and k(cat)). We discovered that glycine does not counteract the effects of urea in terms of both protein stability and functional activity. We also observed that the glycine alone is compatible with enzymes function and increases protein stability in terms of T(m) (midpoint of thermal denaturation) to a great extent. Our study indicates that a most probable reason for the absence of a stabilizing osmolyte, glycine in the urea-rich cells is due to the fact that this osmolyte is non-protective to macromolecules against the hostile effects of urea, and hence is not chosen by evolutionary selection pressure.