Proteins In Various Tissues Research Articles

Pulmonary tuberculosis and renal amyloidosis: A rare entity in children.

Amyloidosis is a group of disorders with extracellular accumulation of autologous fibrillary insoluble proteins in various tissues and organs such as the kidneys, liver, spleen, heart, and gastrointestinal tract leading to impaired function. Renal amyloidosis is usually considered to be a progressive disease manifesting as nephrotic syndrome and renal insufficiency with tuberculosis being one of the most common causes in adults. However, the occurrence of similar associations is rarely described in children. We report a case of an 11-year old girl who presented with nephrotic syndrome and pulmonary tuberculosis and attained disease remission with successful treatment of tuberculosis.

Costal Amyloidosis: First Case in Literature

Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of amyloid proteins in various tissues and organs, which leads to significant morbidity and mortality. The most commonly affected organs include the kidneys, liver, spleen, heart, and nervous system, where the deposition of amyloid proteins disrupts normal function and causes a wide range of clinical manifestations. Involvement of osseous structures, particularly the ribs, is exceedingly rare and has not been extensively documented in the medical literature, making it a subject of significant clinical interest. This study aims to present a rare and fortuitously discovered case of costal amyloidosis in a patient who initially presented with a chest wall mass. The patient’s presentation, diagnostic workup, and subsequent management are detailed to provide a comprehensive overview of this unusual manifestation of amyloidosis. Clinical evaluation revealed a firm, non-tender mass on the chest wall, prompting further investigation. Biological analyses included a series of laboratory tests to rule out common differential diagnoses and identify potential systemic involvement. Radiological evaluation comprised of advanced imaging techniques, including chest X-ray, computed tomography (CT), and magnetic resonance imaging (MRI), which highlighted the nature and extent of the osseous involvement. A biopsy of the mass was performed, and histopathological examination confirmed the diagnosis of amyloidosis through the identification of amyloid deposits using specific staining techniques. The case also examines the evolutionary aspects of the disease, discussing the progression and changes observed over time through regular follow-ups. Therapeutic strategies were implemented based on the latest guidelines and tailored to the patient's specific condition, including both pharmacological and surgical interventions. The short-term and long-term outcomes of these interventions are analyzed, highlighting the challenges and successes encountered during the treatment process. By presenting this case, we aim to shed light on the rare occurrence of costal amyloidosis, its diagnostic challenges, and therapeutic considerations. This case underscores the importance of considering amyloidosis in the differential diagnosis of chest wall masses and contributes to the broader understanding of the disease's clinical spectrum. Additionally, it emphasizes the necessity of a multidisciplinary approach in managing such rare and complex cases, ensuring comprehensive care and improved patient outcomes.

The R436Q missense mutation in WWP1 disrupts autoinhibition of its E3 ubiquitin ligase activity, leading to self-degradation and loss of function.

Muscular dystrophy in the NH-413 chicken is caused by a missense mutation in the WWP1 gene. WWP1 is a HECT-type E3 ubiquitin ligase containing four tandem WW domains that interact with proline-rich peptide motifs of target proteins, and a short region connecting the second and third WW domains is crucial for the E3 ligase to maintain an autoinhibitory state. A mutation of the arginine in the WW2-WW3 linker to glutamine is thought to affect WWP1 function, but there is little information on this mutation to date. In this study, we generated a transgenic (Tg) mouse model expressing the WWP1 transgene with the R436Q mutation, which corresponds to the missense mutation found in the NH-413 chicken. Tg mice showed marked degradation of mutant WWP1 proteins in various tissues, particularly in striated muscle. Immunoprecipitation analysis using a WWP1-specific antibody demonstrated that the mutant WWP1 proteins lacked the C-terminal catalytic cysteine residue that is required for their binding to the E2-substrate complex during their degradation. In vitro analysis using the R436Q mutant of WWP1 lacking this catalytic cysteine residue showed no autodegradation, indicating that the loss-of-function degradation of this protein is caused by self-ubiquitination. Tg mice expressing R436Q WWP1 did not show stunted growth or premature death. Furthermore, histological analysis did not reveal any obvious changes. These observations suggested that the R436Q mutant WWP1 protein, which is released from autoinhibitory mode by its missense mutation, does not have abnormally activated enzyme function to substrates before its self-degradation and loss of enzyme function.

A case of bilateral amyloidosis localized to extraocular muscles mimicking thyroid eye disease

BackgroundAmyloidosis is a rare condition characterized by the abnormal deposition of amyloid proteins in various tissues and organs. While systemic amyloidosis has been well-documented, amyloid deposition in extraocular muscles is an exceptionally rare occurrence, with only 35 reported cases. This case report sheds light on the importance of considering amyloidosis in the differential diagnosis of patients presenting with proptosis and diplopia, which are often associated with thyroid eye disease.Case presentationA woman in her twenties sought medical attention due to a complaint of diplopia. Her ocular examination revealed almost normal findings except for exotropia and proptosis. Orbital magnetic resonance imaging displayed fusiform enlargement of nearly all eye muscles, a presentation typically observed in thyroid eye disease. However, despite corticosteroid therapy, her symptoms showed no improvement. Given the unusual lack of response to conventional treatment, and inhomogeneous enhancement of the muscle, an extraocular muscle biopsy was conducted. This biopsy yielded a unique finding—amyloid deposition within the muscle tissue. This discovery was particularly intriguing due to the extreme rarity of amyloidosis affecting extraocular muscles, with fewer than three dozen documented cases worldwide.ConclusionThis unique case underscores the critical need for a comprehensive approach to diagnosing patients with proptosis and diplopia. While these symptoms are commonly attributed to thyroid eye disease, it is essential to consider alternative diagnoses such as amyloidosis, especially when standard treatments fail to yield results. The discovery of amyloid deposition in the extraocular muscles, although exceedingly rare, emphasizes the significance of a thorough differential diagnosis. In conclusion, this case report highlights the importance of vigilance in clinical practice, encouraging ophthalmologists to explore less common diagnostic possibilities when faced with challenging cases. Further research and clinical investigation are warranted to better understand the mechanisms and potential treatments for amyloidosis affecting the extraocular muscles.

Human collagen decorating microneedle patches for transdermal therapy

AbstractCollagen, the major structural protein in various tissues, is an ideal material for tissue regeneration. However, the collagen molecules cannot penetrate across the skin barrier due to their large molecular weight. It is necessary to develop new methods of delivery for promoting the collagen‐based therapy. Microneedle patches have been used in drug delivery applications as an alternative to traditional puncture delivery. In this study, the human collagen decorating microneedle patch was developed to deliver the collagen into the skin tissue, as the human‐source collagen can overcome the immunogenicity of animal‐source collagens in regenerative applications. The human collagen is usually limited by its source. Here, the collagen is derived from an allogeneic extracellular matrix expressed by human stem cells in vitro. The collagen was then loaded on the tip of the microneedle to achieve a high‐loading dose and efficient delivery. The experimental results proved that the microneedles were sharp and rigid enough to pierce the skin, which has the potential to be used for subcutaneous tissue regeneration. Moreover, the fabrication process was simple and effective to realize large‐scale production.

A biopsy-based pilot clinical study: monitoring the effectiveness of tafamidis treatment of patients with transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and progressive disease associated with high mortality. It is caused by the accumulation of TTR amyloid protein in various tissues, including the myocardium. Tafamidis is currently the only approved therapy for ATTR-CM. The results of the phase III ATTR-ACT trial showed lower rates of mortality and hospitalization, besides lower rate of decline for both quality of life (QoL), and 6-minute walk test (6mwt) distance [1]. Whether the reported clinical outcomes represent a change in myocardial ATTR-accumulation and remodeling remains unclear. Here we monitor the clinical outcome and the corresponding myocardial histological changes of tafamidis-treated patients using endomyocardial biopsy (EMB). Methods Eleven patients with EMB-proven ATTR-CM, 10 wild type, 1 hereditary, 9 males, 2 females age= 77±9 years, were prescribed with 61 mg tafamidis once daily indefinitely. The course of the disease was evaluated via EMB, 99mTc-DPD scintigraphy, cardiac magnetic resonance imaging (cMRI), echocardiography, 6mwt, Minnesota QoL questionnaire and serum N-terminal pro brain natriuretic peptide (NT-proBNP) analysis, at baseline and after 321±72 days of treatment (ethics application number EA2/140/16). EMBs were examined via immunohistochemistry and Imaging mass spectrometry. All patients received standard heart failure medications. Paired clinical measurements were compared via paired t test for parametric data or Wilcoxon rank test for non-parametric data. Results Following the course of treatment, EMB ATTR-positive area measured via immunohistochemistry increased by 7.7±9.5% (p<0.05). Myocardial CD3+ and CD68+ cell counts remained within normal limits. The EMB peak intensities of ATTR, collagen and macrophage migration inhibitory factor, measured via imaging mass spectrometry were increased by 23% (AUC= 0.677, p<0.001), 25% (AUC= 0.620, p<0.001) and 18% (AUC= 0.609, p<0.001), respectively. Echocardiography measured left ventricular (LV) ejection fraction and LV end-diastolic diameter, as well as 6mwt distance, QoL and serum NT-proBNP showed no significant changes. cMRI did not show any significant changes in fibrosis/amyloidosis markers (N=9). 99mTc-DPD scintigraphy-derived Perugini score (N=10) improved by one-point in two patients and remained stable in the rest. The New York Heart Association (NYHA) functional class improved in one patient and remained stable in 10/11 patients. Conclusion Our findings demonstrate, for the first time, the persistence of myocardial ATTR-accumulation and remodeling despite a clinically stable disease course. Whether this finding is relevant in terms of disease-progression or indicate a need for more intensive treatment warrants further investigation.

Diagnostic Challenges and Solutions in Systemic Amyloidosis

Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence.

Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young samples. These insoluble proteins exhibit the typical characteristics of disease-associated aggregates, including insolubility in detergents, protease resistance, and staining with amyloid-binding dye as well as accumulation in aggresomes. We identified the main proteins accumulating in the aging brain using proteomic studies. These results show that the aged brain contain large amounts of misfolded and likely non-functional species of many proteins, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. Our findings reveal a putative role for protein misfolding and aggregation in aging.

Protein sample preparation for tissue distribution study.

The distribution and expression level of a protein among animal tissues is indicative of its possible roles. It is important to establish a generally applicable method to prepare protein samples with high-quality and achieve near 100% recovery of proteins from animal tissues. During preparation, to sufficiently dissolve and maintain stability of almost all proteins from tissues, as well as to avoid most contaminations affecting protein detection, 2×SDS Sample Buffer, sonication and trichloroacetic acid precipitation are applied. Here we provide a relatively simple, reproducible, and broadly applicable method for studying protein distribution in most tissues, in which the issues resulting from protein degradation and modification during sample preparation and assay interference by other cellular components like neutral lipids and glycogen could be overcome. Furthermore, this method represents the protein content by equal wet tissue mass, which is a better means to present the expression level of a protein in various tissues. High-quality protein samples from almost all tissues could be prepared. The samples produced are amenable to tissue distribution analysis by Western blotting and for silver/Coomassie staining, proteomics, and other protein analyses, which would contribute to potential biomarkers or treatments for a disease.

Impact of Starvation, Refeeding of Freshwater Fish Channa punctatus Via Comparatively Protein Level Investigation on Target Tissues

Using Lowry's approach, the current study investigated how starvation and refeeding affected the amount of protein in various tissues of the freshwater fish Channa panctatus (1951). The fish were categorised into two groups, the first group had normal feedings, while the second was denied food for periods of 7, 14, 21, and 28 days respectively. Notably, the previously starved fish were fed again. Fish show a significant rise in protein levels relative to normal following feeding because prolonged starvation causes a steady drop in tissue protein levels.

Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice.

Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in weeks 5-8 of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHY This study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.

Proteomics

Proteomics is a branch of molecular biology that deals with the identification and quantification of proteins in living objects, as well as the analysis of protein functions and their interactions.
 Proteomics is studied by proteins that are expressed in a given cell, tissue or organism over a period of time (under certain conditions).
 It is known that information about the primary structure of a protein (the sequence of amino acid residues in a protein) is contained in a structural gene in the form of a codon sequence (genetic code). On the other hand, less than 10% of genes are functionally active (expressed) in the somatic cells of our body. Moreover, a distinct tissue-specific expression of genes is observed. This, in turn, leads to the peculiarities of the qualitative composition of the synthesized proteins in various tissues. No less important is the fact that the total amount of proteins synthesized by our tissues is much greater than the total number of structural genes containing information about their original structure. This phenomenon is explained by the activity of such mechanisms as alternative splicing and a wide variety of post-translational peptide processing pathways (covalent modification of a polypeptide synthesized on the ribosome) in health and disease. Thus, even a brief review of the semantic content of the term "proteomics" indicates an extremely complex system of protein molecules in our body, which plays a fundamental role in maintaining homeostasis and is involved in the formation of adaptive responses in response to adverse changes in the internal and external environment.

AVOIDING ANCHORING BIAS: DIAGNOSIS OF AL-AMYLOIDOSIS IN WORSENING HEART FAILURE AFTER CORONARY ARTERY BYPASS GRAFTING

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Amyloidosis is a systemic disease caused by deposition of misfolded protein in various tissues and organs. Early recognition of amyloidosis is necessary as cardiac dysfunction is the major determinant of survival(1). The diagnosis is often delayed given the non-specific symptoms at onset. Prognosis in amyloidosis is primarily dependent on the degree of cardiac involvement and, in AL amyloidosis, on circulating light-chain levels(2). CASE PRESENTATION: The patient is a 68-year-old male referred to our institution for assessment of worsening heart failure (HF). Four months prior, he began to experience exertional dyspnea along with jaw pain. Subsequent evaluation included lab work, chest X-ray and electrocardiogram demonstrating troponin elevation, pulmonary edema and complete heart block respectively. An echocardiogram(ECHO) demonstrated a severely reduced ejection fraction(EF). Temporary pacemaker was placed and a subsequent angiogram showed severe multi-vessel coronary artery disease(CAD). He underwent coronary artery bypass graft surgery. Post-operatively EF improved to 45%. Implantable loop recorder was placed due to concerns for post-operative atrial fibrillation. Three months later, he experienced a syncopal event attributed to ventricular tachycardia, and CRT-D was placed. ECHO revealed reduction of his EF (30%) with moderate concentric left ventricular hypertrophy(LVH). A repeat angiogram demonstrated patency of his bypass grafts. After referral to our institution, a repeat ECHO demonstrated findings concerning amyloidosis. Protein electrophoresis revealed monoclonal IgG gammopathy, and fat pad aspirate confirmed the diagnosis of AL amyloidosis. DISCUSSION: Although CAD is the most common cause of HF with reduced EF, other etiologies must be considered when symptoms cannot be explained solely by ischemia. Cardiac amyloidosis was suspected based on a constellation of clinical symptoms as well as suggestive ECHO findings(Biventricular concentric hypertrophy, restrictive filling pattern, Bull's eye appearance on LV strain). The diagnosis should be suspected in patients with HF who have unexplained LVH with no prior history of hypertension(3). Patients also present with syncopal events caused by conduction blocks, bradyarrhythmia, or in the case of our patient, ventricular tachyarrhythmias. Early diagnosis is important given the emerging therapies that can halt cardiac damage, potentially reducing the risk of mortality and allowing amyloid clearance and improved cardiac function. CONCLUSIONS: Anchoring bias is the tendency to stick with initial impressions even as new information becomes available. Clinicians must avoid this and consider alternative diagnoses when patients do not experience the anticipated outcome to a particular treatment. REFERENCE #1: 1. Fontana M. Banypersad SM. Treibel TA, et al. Differential myocyte responses in patients with cardiac transthyretin amyloidosis and light-chain amyloidosis: a cardiac MR imaging study. Radiology. 2015;277:388–97 REFERENCE #2: 2. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30:989-95 REFERENCE #3: 3. Gertz MA. Comenzo R. Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79:319–28 DISCLOSURES: no disclosure on file for Brian Hardaway; No relevant relationships by Michael Liu, source=Web Response No relevant relationships by Amith Reddy Seri, source=Web Response

Functional Assessment of Intestinal Tight Junction Barrier and Ion Permeability in Native Tissue by Ussing Chamber Technique.

The Ussing chamber technique was first invented by the Danish scientist Hans Ussing in 1951 to study the transcellular transport of sodium across frog skin. Since then, this technique has been applied to many different tissues to study the physiological parameters of transport across membranes. The Ussing chamber method is preferable to other methods because native tissue can be used, making it more applicable to what is happening in vivo. However, because native tissue is used, throughput is low, time is limited, and tissue preparation requires skill and training. These chambers have been used to study specific transporter proteins in various tissues, understand disease pathophysiology such as in Cystic Fibrosis, study drug transport and uptake, and especially contributed to the understanding of nutrient transport in the intestine. Given the whole epithelial transport process of a tissue, not only transepithelial pathways, but also paracellular pathways are important. Tight junctions are a key determinant of tissue specific paracellular permeability across the intestine. In this article, the Ussing chamber technique will be used to assess paracellular permselectivity of ions by measuring transepithelial conductance and dilution potentials.

Functional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatment

BackgroundSARS-CoV-2 causes COVID-19 with a widely diverse disease profile that affects many different tissues. The mechanisms underlying its pathogenicity in host organisms remain unclear. Animal models for studying the pathogenicity of SARS-CoV-2 proteins are lacking.MethodsUsing bioinformatic analysis, we found that 90% of the virus-host interactions involve human proteins conserved in Drosophila. Therefore, we generated a series of transgenic fly lines for individual SARS-CoV-2 genes, and used the Gal4-UAS system to express these viral genes in Drosophila to study their pathogenicity.ResultsWe found that the ubiquitous expression of Orf6, Nsp6 or Orf7a in Drosophila led to reduced viability and tissue defects, including reduced trachea branching as well as muscle deficits resulting in a “held-up” wing phenotype and poor climbing ability. Furthermore, muscles in these flies showed dramatically reduced mitochondria. Since Orf6 was found to interact with nucleopore proteins XPO1, we tested Selinexor, a drug that inhibits XPO1, and found that it could attenuate the Orf6-induced lethality and tissue-specific phenotypes observed in flies.ConclusionsOur study established Drosophila as a model for studying the function of SARS-CoV2 genes, identified Orf6 as a highly pathogenic protein in various tissues, and demonstrated the potential of Selinexor for inhibiting Orf6 toxicity using an in vivo animal model system.

Protein-synthesizing function of the liver of cows at experimental fasciolosis

Cattle fasciolosis is quite widespread in the world, including in Ukraine. Animal blood proteins, being in close functional connection with proteins of various tissues, reflect the changes that occur in the tissues and organs of the body during disorders of their metabolic processes caused by pathological factors. The aim of the study was to investigate the level of total protein and its fractions in the blood of cows in experimental fasciolosis. 12 cows of 4–5 years of age, black-spotted breed, were selected for experiment, out of which 2 groups were formed, six animals in each. Animals in the control group were clinically healthy. Animals of the experimental group were experimentally infected with adolescents. During the research, the rules of compulsory experiments were followed - selection and keeping of analogue animals in groups. The cows' diet was balanced in terms of nutrients and minerals. In the study of protein-sensitizing function of the liver of cows, it was found that during fasciolosis invasion, the content of total protein decreased by 13.8 %. These changes were due to a decrease in albumin and an increase in globulins. Thus, in fasciological invasion of cows, the level of albumin in the serum decreased by 24.4 %, and the level of globulins increased by 7.9 %. The value of the albumin / globulin ratio in the blood of infested cows with the causative agent of fasciolosis is quite indicative. It was found that the albumin-globulin ratio in the blood of cows of the experimental group was probably lower compared to the control group of animals. This value of the coefficient, of course, indicates the suppression of protein-synthesizing function of the liver in these periods of research. In the future it is planned to investigate the functional state of the liver of cows with experimental fasciolosis.

Perspective natural sources of chondroprotectors

The research objects in the work were natural sources of chondroprotectors. The research purpose was to study perspective natural sources of substances with chondroprotective properties. Such natural chondroprotectors as nutraceutical products made from green tea are studied in the work. Turmeric and ginger have been used since ancient times to treat osteoarthrosis. It has been established that collagen is a part of combined chondroprotectors. The mass fraction of structural protein in various tissues and organs of a living organism varies to a large extent. In pig skin the mass fraction of structural protein reaches 64%, in human skin the content of collagen is 8% higher, in cattle skin 80%, in marine mammals more than 80%; a significant amount of collagen is found in the skin of fish. In the connective tissue of whale fat, up to 88% of collagen is contained, in whale fins up to 83%. The percentage of collagen-containing raw fish is as follows: skin up to 12.6% (of the total weight of the fish); fins up to 8%, air bladder up to 11.4%, scales to 6%, bones up to 19%, sturgeon chord up to 10.2%. Glucosamine, extracted from mollusk shells, chondroitin from shark and bovine cartilage, and collagen hydrolysates are widely used since they are the main components of cartilage matrix. The novelty of this work lies in the systematization of scientific data on perspective natural sources of substances with chondroprotective and combined properties.

Investigating the pernicious effects of heparan sulfate in serum amyloid A1 protein aggregation: a structural bioinformatics approach

Amyloid-A mediated (AA) amyloidosis is the pathogenic byproduct of body’s prolonged exposure to inflammatory conditions. It is described by the aggregation of mutated/misfolded serum amyloid A1 (SAA1) protein in various tissues and organs. Genetic polymorphism G90D is suspected to cause AA amyloidosis, although the causal mechanism remains cryptic. Recent experimental findings insinuate that heparan sulphate (HS), a glycosaminoglycans, exhibits binding with SAA1 to promote its aggregation. To foster the enhanced binding of HS, we computationally determined the pernicious modifications in G90D mutant SAA1 protein. Also, we examined the influence of HS on the dynamic conformation of mutant SAA1 that could potentially succor amyloidosis. Accordingly, the protein-ligand binding studies indicate that upon SNP G90D, SAA1 protein exhibited an augmented association with HS. Further, the simulation of HS bound mutant SAA1 complex delineates an increase in RMSD, Rg, and RMSF. Also, both RMSD and Rg evinced a fluctuating trajectory. Further, the complex showed increase of beta turn in its secondary structural composition. Additionally, the free energy landscape of mutant SAA1-HS complex posits the occurrence of multiple global minima conformers as opposed to the presence of a single global energy minima conformation in native SAA1 protein. In conclusion, the aforementioned conformational ramifications induced by HS on SAA1 could potentially be the proteopathic incendiary behind AA amyloidosis; this incendiary will need to be considered in future studies for developing effective therapeutics against AA amyloidosis. Communicated by Ramaswamy H. Sarma

Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase.

Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1G184R/+) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1G184R/+ mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.

βPix heterozygous mice have defects in neuronal morphology and social interaction

βPix activates Rho family small GTPases, Rac1 and Cdc42 as a guanine nucleotide exchange factor. Although overexpression of βPix in cultured neurons indicates that βPix is involved in spine morphogenesis and synapse formation in vitro, the in vivo role of βPix in the neuron is not well understood. Recently, we generated βPix knockout mice that showed lethality at embryonic day 9.5. Here, we investigate the neuronal role of βPix using βPix heterozygous mice that are viable and fertile. βPix heterozygous mice show decreased expression levels of βPix proteins in various tissues including the brain. Cultured hippocampal neurons from βPix heterozygous mice show a decrease in neurite length and complexity as well as synaptic density. Both excitatory and inhibitory synapse densities are decreased in these neurons. Golgi-staining of hippocampal tissues from the brain of these mice show reduced dendritic complexity and spine density in the hippocampal neurons. Expression levels of NMDA- and AMPA-receptor subunits and Git1 protein in hippocampal tissues are also decreased in these mice. Behaviorally, βPix heterozygous mice exhibit impaired social interaction. Altogether, these results indicate that βPix is required for neurite morphogenesis and synapse formation, and the reduced expression of βPix proteins results in a defect in social behavior.