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Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full-length mutant huntingtin knock-in cells. Aralkylamine N-acetyltransferase (AANAT) is the rate-limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant-huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Biomedical application is based on the use of LIBS-derived data on chemical contents of tissues in diagnosis of diseases, forensic investigation, as well as a mechanism for providing online feedback for laser surgery. Although LIBS has certain advantages, the issue of correlation of LIBS-derived data on chemical element content in different human and animal tissues with other methods, and especially ICP-MS, remains pertinent. The objective of the present review was to discuss the application of laser-induced breakdown spectroscopy (LIBS) for elemental analysis of human biosamples or tissues from experimental models of human diseases., Methods: A systematic search in the PubMed-Medline, Scopus, and Google Scholar databases using the terms laser-induced breakdown spectroscopy, LIBS, metals, trace elements, minerals, and names of particular chemical elements was performed up through 25 February, 2023. Of all extracted studies only those dealing with human subjects, human tissues, in vivo animal and in vitro cell line models of human diseases were reviewed in detail., Results: The majority of studies revealed a wide number of metals and metalloids in solid tissues including teeth (As, Ag, Ca, Cd, Cr, Cu, Fe, Hg, Mg, Ni, P, Pb, Sn, Sr, Ti, and Zn), bones (Al, Ba, Ca, Cd, Cr, K, Mg, Na, Pb, Sr), and nails (Al, As, Ca, Fe, K, Mg, Na, P, Pb, Si, Sr, Ti, Zn). At the same time, LIBS was also used for estimation of trace element and mineral content in hair (Ca, Cu, Fe, K, Mg, Na, Zn), blood (Al, Ca, Co, Cd, Cu, Fe, Mg, Mn, Ni, Pb, Si, Sn, Zn), cancer tissues (Ca, Cu, Fe, Mg, K, Na, Zn) and other tissues. Single studies revealed satisfactory correspondence between quantitative LIBS and ICP-OES/MS data on the level of As (81-93 %), Pb (94-98 %), Cd (50-94 %) in teeth, Cu (97-105 %), Fe (117 %), Zn (88-117 %) in hair, Ca (97-99 %), Zn (90-95 %), and Pb (61-82 %) in kidney stones. LIBS also estimated specific patterns of trace element and mineral content associated with multiple pathologies, including caries, cancer, skin disorders, and other systemic diseases including diabetes mellitus type 2, osteoporosis, hypothyroidism, etc. Data obtained from in situ tissue LIBS analysis were profitably used for discrimination between tissue types., Conclusions: Taken together, the existing data demonstrate the applicability of LIBS for medical studies, although further increase in its sensitivity, calibration range, cross-validation, and quality control is required., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Mutant huntingtin (mHTT), the causative protein in Huntington's disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases., Competing Interests: Conflict of interest statement: R.M.F. is on the board of NeuBase Therapeutics. No funding for this work was received from NeuBase Therapeutics.

Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon "neuritosis." Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability., Competing Interests: The authors declare no conflict of interest.

G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT 1 ), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT 1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT 1 overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology., Competing Interests: The authors declare no conflict of interest.

Background: Functional and structural properties of mitochondria are highly tissue and cell dependent, but isolation of highly purified human neuronal mitochondria is not currently available., New Method: We developed and validated a procedure to isolate purified neuronal mitochondria from brain tissue. The method combines Percoll gradient centrifugation to obtain synaptosomal fraction with nitrogen cavitation mediated synaptosome disruption and extraction of mitochondria using anti mitochondrial outer membrane protein antibodies conjugated to magnetic beads. The final products of isolation are non-synaptosomal mitochondria, which are a mixture of mitochondria isolated from different brain cells (i.e. neurons, astrocytes, oligodendrocytes, microglia) and synaptic mitochondria, which are of neuronal origin. This method is well suited for preparing functional mitochondria from human cortex tissue that is surgically extracted., Results: The procedure produces mitochondria with minimal cytoplasmic contaminations that are functionally active based on measurements of mitochondrial respiration as well as mitochondrial protein import. The procedure requires approximately four hours for the isolation of human neuronal mitochondria and can also be used to isolate mitochondria from mouse/rat/monkey brains., Comparison With Existing Methods and Conclusions: This method will allow researchers to study highly enriched neuronal mitochondria without the confounding effect of cellular and organelle contaminants., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Mitochondrial dysfunction is associated with neuronal loss in Huntington's disease (HD), a neurodegenerative disease caused by an abnormal polyglutamine expansion in huntingtin (Htt). However, the mechanisms linking mutant Htt and mitochondrial dysfunction in HD remain unknown. We identify an interaction between mutant Htt and the TIM23 mitochondrial protein import complex. Remarkably, recombinant mutant Htt directly inhibited mitochondrial protein import in vitro. Furthermore, mitochondria from brain synaptosomes of presymptomatic HD model mice and from mutant Htt-expressing primary neurons exhibited a protein import defect, suggesting that deficient protein import is an early event in HD. The mutant Htt-induced mitochondrial import defect and subsequent neuronal death were attenuated by overexpression of TIM23 complex subunits, demonstrating that deficient mitochondrial protein import causes mutant Htt-induced neuronal death. Collectively, these findings provide evidence for a direct link between mutant Htt, mitochondrial dysfunction and neuronal pathology, with implications for mitochondrial protein import-based therapies in HD.

Therapy of rats with CCl4 hepatitis with Stellaria media L. water-soluble polysaccharide fraction in a dose of 100 mg/kg reduces serum activities of transaminases (ALT and AST), alkaline phosphatase, bilirubin, and the thymol test values. In the liver, the density of inflammatory infiltration of the organ parenchyma, total count of necrotic hepatocytes, fatty and protein degeneration are reducing. Hence, water-soluble polysaccharide fraction, isolated from the terrestrial part of Stellaria media L., is characterized by hepatoprotective activity.

Comparative experimental evaluation of the efficiency of prostatotropic drugs Prostamol Uno and Samprost on the model of the chronic aseptic prostate inflammation in rats was performed. It was established that peptide drug Samprost decelerates sclerotic processes in the prostate gland to a greater extent than herbal preparation Prostamol Uno. Both products equally stimulate secretory activity of the gland. Prostamol Uno, unlike Samprost, prevents the development of reduced sexual motivation, one of the complications of chronic prostatitis.

The human oral microbiome is the most studied human microflora, but 53% of the species have not yet been validly named and 35% remain uncultivated. The uncultivated taxa are known primarily from 16S rRNA sequence information. Sequence information tied solely to obscure isolate or clone numbers, and usually lacking accurate phylogenetic placement, is a major impediment to working with human oral microbiome data. The goal of creating the Human Oral Microbiome Database (HOMD) is to provide the scientific community with a body site-specific comprehensive database for the more than 600 prokaryote species that are present in the human oral cavity based on a curated 16S rRNA gene-based provisional naming scheme. Currently, two primary types of information are provided in HOMD--taxonomic and genomic. Named oral species and taxa identified from 16S rRNA gene sequence analysis of oral isolates and cloning studies were placed into defined 16S rRNA phylotypes and each given unique Human Oral Taxon (HOT) number. The HOT interlinks phenotypic, phylogenetic, genomic, clinical and bibliographic information for each taxon. A BLAST search tool is provided to match user 16S rRNA gene sequences to a curated, full length, 16S rRNA gene reference data set. For genomic analysis, HOMD provides comprehensive set of analysis tools and maintains frequently updated annotations for all the human oral microbial genomes that have been sequenced and publicly released. Oral bacterial genome sequences, determined as part of the Human Microbiome Project, are being added to the HOMD as they become available. We provide HOMD as a conceptual model for the presentation of microbiome data for other human body sites. Database URL: http://www.homd.org.

The authors report a rare a case of gliosarcoma metastases in a 28-year-old male patient. The cauda equina roots were involved after brain tumor 16 months ago, which, on microscopic study, had a biphasic pattern and heterogeneous staining in the reaction with antibody to GFAP and vimentin; the tumor cells did not express EMA, EA, and desmin. Gliosarcoma was diagnosed, by taking into account morphological and immunohistochemical data. Tumor tissue of the cauda equine roots had the same immunophenotype as the brain tumor with a predominance of glial component, which permitted the source of metastases to be ascertained.

The paper describes the results of comparatively analyzing the parameters of apoptosis, micro- and macroelement spectrum of peripheral blood lymphocytes in healthy donors and in patients with chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis. In drug-responsive and drug-resistant pulmonary tuberculosis, unidirectional pretreatment changes were generally recorded in the activity of apoptosis and the spectrum of chemical elements of peripheral blood lymphocytes, which were most pronounced after completion of a phase of intensive antituberculosis chemotherapy. After termination of a complete course of the therapy, apoptotic activity lowered with the cationic composition of cells being normalized. The parameters differentiating pulmonary tuberculosis from COPD were ascertained, these included increases in the count of apoptotic cells and the cell concentrations of Ca2+, Zn2+, and Mg2+.

The genetic model of diabetes mellitus was studied on mutant C57Bl/KsLepr(db/+) mice. These mice were characterized by high concentrations of glucose and glycosylated hemoglobin in the blood, polyuria, polyphagia, polydipsia, progressive obesity, biphasic morphological changes in insular islets of the pancreas (hyperplasia and atrophy), fatty degeneration of the liver, and hypoplasia of the spleen tissue and lymph nodes. Our results indicate that C57Bl/KsLepr(db/+) mice serve as an adequate model of type 2 diabetes mellitus. This model is suitable for testing of therapeutic methods for type 2 diabetes mellitus.

Recent advances in cancer cell biology have focused on histone deacetylase inhibitors (HDACi's) because they target pathways critical to the development and progression of disease. In particular, HDACi's can induce expression of epigenetically silenced genes that promote growth arrest, differentiation and cell death. In glioma cells, one such repressed gene is the tetraspanin CD81, which regulates cytostasis in various cell lines and in astrocytes, the major cellular component of gliomas. Our studies show that HDACi's, trichostatin and sodium butyrate, promote growth arrest and differentiation with negligible cell death in glioma cells and induce expression of CD81 and cyclin-dependent kinase inhibitor 1A (p21(CIP/WAF-1)), another regulator of cytostasis in astrocytes. Interference RNA knock-down of CD81 abrogates cytostasis promoted by HDAC inhibition indicating that HDACi-induced CD81 is responsible for growth arrest. Induction of CD81 expression through HDAC inhibition is a novel strategy to promote growth arrest in glioma cells.

The article this research is devoted to the Orenburg student youth diet. The revealed deficiency of major nutrients (protein, fats and especially carbohydrates), as vitamins (C, PP, E, D, B groups) and analysis of diet ration concerning basis nourishing components, vitamins, macro- micro elements (Zn, Cu, I, Cr, Se).

Morphological and morphometric assays showed that administration of antibodies to the prostate-specific antigen in ultralow doses for 1.5 months delayed the development of atrophic and sclerotic processes in rats with chronic aseptic prostatitis. The concentration of zinc ions playing an important role in binding of androgens increased in the prostate of rats receiving the preparation. Studies of copulatory behavior showed that male rats with chronic prostatitis receiving antibodies to the prostate-specific antigen displayed increased sexual activity compared to control and intact animals.

The authors carried out comparative assessment of sensitivity and specificity of ultrasonic examination with color dopper mapping (USE with CDM), thin-needle aspiration biopsy--TAB (palpation- and US-assisted), express histologic examination--(EHE), intraoperative laser autofluorescent spectroscopy (IOLAS) with retrospective assessment by results of elective histologic examination in adenomas of thyroid gland (TG). Medical histories of 135 patients hospitalized with adenomas of TG of follicular cells were analyzed. Based on comparison of USE with CDM and morphologic analysis of TG adenomas three types of specific echographic symptomcomplexes were recognized. USE with CDM in combination with US-assisted TAB was the most effective diagnostic complex before operation. Comparative analysis of results of these methods with express histologic examination showed equal efficacy, that permitted to reject routene EHE. For the first time IOLAS was used as "optic instant-biopsy" for selection of optimum scope of surgery when "follicular neoplasia" was suspected. Combined use of USE with CDM and TAB before operation as well as IOLAS enabled correct diagnosis of the nature of TG lesion, it morphologic type, and based on these data adegnatechoice.

The influence of nucleotides on 2,4-dinitrophenol (DNP)-induced K+ efflux from intact rat liver mitochondria has been studied. ATP and ADP at micromolar concentrations were found to inhibit mitochondrial potassium transport, whereas GTP, GDP, CTP, and UTP did not show tha same effect. The values of half-maximal inhibition (IC50) were approximately 20 microM for ATP and approximately 60 microM for ADP. It is suggested that adenine nucleotides exert their inhibitory action at the matrix side of the inner mitochondrial membrane since the inhibitor of adenine nucleotide translocase atractyloside at concentration of 1 microM completely removed the inhibitory effect of ATP and ADP. The mitochondrial ATPase inhibitor oligomycin (2 microg/ml) was found to reduce slightly the rate of DNP-induced K+ efflux and had no effect on inhibition by adenine nucleotides; the latter was insensitive to Mg2+ and the changes in pH. It seems likely that the regulation of potassium transport is not due to phosphorylation of the channel-forming protein but to binding of the nucleotides in specific regulatory sites. The possibility of potassium efflux from mitochondria in the presence of uncoupler via the ATP-dependent potassium channel is discussed.

As shown by a semiquantitative analysis of histological changes in the thyroid tissue, there is a correlation between some characteristic features of autoimmune thyroiditis (Hashimoto's thyroiditis). Formation of lymphoid nodules in the thyroid in autoimmune thyroiditis was followed up and its three stages were distinguished. Autoimmune thyroiditis has three degrees of activity by diffuse lymphoid-plasmocytic infiltration, thyroid tissue destruction and lymphoid nodules formation. Differences between autoimmune thyroiditis and focal thyroiditis are revealed. The above differences include spread and cellular composition, content of the lymphoid-plasmocytic infiltrate, the degree of the destructive changes, B-cell hyperplasia, expression of CD-4 on T-helpers and CD-19 on B-lymphocytes, cytological picture. These differences allow differential diagnosis between these diseases.

Malignant retroperitoneal neurilemmoma has developed in a female of 50 and reached a huge size (40 x 30 x 15 cm, weight 5 kg). Histologically, there were signs of atypia and penetration into the stomach wall. The attempts to separate a tumor resulted in a massive bleeding.