In the original publication [...].

Schizophrenia (SZ) is a chronic psychiatric disorder affecting several people worldwide. Mitochondrial DNA (mtDNA) variations could invoke changes in the OXPHOS system, calcium buffering, and ROS production, which have significant implications for glial cell survival during SZ. Oxidative stress has been implicated in glial cells-mediated pathogenesis of SZ; the brain comparatively more prone to oxidative damage through NMDAR. A confluence of scientific evidence points to mtDNA alterations, Nrf2 signaling, dynamic alterations in dorsolateral prefrontal cortex (DLPFC), and provocation of oxidative stress that enhance pathophysiology of SZ. Furthermore, the alterations in excitatory signaling related to NMDAR signaling were particularly reported for SZ pathophysiology. Current review reported the recent evidence for the role of mtDNA variations and oxidative stress in relation to pathophysiology of SZ, NMDAR hypofunction, and glutathione deficiency. NMDAR system is influenced by redox dysregulation in oxidative stress, inflammation, and antioxidant mediators. Several studies have demonstrated the relationship of these variables on severity of pathophysiology in SZ. An extensive literature search was conducted using Medline, PubMed, PsycINFO, CINAHL PLUS, BIOSIS Preview, Google scholar, and Cochrane databases. We summarize consistent evidence pointing out a plausible model that may elucidate the crosstalk between mtDNA alterations in glial cells and redox dysregulation during oxidative stress and the perturbation of NMDA neurotransmitter system during current therapeutic modalities for the SZ treatment. This review can be beneficial for the development of promising novel diagnostics, and therapeutic modalities by ascertaining the mtDNA variations, redox state, and efficacy of pharmacological agents to mitigate redox dysregulation and augment NMDAR function to treat cognitive and behavioral symptoms in SZ.

Circular RNAs (circRNAs) are a class of single-stranded closed non-coding RNA molecules (ncRNAs), which are formed as a result of reverse splicing of mRNAs. Despite their relative abundance, an interest in understanding their regulatory importance is rather recent. High stability, abundance and evolutionary conservation among species underline some of their important traits. CircRNAs perform a variety of cellular functions ranging from miRNA and proteins sponges to transcriptional modulation and splicing. Additionally, most circRNAs are expressed aberrantly in pathological conditions suggesting their possible exploitation as diagnostic biomarkers. Their covalent closed cyclic structure resulting in resistance to RNases further makes them suitable as cancer biomarkers. Studies involving human tumors have verified differences in the expression profiles of circRNAs, indicating a regulatory role in cancer pathogenesis and metastasis. As endogenous competitive RNA, circRNAs can regulate tumor proliferation and invasion. Further, some circRNAs located in the nucleus can regulate transcription of genes by binding to RNA polymerase II. In this review, we elaborate the characteristics, functions and mechanisms of action of circRNAs in cancer. We also discuss the possibility of using circRNAs as potential therapeutic targets and biomarkers for cancer.

Exposure to environmental toxicants such as Arsenic (As) can result in As-induced alterations in immune regulators. Consequently, people who are more prone to viral infections like influenza A or B, H1N1, SARS CoV (Severe Acute Respiratory Syndrome Coronavirus), and SARS CoV2 may develop a susceptibility to immune responses in their lungs because our previous reports delineated the ability of QIAPI 1®, a melanin precursor, to dissociate water molecules with simultaneous therapeutic efficacy against central nervous system (CNS) diseases, retinopathy, and As-induced renal toxicity. Considering the commonalitie of lung pathology of SARS CoV and As-induced toxicity, the aim of this study is to decipher the efficacy of QIAPI 1® against pentavalent As-induced lung toxicity by examining the pulmonary pathology. Hematoxylin & Eosin (H&E) staining was used for ascertaining the lung pathology in Wistar rat models. Animals were divided into 3 groups: control group, group treated with pentavalent As, and a group treated with pentavalent As and QIAPI 1®. There were no significant changes in lung histopathology in the control group as indicated by intact morphology. The As-treated group revealed damage to the histoarchitecture with pulmonary edema, interstitial fibrosis, diffuse alveolar damage, Bronchiolitis obliterans organizing pneumonia (BOOP)-lesions, formation of hyaline membrane, multinucleated giant pneumocytes, atypical pneumocytes, inflammatory cell infiltration, and interstitial edema. The group treated with As and QIAPI 1® significantly associated with mitigated histological signs of lung inflammation induced by Arsenic. Therefore, QIAPI 1® can be recommended as antagonistic to Asinduced lung toxicity. In conclusion, this model could be preferred as a hypothetical model to examine the efficacy of QIAPI 1® in SARS CoV2-induced pulmonary damage. Future studies are warranted to delineate the efficacy of QIAPI 1® against SARS CoV and SARS CoV2 lung pathology.

Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.

BACKGROUND:Ionizing Radiation (IR) is one of the major limiting factors for human deep-space missions. Preventing IR-induced cognitive alterations in astronauts is a critical success factor. It has been shown that cognitive alterations in rodents can be inferred by alterations of a psycho- emotional balance, primarily an anxiogenic effect of IR. In our recent work, we hypothesized that the neurokinin-1 (NK1) receptor might be instrumental for such alterations.OBJECTIVE:The NK1 receptor antagonist rolapitant and the classic anxiolytic diazepam (as a comparison drug) were selected to test this hypothesis on Wistar rats.METHODS:Pharmacological substances were administered through intragastric probes. We used a battery of tests for a comprehensive ethological analysis. High-performance liquid chromatography was applied to quantify monoamines content. An analysis of mRNA expression was performed by real-time PCR. Protein content was studied by the Western blotting technique.RESULTS:Our salient finding includes no substantial changes in anxiety, locomotor activity and cognitive abilities of treated rats under irradiation. No differences were found in the content of monoamines. We discovered a synchronous effect on mRNA expression and protein content of 5- HT2a and 5-HT4 receptors in the prefrontal cortex, as well as decreased content of serotonin transporter and increased content of tryptophan hydroxylase in the hypothalamus of irradiated rats. Rolapitant affected the protein amount of a number of serotonin receptors in the amygdala of irradiated rats.CONCLUSION:Rolapitant may be the first atypical radioprotector, providing symptomatic treatment of CNS functional disorders in astronauts caused by IR.

Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.

Suicides on railway tracks are one of the most drastic ones. No research concerning this phenomenon has been done to this date in Poland. This article focuses on the connection between suicidal behaviors on Polish railway tracks and sociodemographic traits and presents risk factors.BACKGROUND:The suicide behavior is largely spread among many European countries. Of these, Poland ranks 22nd in terms of suicide attempts. This study aims to highlight the suicide attempts rates on Polish railways lines and their main risk factors.LIMITATIONS:Limited number of available statistical data before 2013.METHOD:Statistical review of the available Central Police headquarters database and analyses of the influence of the risk factors on people's awareness during the suicide attempts and their geographical distribution in Poland during the years 2013 - 2016. The prevalence of railway suicides in individual voivodeships (provinces) in Poland have been indicated in a 3D map.RESULTS:There were 834 cases of railway suicide fatalities across the entire country. Of the total suicide statistics by any means, 3.75% are railway related. The average known age of those committing railway suicides were: 37.9 years for men (n = 627) and 34.6 for women (n = 155). In most cases, suicides were committed by bachelors (54.3%). The largest group of people who committed suicide had a primary level of education (42.0%). Among the suicides, a significant group are unemployed (45.2%). Alcohol intoxication have been established as responsible for a person's lower awareness of his actions in 70.9% of cases. Almost 63.3% of people had a higher propensity for suicidal ideation and behavior, resulting in their being treated for mental health issues.CONCLUSION:Alcohol intoxication, illegal narcotics and psychotropic medication are responsible for a person's lower awareness during his ore her actions, in most of the cases of suicide on Polish railway lines.

: The root cause of non-inherited Alzheimer’s disease (AD) remains unknown despite hundreds of research studies performed to attempt to solve this problem. Since proper prophylaxis remains the best strategy, many scientists have studied the risk factors that may affect AD development. There is robust evidence supporting the hypothesis that cardiovascular diseases (CVD) may contribute to AD progression, as the diseases often coexist. Therefore, a lack of well-defined diagnostic criteria makes studying the relationship between AD and CVD complicated. Additionally, inflammation accompanies the pathogenesis of AD and CVD, and is not only a consequence but also implicated as a significant contributor to the course of the diseases. Of note, АроЕε4 is found to be one of the major risk factors affecting both the cardiovascular and nervous systems. According to genome wide association and epidemiological studies, numerous common risk factors have been associated with the development of AD-related pathology. Furthermore, the risk of developing AD and CVDs appears to be increased by a wide range of conditions and lifestyle factors: hypertension, dyslipidemia, hypercholesterolemia, hyperhomocysteinemia, gut/oral microbiota, physical activity, and diet. This review summarizes the literature and provides possible mechanistic links between CVDs and AD.

Atremorine is a potent dopamine (DA) enhancer obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine affects the neuronal dopaminergic system by acting as a neuroprotective agent against Parkinson's disease (PD). PD patients (N = 127) responded to a single dose of Atremorine (5 g, p.o.) 1 h after administration in a sex-, time-, dose-, and genotype-dependent fashion. Drug-free patients (N = 81) showed an increase in DA levels from 12.14 +/- 0.34 pg/ml to 6463.21 +/- 1306.90 pg/ml; and patients chronically treated with anti-PD drugs (N = 46) showed an increase in DA levels from 1321.53 +/- 389.94 pg/ml to 16,028.54 +/- 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effect of conventional anti-PD drugs. The variability in Atremorine-induced DA response is strongly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes influence the DA response to Atremorine. Genetic variation in the DA (SLC6A3; rs460000), noradrenaline (NA) (SLC6A2; rs12708954, rs3785143, rs5569), and serotonin (5-HT) transporter (SLC6A4; rs2020934, rs2020936, rs4251417, rs6354) genes exert a genotype-dependent Atremorine-induced DA response in PD, with potential impact on the DA-related pharmacogenetic outcome and minimum effects on NA and 5-HT levels.

Background: Given the evidence of little or no therapeutic benefit of injection-based growth factor therapies, it has been proposed that a naturally triggered uninterrupted blood circulation of the growth factors would be superior. Objective: We seek to stimulate discussions and more research about the possibility of using the already available growth factors found in the prostate gland and endometrium by starting novel educable physiology, known as biological transformations controlled by the mind. Methods: We summarized the stretch-gated ion channel mechanism of the cell membrane and offer several practical methods that can be applied by anyone, in order to stimulate and enhance the blood circulation of the growth factors from the seminal fluid to sites throughout the body. This study describes, in detail, the practical application of our earlier published studies about biological transformations. Results: A previously reported single-patient case study has been extended, adding more from his personal experiences to continually improve this novel physiological training and extending the ideas from our earlier findings in detail. Conclusion: The biological transformation findings demonstrate the need for additional research to establish the benefits of these natural therapies to repair and rejuvenate tissues affected by various chronic diseases or aging processes.

Background: A patient was evaluated with respect to the effects and results of a complex treatment plan for complete dental rehabilitation. Several steps were required. Each step included immunological tests of salivary biomarkers. Clinical and immunological assessments were evaluated on Day 3, Week 2, Month 3, and Month 6 post-surgery. These evaluations guided the decision-making process with regard to preparation of a permanent prosthesis. Objective: The aim of the study is to evaluate the response of tissues and organs of the maxillofacial region in patients during dental rehabilitation after maxillofacial surgery. Methods: Complex treatment and rehabilitation involving cooperation between the specialists in maxillofacial surgery, prosthetic dentistry, and cancer immunology. Results: Long-term monitoring and clinical examination showed a direct relationship between the patient's clinical and dental status and the changes in oral fluid biomarkers. Conclusion: The data revealed that the oral fluid biomarkers reflected the patient's adaptation to prosthodontic rehabilitation. Treatment and monitoring of a maxillofacial tumor patient could use biomarkers as a non-invasive indicator.

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Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.

OBJECTIVE Serrated colorectal lesions are a group of colonic lesions with a serrated (saw-tooth) profile of the surface epithelium and crypts, and peculiar molecular and genetic developmental mechanisms that are incompletely understood. These formations cause concern due to their premalignant potential. AIM The review is dedicated to serrated lesions of colon and appendix. We focused on modern classification, role in carcinogenesis, as well as new approaches to morphological diagnosis. METHODS A literature search was performed using PubMed, Scopus, ResearchGate, Google, MEDLINE, and ScienceDirect databases to find studies of serrated colorectal lesions related cancer published between 2000 and 2020 that address epidemiological risk factors, underlying pathophysiological mechanism and enable our review of these factors as well as molecular, genetics, and structural patterns. RESULTS Serrated colorectal lesions take one third of all benign neoplasms of the colon in the pathologist's practice. The active study of serrated lesions began in the 1900s. Terminology and diagnostic criteria changed in the updated classification in 2019. Morphological criteria, immunohistochemical and molecular profile, endoscopic and clinical characteristics are reviewed. CONCLUSION Although significant efforts were made in attempt to improve our understanding and diagnostic criteria of serrated polyps of colorectum, very little has changed since the original morphologic description of preneoplastic serrated lesions in early 2000s. There remains a need for more research in order to develop more definitive immuophenotypic and molecular biomarkers in order to distinguish between non-neoplastic and neoplastic serrated lesions.

Postpartum uterine diseases are associated with significant imbalance in the levels of biogenic amines (BAs) in rat uterus. Mast cells (MCs) are the main suppliers of BAs such as serotonin, catecholamines, and histamine in uterus. There is limited evidence of the BA-positive elements involved in the physiological regulation of uterus during postpartum involution. The aim of present study is to determine the concentration and distribution of biogenic amines (BAs) such as histamine, serotonin, and catecholamines in the uterine endometrium, myometrium, and peritoneal fluid (PF) during the postpartum uterine involution. A total of 110 nulliparous outbred female nonpregnant Wistar rats of mature age were divided into eleven groups (n=10 per group) according to days of postpartum involution. Tissue specimens of uterine segments, PF were prepared. Serotonin, catecholamines, and histamine concentrations were examined by fluorescence-histochemical techniques. The fluorescence of the BA-positive elements was detected and analyzed by microspectrofluorimetry. Results were analyzed using the Kruskal-Wallis chi-squared test and pairwise Mann-Whitney-Wilcoxon tests with "Benjamini-Hochberg correction" in R 3.6.3. Mast cells in uterine segments, PF exhibited characteristic yellowish-green fluorescence. The highest MCs number was reported in corpus uteri on the 15th day of postpartum involution. Serotonin, catecholamines, and histamine levels were significantly higher in BA-positive elements in the initial days. BA content was dynamic and relies on the time elapsed after parturition. There was statistically significant difference in the levels of BAs in the cornu and cervix uteri. A single morphofunctional complex of BA supply was noticed in the reproductive system of the rats. The coupled interactions of intra- and extra-organic BA-positive elements was associated with anabolic/catabolic equilibrium in uterus through the metabolism of serotonin, catecholamines, and histamine during postpartum involution.

The root cause of non-inherited Alzheimer's disease (AD) remains unknown despite hundreds of research studies performed to attempt to solve this problem. Since proper prophylaxis remains the best strategy, many scientists have studied the risk factors that may affect AD development. There is robust evidence supporting the hypothesis that cardiovascular diseases (CVD) may contribute to AD progression, as the diseases often coexist. Therefore, a lack of well-defined diagnostic criteria makes studying the relationship between AD and CVD complicated. Additionally, inflammation accompanies the pathogenesis of AD and CVD, and is not only a consequence but also implicated as a significant contributor to the course of the diseases. Of note, АроЕε4 is found to be one of the major risk factors affecting both the cardiovascular and nervous systems. According to genome wide association and epidemiological studies, numerous common risk factors have been associated with the development of AD-related pathology. Furthermore, the risk of developing AD and CVDs appears to be increased by a wide range of conditions and lifestyle factors: hypertension, dyslipidemia, hypercholesterolemia, hyperhomocysteinemia, gut/oral microbiota, physical activity, and diet. This review summarizes the literature and provides possible mechanistic links between CVDs and AD.

Background: Psychosocial stress-induced depressive behavior is linked to the etiology of several neurological diseases viz., PTSD, and neurodegenerative disease like Alzheimer's Disease (AD). The repeated bouts of social stress defeat can be induced using Resident-Intruder- Paradigm (RIP) and Chronic Mild Social Stress (CMSS) animal models to assess the stress-induced depressive behavioral patterns. Objectives: The aim of this study to examine the anti-depressive efficacy of 3-methoxythietane- 1,1-dioxide (N-14) in RIP models of behavioral alterations. Methods: In this study, we have used Sprague-Dawley rats in Resident-Intruder-Paradigm (RIP), where intruders interacted with residents Day 0 to Day +5 for 10 minutes to invoke CMSS in intruders and became defeated/submissive rats due to the depressive-like behavioral alterations in social activity, explorations, grooming, defense, aggressive behavior, social interaction, freeze, rearing etc., with residents. Control intact animals are included in group I, group II received N-14 alone; group III received CMSS, and group IV received cotreatment of N14 with CMSS. N-14 (2 mg/kg) was administered intraperitoneally from Day 0 to Day +5 to intact animals and intruder animals under conditions of CMSS. Results: Several behavioral tests viz., forced swim test, open field test, and elevated-plus maze test were used to examine the above behavioral dynamic parameters. The dynamic interaction between Residents and Intruders during the study showed substantial alterations in exploratory activity, aggressiveness, defensive behavior, body weight, and thymus mass in stressed animals. N-14 cotreatment has mitigated sociability, exploratory activity, aggressiveness increased social adaptability and defensive behavior. An extensive rise in active forms of defense and submission latency indicates that N-14 has induced antidepressant activity with a psycho-sedative component of action. Conclusion: Serendipitously, we observed the ameliorative capability of N-14 cotreatment to mitigate depressive-behavioral symptoms in intruders.

Tumor associated macrophages (TAMs), located in the tumor microenvironment (TME), play a significant role in cancer cell survival and progression. TAMs have been involved in producing immuno-suppressive TME in the tumor by generating inflammatory mediators, growth factors, cytokines, chemokines, etc. TAMs can influence the angiogenesis, metastatic behavior of tumor cells (TCs) and cause multidrug resistance. TAMs within the TME can enhance cancer cell metastasis and are stromal and perivascular. The angiogenesis is promoted at the hypoxia, and the avascular zones of TME. Differentiation states of TAMs are considered 'plastic' as they exhibit temporal expression of one or several phenotypes depending on local cues. Emerging cancer research depicted the epigenetic regulation of macrophage polarization (both M1s, M2s) and their potential implications to develop pharmacologic modulators and microRNAs to act as molecular switches and even to serve as targeted therapies to inhibit tumor growth. In the present article, the role of TAMs in tumor progression, angiogenesis and metastasis was discussed. In addition, key signaling cascades regulated by TAMs, which have a role in chemoresistance, were also discussed. Currently, novel pleiotropic properties of various anticancer phytomedicines are gaining importance as they assist in overcoming TAMs-induced chemoresistance. Moreover, these phytomedicines are being tested as 'adjunct therapeutics' along with chemotherapeutic agents, anti-angiogenic molecules, anti-metastatic compounds, and other immune-checkpoint blockers against tumor metastasis/angiogenesis. Hence, a brief note on natural products targeting TAMs was provided. In summary, this review would benefit pharmacologists and medical professionals to develop therapies to target TAMs using multi-OMICs approaches, including genomics, epigenomics, transcriptomics, and proteomics.