Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). AIMS OF REVIEW: In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology. KEY SCIENTIFIC CONCEPTS OF REVIEW: The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

Benefits and limitations of nanomedicine treatment of brain cancers and age-dependent neurodegenerative disorders.

The treatment of central nervous system (CNS) malignancies, including brain cancers, is limited by a number of obstructions, including the blood-brain barrier (BBB), the heterogeneity and high invasiveness of tumors, the inaccessibility of tissues for early diagnosis and effective surgery, and anti-cancer drug resistance. Therapies employing nanomedicine have been shown to facilitate drug penetration across the BBB and maintain biodistribution and accumulation of therapeutic agents at the desired target site. The application of lipid-, polymer-, or metal-based nanocarriers represents an advanced drug delivery system for a growing group of anti-cancer chemicals. The nanocarrier surface is designed to contain an active ligand (cancer cell marker or antibody)-binding structure which can be modified to target specific cancer cells. Glioblastoma, ependymoma, neuroblastoma, medulloblastoma, and primary CNS lymphomas were recently targeted by easily absorbed nanocarriers. The metal- (such as transferrin drug-loaded systems), polymer- (nanocapsules and nanospheres), or lipid- (such as sulfatide-containing nanoliposomes)-based nano-vehicles were loaded with apoptosis- and/or ferroptosis-stimulating agents and demonstrated promising anti-cancer effects. This review aims to discuss effective nanomedicine approaches designed to overcome the current limitations in the therapy of brain cancers and age-dependent neurodegenerative disorders. To accent current obstacles for successful CNS-based cancer therapy, we discuss nanomedicine perspectives and limitations of nanodrug use associated with the specificity of nervous tissue characteristics and the effects nanocarriers have on cognition.

Histone modifications in epigenetic regulation of cancer: Perspectives and achieved progress.

Epigenetic changes associated with histone modifications play an important role in the emergence and maintenance of the phenotype of various cancer types. In contrast to direct mutations in the main DNA sequence, these changes are reversible, which makes the development of inhibitors of enzymes of post-translational histone modifications one of the most promising strategies for the creation of anticancer drugs. To date, a wide variety of histone modifications have been found that play an important role in the regulation of chromatin state, gene expression, and other nuclear events. This review examines the main features of the most common and studied epigenetic histone modifications with a proven role in the pathogenesis of a wide range of malignant neoplasms: acetylation / deacetylation and methylation / demethylation of histone proteins, as well as the role of enzymes of the HAT / HDAC and HMT / HDMT families in the development of oncological pathologies. The data on the relationship between histone modifications and certain types of cancer are presented and discussed. Special attention is devoted to the consideration of various strategies for the development of epigenetic inhibitors. The main directions of the development of inhibitors of histone modifications are analyzed and effective strategies for their creation are identified and discussed. The most promising strategy is the use of multitarget drugs, which will affect multiple molecular targets of cancer. A critical analysis of the current status of approved epigenetic anticancer drugs has also been performed.

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment.

Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-ß, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.

Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer's Disease: Synthesis, Docking and Biological Evaluation.

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood-brain barrier. According to the in vitro testing, hydroxamic acids 15 and 25, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against ß-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer's disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid 15 restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer's disease.

N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects.

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.

The Hydroxamic Acids as Potential Anticancer and Neuroprotective Agents.

Hydroxamic acids are a promising class of chemical compounds with proven antitumor potential, primarily due to their ability to inhibit the activity of histone deacetylase enzymes. The analysis of modern experimental data shows a wide range of biological activities of hydroxamic acids, which make them equally worthy candidates for the fight against neuropathologies. A characteristic feature of hydroxamic acids is their ability to act simultaneously on several promising molecular targets for the correction of both neuropathologies and oncological diseases, thereby exhibiting multifunctionality. This review discusses the effect of hydroxamic acids on key parts of cancer and neurodegenerative disorders' pathogenesis. Pathological changes in the processes associated with oxidative stress, the functioning of mitochondria, and the activity of metal enzymes of the class of histone deacetylases, as the main links in the epigenetic regulation of pathological conditions, are such molecular targets.

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents.

AIMS: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. BACKGROUND: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. OBJECTIVE: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. METHODS: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. RESULTS: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. CONCLUSION: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Implications of nanotechnology for the treatment of cancer: Recent advances.

The use of nanoparticles dramatically increases the safety and efficacy of the most common anticancer drugs. The main advantages of nano-drugs and delivery systems based on nano-technology are effective targeting, delayed release, increased half-life, and less systemic toxicity. The use of nano-carriers has led to significant improvements in drug delivery to targets compared with traditional administration of these drugs. In this review, the main tendencies in nano-drug formulations as well as factors limiting their use in clinical settings are discussed. Additionally, the current status of approved nano-drugs for cancer treatment is reviewed.

Extracellular vesicles in cancer nanomedicine.

To date, a lot of nanotechnological optitions are available for targeted drug delivery. Extracellular vesicles (EVs) are membrane structures that cells use for storage, transport, communication, and signaling. Recent research has focused on EVs as natural nanoparticles for drug delivery. This review sheds light on the application of EVs in cancer therapy, such as targeted chemotherapy, gene therapy, and vaccine development. Aspects of biogenesis, isolation, targeting, and loading of EVs are discussed in detail.

Unique indolizidine alkaloid securinine is a promising scaffold for the development of neuroprotective and antitumor drugs.

Alkaloids, secondary plant metabolites, are used in traditional medicine in many countries to treat various pathological conditions. Securinine, a unique indolizidine alkaloid combining four cycles, "6-azobicyclo[3.2.1]octane" as a key structure fused with α,ß-unsaturated-γ-lactone and piperidine ring, has a broad spectrum of actions including anti-inflammatory, antibacterial, neuroprotective and antitumor, and has been previously used in medical practice. It has several reactive centers, which are double bonds at positions 12-13 and 14-15, and this is a challenging scaffold for the synthesis of biologically active compounds. In this review, works on the production of modified securinine derivatives and their biological activity are addressed. Both monovalent and bivalent derivatives that are most promising in our opinion, and have potential for further research, are considered.

The Association of Sleep Disorders, Obesity and Sleep-Related Hypoxia with Cancer.

BACKGROUND: Sleep disorders have emerged as potential cancer risk factors. OBJECTIVE: This review discusses the relationships between sleep, obesity, and breathing disorders with concomitant risks of developing cancer. RESULTS: Sleep disorders result in abnormal expression of clock genes, decreased immunity, and melatonin release disruption. Therefore, these disorders may contribute to cancer development. Moreover, in sleep breathing disorder, which is frequently experienced by obese persons, the sufferer experiences intermittent hypoxia that may stimulate cancer cell proliferation. DISCUSSION: During short- or long- duration sleep, sleep-wake rhythm disruption may occur. Insomnia and obstructive sleep apnea increase cancer risks. In short sleepers, an increased risk of stomach cancer, esophageal squamous cell cancer, and breast cancer was observed. Among long sleepers (>9 hours), the risk of some hematologic malignancies is elevated. CONCLUSION: Several factors including insomnia, circadian disruption, obesity, and intermittent hypoxia in obstructive sleep apnea are contributing risk factors for increased risk of several types of cancers. However, further studies are needed to determine the more significant of these risk factors and their interactions.

Updated Understanding of the Degenerative Disc Diseases - Causes Versus Effects - Treatments, Studies and Hypothesis.

BACKGROUND: In this review we survey medical treatments and research strategies, and we discuss why they have failed to cure degenerative disc diseases or even slow down the degenerative process. OBJECTIVE: We seek to stimulate discussion with respect to changing the medical paradigm associated with treatments and research applied to degenerative disc diseases. METHOD PROPOSAL: We summarize a Biological Transformation therapy for curing chronic inflammations and degenerative disc diseases, as was previously described in the book Biological Transformations controlled by the Mind Volume 1. PRELIMINARY STUDIES: A single-patient case study is presented that documents complete recovery from an advanced lumbar bilateral discopathy and long-term hypertrophic chronic rhinitis by application of the method proposed. CONCLUSION: Biological transformations controlled by the mind can be applied by men and women in order to improve their quality of life and cure degenerative disc diseases and chronic inflammations illnesses.

Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review.

This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and endometriosis-associated ovarian tumors are important problems that require further study in the context of advanced therapeutic strategies to provide maximal health benefits to patients.

Synthesis and Cytotoxic Activity of Azine Derivatives of 6-Hydroxyxanthanodiene.

BACKGROUND: The conjugates of the sesquiterpene lactone of the eremophilane series of 6- hydroxyxanthanodiene with hydrogenated azines (piperidines and piperazines) have been synthesized and identified by NMR spectrometer. OBJECTIVE: A lactone with an unusual skeleton "6-hydroxyxanthanodiene" was extracted from the plant Elecampane (Inula helenium L) and identified various species with NMR spectrometer. METHODS: The cytotoxic, mitochondrial, and antioxidant activities on different tumor lines such as A549, HCT116, RD and Jurkat were investigated and determined possible mechanisms. RESULTS: The results showed that the most potent compound was IIIi exhibiting highest cytotoxicity against RD cells (IC50 25.23 ± 0.04 µM), depolarized the mitochondrial membrane and was an effective antioxidant (IC50 inhibition of LP 10.68 ± 3.21 µM) without any toxic side effect on healthy cells. CONCLUSION: The conjugates of sesquiterpene lactone 6-hydroxyxanthanodiene III and hydrogenated azines may help to design potential promising anticancer drugs.

Publisher Correction: Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target.

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.

Feasibility of Targeting Glioblastoma Stem Cells: From Concept to Clinical Trials.

OBJECTIVE: Glioblastoma is a highly aggressive and invasive brain and Central Nervous System (CNS) tumor. Current treatment options do not prolong overall survival significantly because the disease is highly prone to relapse. Therefore, research to find new therapies is of paramount importance. It has been discovered that glioblastomas contain a population of cells with stem-like properties and that these cells are may be responsible for tumor recurrence. METHODS: A review of relevant papers and clinical trials in the field was conducted. A PubMed search with related keywords was used to gather the data. For example, "glioblastoma stem cells AND WNT signaling" is an example used to find information on clinical trials using the database ClinicalTrials.gov. RESULTS: Cancer stem cell research has several fundamental issues and uncertainties that should be taken into consideration. Theoretically, a number of treatment options that target glioblastoma stem cells are available for patients. However, only a few of them have obtained promising results in clinical trials. Several strategies are still under investigation. CONCLUSION: The majority of treatments to target cancer stem cells have failed during clinical trials. Taking into account a number of biases in the field and the number of unsuccessful investigations, the application of the cancer stem cells concept is questionable in clinical settings, at least with respect to glioblastoma.

A Novel Heterocyclic System Based on Natural Epoxyalantolactone.

Natural sesquiterpene lactones which contain an exocyclic methylene group in the ß-position of the lactone ring react readily with N-nucleophiles. When studying the reaction of the natural epoxyalantolactone with the primary amines we demonstrate the formation of a new heterocyclic system-the hydrogenated benzo[g]furo[4,3,2-cd]indol-3(1H)-one. Spectral data on the characteristics of the synthesized compounds are presented. The data on the reaction mechanisms and its applicability for the preparation are discussed.

Increased Pain Sensitivity in Obese Patients After Lung Cancer Surgery.

Background: Obesity and cancer are recognized worldwide health threats. While there is no reported causal relationship, the increasing frequency of both conditions results in a higher incidence of obese patients who are being treated for cancer. Physiological data indicate that there is a relationship between obesity and susceptibility to pain; however, currently, there are no specific pharmacological interventions. Objective: To evaluate the self-reported intensity of postoperative pain in obese and nonobese lung cancer who receive either thoracotomy or video-assisted thoracic surgery (VATS) surgical therapy. Material and Methods: In 50 obese [mean body mass index (BMI) of 34.1 ± 3.2 kg/m2] and 62 nonobese (mean BMI of 24.9 ± 3 kg/m2) lung cancer patients, the intensity of pain was estimated every 4 h using a visual analog scale (VAS, 0 indicating no pain and 10 indicating "worst imaginable pain") beginning shortly after surgery (Day O) and continuing until the day of discharge (Day D). Results: The self-reported pain was more severe in obese than in nonobese patients, both at the time of the operation [Day O (4.5 ± 1.2 vs 3.4 ± 1.1; p < 0.0001)] and at the day of discharge [Day D (3.9 ± 1.4 vs 2.6 ± 0.9, p < 0.0001)]. This finding was consistent both in the patients after thoracotomy and after video-assisted thoracic surgery (VATS, p < 0.0001). The patients with severe pain shortly after surgery (VAS score >4) had significantly higher BMI (31.8 ± 5.6 kg/m2 vs 28.8 ± 5.2 kg/m2, p < 0.01) and were hospitalized longer than the remaining patients (13.0 ± 13.6 days vs 9.5 ± 3.6 days, p < 0.05). Conclusion: The reported perception of pain in obese lung cancer patients is greater than in nonobese patients undergoing the same thoracic surgery. In obese patients, severe pain persisted longer. Pain management is an important consideration in the postoperative care of lung cancer patients, even more so with obese patients.