Biomedicines

In post-COVID-19 syndrome (PCS), neurocognitive symptoms and fatigue are often associated with alterations in electroencephalographic (EEG) activity. The present study investigates the brain source activity at rest in PCS patients (PCS-pts) perceiving cognitive deficits and fatigue. A total of 18 PCS-pts and 18 healthy controls (HCs) were enrolled. A Montreal Cognitive Assessment (MoCA), Perceived Cognitive Difficulties Scale (PDCS) and Fatigue Severity Scale (FSS) were administered for assessing the symptoms’ severity. Brain activity at rest, both with open (OE) and closed eyes (CE), was recorded by high-density EEG (Hd-EEG) and localized by source estimation. Compared to HCs, PCS-pts exhibited worse performance in executive functions, language and memory, and reported higher levels of fatigue. At resting OE state, PCS-pts showed lower delta source activity over brain regions known to be associated with executive processes, and these changes were negatively associated with PDCS scores. Consistent with recent literature data, our findings could indicate a dysfunction in the neuronal networks involved in executive functions in PCS-pts complaining of fatigue and cognitive impairment. Full article

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD. Full article

In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting. Full article

Over the last 20 years we have seen an increase in techniques in the field of computational pathology and machine learning, improving our ability to analyze and interpret imaging. Neural networks, in particular, have been used for more than thirty years, starting with the computer assisted smear test using early generation models. Today, advanced machine learning, working on large image data sets, has been shown to perform classification, detection, and segmentation with remarkable accuracy and generalization in several domains. Deep learning algorithms, as a branch of machine learning, are thus attracting attention in digital pathology and cytopathology, providing feasible solutions for accurate and efficient cytological diagnoses, ranging from efficient cell counts to automatic classification of anomalous cells and queries over large clinical databases. The integration of machine learning with related next-generation technologies powered by AI, such as augmented/virtual reality, metaverse, and computational linguistic models are a focus of interest in health care digitalization, to support education, diagnosis, and therapy. In this work we will consider how all these innovations can help cytopathology to go beyond the microscope and to undergo a hyper-digitalized transformation. We also discuss specific challenges to their applications in the field, notably, the requirement for large-scale cytopathology datasets, the necessity of new protocols for sharing information, and the need for further technological training for pathologists. Full article

Monoclonal antibodies (mAbs) are important treatment modalities for preventing and treating infectious diseases, especially for those lacking prophylactic vaccines or effective therapies. Recent advances in mAb gene cloning from naturally infected or immunized individuals has led to the development of highly potent human mAbs against a wide range of human and animal pathogens. While effective, the serum half-lives of mAbs are quite variable, with single administrations usually resulting in short-term protection, requiring repeated doses to maintain therapeutic concentrations for extended periods of time. Moreover, due to their limited time in circulation, mAb therapies are rarely given prophylactically; instead, they are generally administered therapeutically after the onset of symptoms, thus preventing mortality, but not morbidity. Adeno-associated virus (AAV) vectors have an established record of high-efficiency in vivo gene transfer in a variety of animal models and humans. When delivered to post-mitotic tissues such as skeletal muscle, brain, and heart, or to organs in which cells turn over slowly, such as the liver and lungs, AAV vector genomes assume the form of episomal concatemers that direct transgene expression, often for the lifetime of the cell. Based on these attributes, many research groups have explored AAV-vectored delivery of highly potent mAb genes as a strategy to enable long-term expression of therapeutic mAbs directly in vivo following intramuscular or intranasal administration. However, clinical trials in humans and studies in nonhuman primates (NHPs) indicate that while AAVs are a powerful and promising platform for vectored immunoprophylaxis (VIP), further optimization is needed to decrease anti-drug antibody (ADA) and anti-capsid antibody responses, ultimately leading to increased serum transgene expression levels and improved therapeutic efficacy. The following review will summarize the current landscape of AAV VIP in NHP models, with an emphasis on vector and transgene design as well as general delivery system optimization. In addition, major obstacles to AAV VIP, along with implications for clinical translation, will be discussed. Full article

Numerous studies showed that patients with heart failure (HF) and COVID-19 are at high risk of in-hospital complications and long-term mortality. Changes in the organisation of the medical system during the pandemic also worsened access to standard procedures, increasing the general mortality in HF and forcing the systems to be reorganised with the implementation and development of telemedical technologies. The main challenges for HF patients during the pandemic could be solved with new technologies aimed to limit the risk of SARS-CoV-2 transmission, optimise and titrate the therapy, prevent the progression and worsening of HF, and monitor patients with acute HF events in the course of and after COVID-19. Dedicated platforms, phone calls or video conferencing and consultation, and remote non-invasive and invasive cardiac monitoring became potential tools used to meet the aforementioned challenges. These solutions showed to be effective in the model of care for patients with HF and undoubtedly will be developed after the experience of the pandemic. However, the multitude of possibilities requires central coordination and collaboration between institutes with data protection and cost reimbursement to create effective mechanisms in HF management. It is crucial that lessons be learned from the pandemic experience to improve the quality of care for HF patients. Full article

Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma. Furthermore, the inhibition of NF-κB signaling significantly potentiates the antineoplastic activity of the NAC1 inhibition in both the cultured melanoma cells and xenograft tumors. This study identifies a novel NAC1-NF-κB signaling axis in melanoma, offering a promising new therapeutic option to treat melanoma. Full article

Transforming growth factor beta-1 (TGFβ1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFβ1 in pregnancy and child growth and the source of cord TGFβ1 are yet unknown. In this study, we sought to clarify the correlation of TGFβ1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother–child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann–Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFβ1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFβ1 levels at birth and child weight at U6. Furthermore, cord TGFβ1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFβ1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that leads to numerous impairments in motor function that compromise the ability to perform activities of daily living. Practical and effective adjunct therapies are needed to complement current treatment approaches in PD. Transcranial direct current stimulation applied to the cerebellum (c-tDCS) can increase motor skill in young and older adults. Because the cerebellum is involved in PD pathology, c-tDCS application during motor practice could potentially enhance motor skill in PD. The primary purpose was to examine the influence of c-tDCS on motor skill acquisition in a complex, visuomotor isometric precision grip task (PGT) in PD in the OFF-medication state. The secondary purpose was to determine the influence of c-tDCS on transfer of motor skill in PD. The study utilized a double-blind, SHAM-controlled, within-subjects design. A total of 16 participants completed a c-tDCS condition and a SHAM condition in two experimental sessions separated by a 7-day washout period. Each session involved practice of the PGT concurrent with either c-tDCS or SHAM. Additionally, motor transfer tasks were quantified before and after the practice and stimulation period. The force error in the PGT was not significantly different between the c-tDCS and SHAM conditions. Similarly, transfer task performance was not significantly different between the c-tDCS and SHAM conditions. These findings indicate that a single session of c-tDCS does not elicit acute improvements in motor skill acquisition or transfer in hand and arm tasks in PD while participants are off medications. Full article

Cerebellar transcranial alternating current stimulation (tACS) is an emerging non-invasive technique that induces electric fields to modulate cerebellar function. Although the effect of cortical tACS seems to be state-dependent, the impact of concurrent motor activation and the duration of stimulation on the effects of cerebellar tACS has not yet been examined. In our study, 20 healthy subjects received neuronavigated 50 Hz cerebellar tACS for 40 s or 20 min, each during performance using a motor sequence learning task (MSL) and at rest. We measured the motor evoked potential (MEP) before and at two time points after tACS application to assess corticospinal excitability. Additionally, we investigated the online effect of tACS on MSL. Individual electric field simulations were computed to evaluate the distribution of electric fields, showing a focal electric field in the right cerebellar hemisphere with the highest intensities in lobe VIIb, VIII and IX. Corticospinal excitability was only increased after tACS was applied for 40 s or 20 min at rest, and motor activation during tACS (MSL) cancelled this effect. In addition, performance was better (shorter reaction times) for the learned sequences after 20 min of tACS, indicating more pronounced learning under 20 min of tACS compared to tACS applied only in the first 40 s. Full article

Since the corticotropin-releasing factor (CRF) was isolated from an ovine brain, a growing family of CRF-related peptides has been discovered. Today, the mammalian CRF system consists of four ligands (CRF, urocortin 1 (Ucn1), urocortin 2 (Ucn2), and urocortin 3 (Ucn3)); two receptors (CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2)); and a CRF-binding protein (CRF-BP). Besides the regulation of the neuroendocrine, autonomic, and behavioral responses to stress, CRF and CRF-related peptides are also involved in different aspects of social behavior. In the present study, we review the experiments that investigated the role of CRF and the urocortins involved in the social behavior of rats, mice, and voles, with a special focus on sociability and preference for social novelty, as well as the ability for social recognition, discrimination, and memory. In general, these experiments demonstrate that CRF, Ucn1, Ucn2, and Ucn3 play important, but distinct roles in the social behavior of rodents, and that they are mediated by CRF1 and/or CRF2. In addition, we suggest the possible brain regions and pathways that express CRF and CRF-related peptides and that might be involved in social interactions. Furthermore, we also emphasize the differences between the species, strains, and sexes that make translation of these roles from rodents to humans difficult. Full article

Antimicrobial resistance (AMR) has become a topic of great concern in recent years, with much effort being committed to developing alternative treatments for resistant bacterial pathogens. Drug combinational therapies have been a major area of research for several years, with modern iterations using combining well-established antibiotics and other antimicrobials with the aim of discovering complementary mechanisms. Previously, we characterised four GRAS antimicrobials that can withstand thermal polymer extrusion processes for novel medical device-based and therapeutic applications. In the present study, four antimicrobial bioactive—silver nitrate, nisin, chitosan and zinc oxide—were assessed for their potential combined use as an alternative synergistic treatment for AMR bacteria via a broth microdilution assay based on a checkerboard format. The bioactives were tested in arrangements of two-, three- and four-drug combinations, and their interactions were determined and expressed in terms of a synergy score. Results have revealed interesting interactions based on treatments against recognised test bacterial strains that cause human and animal infections, namely E. coli, S. aureus and S. epidermidis. Silver nitrate was seen to greatly enhance the efficacy of its paired treatment. Combinations with nisin, which is a lantibiotic, exhibited the most interesting results, as nisin has no effect against Gram-negative bacteria when used alone; however, it demonstrated antimicrobial effects when combined with silver nitrate or chitosan. This study constitutes the first study to both report on practical three- and four-drug combinational assays and utilise these methods for the assessment of established and emerging antimicrobials. The novel methods and results presented in this study show the potential to explore previously unknown drug combination compatibility measures in an ease-of-use- and high-throughput-based format, which can greatly help future research that aims to identify appropriate alternative treatments for AMR, including the screening of potential new bioactives biorefined from various sources. Full article

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic. However, studies on AR expression in non-prostatic malignancies uncovered that AR-SVs are expressed in glioblastoma, breast, salivary, bladder, kidney, and liver cancers, where they have diverse roles in tumorigenesis. AR-SVs also have roles in non-cancer pathologies. In granulosa cells from women with polycystic ovarian syndrome, unique AR-SVs lead to an increase in androgen production. In patients with nonobstructive azoospermia, testicular Sertoli cells exhibit differential expression of AR-SVs, which is associated with impaired spermatogenesis. Moreover, AR-SVs have been identified in normal cells, including blood mononuclear cells, neuronal lipid rafts, and the placenta. The detection and characterization of AR-SVs in mammalian and non-mammalian species argue that AR-SV expression is evolutionarily conserved and that AR-SV-dependent signaling is a fundamental regulatory feature in multiple cellular contexts. These discoveries argue that alternative splicing of the AR transcript is a commonly used mechanism that leads to an expansion in the repertoire of signaling molecules needed in certain tissues. Various malignancies appropriate this mechanism of alternative AR splicing to acquire a proliferative and survival advantage. Full article

Leflunomide is an isoxazole immunomodulating drug used to treat rheumatoid arthritis (RA). It is adopted as a metal-containing molecule to proceed with saturated salts of essential and detected metals; it amends the pharmacokinetic and pharmacodynamics activity of leflunomide to provide [M(Lef)₄]X₂-type complexes. Earlier it has been reported that after forming complexes with metals, leflunomide anti-arthritic activity was significantly altered in an acute arthritic model. In the present study, we evaluated the possible modification in anti-arthritic activities of leflunomide–metal complexes (Mg⁺², Ca⁺², Fe⁺², Zn⁺²) with and without an anti-depressant drug, i.e., fluoxetine (10 mg/kg) in a chronic AIA model. Rats (n = 5) were administered with 0.1 mL of CFA into the right hind paw while treated groups received leflunomide and its metal complexes orally (3.2 mg/kg) for 24 days. On the final day of experiment, rats were sacrificed; a specific rat immunoassay ELISA kit was used to assess TNF-α in serum samples and read at 450 nm; a tissue sample of a paw was homogenized in a phosphate buffer using DCFH-DA dye for binding to assess ROS. A rat’s brain sample was homogenized and evaluated for tryptophan, serotonin (5-HT), and HIAA by RP-HPLC with EC detector. The overall TNF production was altered in treated rats. In addition, a decreased ROS was observed in all categories, except lef+Mg⁺² group. Moreover, depletion in the brain indolamine levels were found in treated groups; an upraised level of these indolamines was observed when fluoxetine was added. It is concluded that metals affect leflunomide activity on complexation and simultaneous administration of fluoxetine cope up with the depression in arthritic-induced rats. Full article

Background: This systematic review and meta-analysis examines how pulmonary rehabilitation impacts in patients suffering from subacute and long COVID-19 infections, gauging enhancements in of dyspnea, physical function, quality of life, psychological state (anxiety and depression), and fatigue. Methods: Three electronic databases (PubMed, Web of Science, Cochrane Library) were systematically searched for full-text articles published from inception to January 2023. Randomized, quasi-experimental, and observational studies were included, with adults diagnosed with subacute or long COVID-19 who received pulmonary rehabilitation as intervention. Outcomes related to dyspnea, physical function, quality of life, fatigue, and psychological status were included. Risk of bias was assessed with Cochrane Risk of Bias Tool for Randomized Controlled Trials and Risk of bias in non-randomized studies of intervention. The review was registered before starting in PROSPERO (CRD: 42022373075). Results: Thirty-four studies were included, involving 1970 patients with subacute and long COVID-19. The meta-analysis demonstrated moderate to large effects on dyspnea, physical function, quality of life, and depressive symptoms compared to usual care intervention. No significant differences were found in fatigue compared to usual care, nor in anxiety levels after pulmonary rehabilitation intervention. Conclusions: Pulmonary rehabilitation has the potential to improve health outcomes in patients with subacute and long COVID-19. However, due to the high risk of bias of included studies, conclusions should be taken with caution. Full article

Several studies have showed that hyperuricemia is related to the development of ischemic heart disease (IHD). There is also growing evidence indicating that hyperuricemia may contribute to the progression of IHD as a pathogenic factor. Ironically, uric acid can be an antioxidant agent, as shown in experimental studies. The aim of our study is to analyse the association between uric acid and IHD with early-stage chronic kidney disease (CKD). Data were assessed from 17,492 participants without cardiovascular disease from the Korean Genome and Epidemiology Study (KoGES) and Korea Health Insurance Review and Assessment (HIRA) data. The subjects were categorized as four groups according to CKD and uric acid levels. We retrospectively evaluated hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD by using multivariate Cox regression analysis over a 4-year period from the baseline survey. During the follow-up, 335 individuals (3.4%; 236 men and 99 women) developed IHD. Compared to the participants without elevated uric acid and early CKD HRs for incident IHD according to uric acid levels and early CKD, the uric acid level was 1.13 (95% CI, 0.86–1.48) in participants with elevated uric acid and without early CKD, 0.99 (95% CI, 0.55–1.77) in participants without elevated uric acid and with early CKD, and 1.65 (95% CI, 1.03–2.66) in participants with elevated uric acid and early CKD after adjusting for confounding metabolic factors. Early CKD and high uric acid levels increased the risk of new-onset IHD (HR, 1.65; 95% CI, 1.03–2.66). Elevated uric acid levels were related to an increased risk of incident IHD in early-stage CKD patients. It is expected that uric acid can be a reliable predictor for IHD, even in early-stage CKD patients; thus, in those with CKD, proactively managing uric acid levels can play a significant role in reducing the risk of cardiovascular disease. Full article

Objective: This study aims to explore the correlation between the free-triiodothyronine (FT3)-to-free-thyroxine (FT4) ratio (FT3/FT4) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: This study retrospectively analyzed 1729 patients with T2DM hospitalized in the Department of Endocrinology, Peking University International Hospital, from January 2017 to August 2021, including 1075 males and 654 females. In accordance with the FT3/FT4, the patients were divided into three groups. Results: (1) The levels of glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (PBG) among the three groups were significantly different, with the low FT3/FT4 group having the highest HbA1c, FBG and PBG among the three groups (F = 39.39, p < 0.01; F = 27.04, p < 0.01; F = 5.76, p = 0.03; respectively). (2) The proportion of DKD is the highest in the low FT3/FT4 group and the lowest in the high FT3/FT4 group (χ² = 25.83, p < 0.01). (3) Logistic regression showed that low FT3/FT4 were independent risk factors for DKD (OR = 2.36, 95 CI% 1.63, 3.43; p = 0.01). Conclusion: A decrease in the FT3/FT4 is an independent predictor of DKD occurrence in patients with T2DM. Full article

Endometriosis is a gynecological disorder prevalent in women of reproductive age. The primary symptoms include dysmenorrhea, irregular menstruation, and infertility. However, the pathogenesis of endometriosis remains unclear. With the advent of high-throughput technologies, various omics experiments have been conducted to identify genes related to the pathophysiology of endometriosis. This review highlights the molecular mechanisms underlying endometriosis using omics. When genes identified in omics experiments were compared with endometriosis disease genes identified in independent studies, the number of overlapping genes was moderate. However, the characteristics of these genes were found to be equivalent when functional gene set enrichment analysis was performed using gene ontology and biological pathway information. These findings indicate that omics technology provides invaluable information regarding the pathophysiology of endometriosis. Moreover, the functional characteristics revealed using enrichment analysis provide important clues for discovering endometriosis disease genes in future research. Full article