Search Results (2,135)

Keratins 6, 16, and 17 occupy unique positions within the keratin family. These proteins are not commonly found in the healthy, intact epidermis, but their expression increases in response to damage, inflammation, and hereditary skin conditions, as well as cancerous cell transformations and tumor growth. As a result, there is an active investigation into the potential use of these proteins as biomarkers for different pathologies. Recent studies have revealed the role of these keratins in regulating keratinocyte migration, proliferation, and growth, and more recently, their nuclear functions, including their role in maintaining nuclear structure and responding to DNA damage, have also been identified. This review aims to summarize the latest research on keratins 6, 16, and 17, their regulation in the epidermis, and their potential use as biomarkers in various skin conditions. Full article

In this study, the effects of different combinations of the genes Vegf, Ang, and Gdnf injected both using direct virus-mediated injection (adenovirus, Ad5) and umbilical cord blood mononuclear cells (UCBCs) on the processes of stimulation of post-ischemic innervation, angiogenesis, and regeneration in skeletal muscle were investigated in a rat hindlimb chronic ischemia model. It was shown that more pronounced stimulation of angiogenesis and restoration of post-ischemic innervation were achieved both in the early (28 days post-ischemia, dpi) and late (42 dpi) terms of the experiment in the calf muscle when UCBCs delivered the combination of Ad5-Vegf and Ad5-Ang compared to the direct injection of the same vector combination into the area of ischemia. At the same time, the inclusion of Ad5-Gdnf in the combination of Ad5-Vegf and Ad5-Ang directly injected or administered by UCBCs provided a significant increase in the number of centronuclear muscle fibers, indicating stimulation of post-ischemic reparative myogenesis. This study allowed us to determine the most effective gene combinations for angiogenesis and neurogenesis, which, in the future, may serve as the basis for the development of gene and gene cell products for the treatment of chronic lower limb ischemia. Full article

Colorectal cancer (CRC), found in the intestinal tract, is initiated and progresses through various mechanisms, including the dysregulation of signaling pathways. Several signaling pathways, such as EGFR and MAPK, involved in cell proliferation, migration, and apoptosis, are often dysregulated in CRC. Although cannabidiol (CBD) has previously induced apoptosis and cell cycle arrest in vitro in CRC cell lines, its effects on signaling pathways have not yet been determined. An in silico analysis was used here to assess partner proteins that can bind to CBD, and docking simulations were used to predict precisely where CBD would bind to these selected proteins. A survey of the current literature was used to hypothesize the effect of CBD binding on such proteins. The results predict that CBD could interact with EGFR, RAS/RAF isoforms, MEK1/2, and ERK1/2. The predicted CBD-induced inhibition might be due to CBD binding to the ATP binding site of the target proteins. This prevents the required phosphoryl transfer to activate substrate proteins and/or CBD binding to the DFG motif from taking place, thus reducing catalytic activity. Full article

Transposable elements (TEs) comprise a substantial portion of the mammalian genome, with potential implications for both embryonic development and cancer. This study aimed to characterize the expression profiles of TEs in embryonic stem cells (ESCs), cancer cell lines, tumor tissues, and the tumor microenvironment (TME). We observed similarities in TE expression profiles between cancer cells and ESCs, suggesting potential parallels in regulatory mechanisms. Notably, four TE RNAs (HERVH, LTR7, HERV-Fc1, HERV-Fc2) exhibited significant downregulation across cancer cell lines and tumor tissues compared to ESCs, highlighting potential roles in pluripotency regulation. The strong up-regulation of the latter two TEs (HERV-Fc1, HERV-Fc2) in ESCs has not been previously demonstrated and may be a first indication of their role in the regulation of pluripotency. Conversely, tandemly repeated sequences (MSR1, CER, ALR) showed up-regulation in cancer contexts. Moreover, a difference in TE expression was observed between the TME and the tumor bulk transcriptome, with distinct dysregulated TE profiles. Some TME-specific TEs were absent in normal tissues, predominantly belonging to LTR and L1 retrotransposon families. These findings not only shed light on the regulatory roles of TEs in both embryonic development and cancer but also suggest novel targets for anti-cancer therapy. Understanding the interplay between cancer cells and the TME at the TE level may pave the way for further research into therapeutic interventions. Full article

Astaxanthin, a keto-carotenoid, is known to have potent antioxidant properties. This study aims to investigate the anti-inflammatory effect of astaxanthin and its mechanism in human neutrophils. The effects of astaxanthin on lipopolysaccharide (LPS)-stimulated human neutrophils were investigated in vitro. Neutrophils were isolated from healthy volunteers and stimulated with LPS in the presence and absence of astaxanthin. We assessed cytokine production, signaling pathway activation via mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), and apoptosis. Astaxanthin’s impact was evaluated at different concentrations, and both pretreatment and cotreatment protocols were tested. The results demonstrated that astaxanthin significantly reduced the production of pro-inflammatory cytokines TNF-α and IL-1β in LPS-stimulated neutrophils. It effectively inhibited the phosphorylation of ERK1/2 MAPK, without notably affecting p38 MAPK or NF-κB pathways. Furthermore, astaxanthin promoted apoptosis in neutrophils, counteracting the apoptosis-delaying effects of LPS. These effects were more pronounced with pretreatment. In conclusion, astaxanthin has protective effects on inflammatory responses in neutrophils by reducing cytokine production and enhancing apoptosis while selectively modulating intracellular signaling pathways. Astaxanthin demonstrates significant potential as a therapeutic agent in the management of severe inflammatory conditions. Full article

Hemerocallis citrina Baroni (H. citrina) is an important specialty vegetable that is not only edible and medicinal but also has ornamental value. However, much remains unknown about the regulatory mechanisms associated with the growth, development, and flowering rhythm of this plant. CO, as a core regulatory factor in the photoperiod pathway, coordinates light and circadian clock inputs to transmit flowering signals. We identified 18 COL genes (HcCOL1-HcCOL18) in the H. citrina cultivar ‘Mengzihua’ and studied their chromosomal distribution, phylogenetic relationships, gene and protein structures, collinearity, and expression levels in the floral organs at four developmental stages. The results indicate that these genes can be classified into three groups based on phylogenetic analysis. The major expansion of the HcCOL gene family occurred via segmental duplication, and the Ka/Ks ratio indicated that the COL genes of Arabidopsis thaliana, Oryza sativa, Phalaenopsis equestris, and H. citrina were under purifying selection. Many cis-elements, including light response elements, abiotic stress elements, and plant hormone-inducible elements, were distributed in the promoter sequences of the HcCOL genes. Expression analysis of HcCOL genes at four floral developmental stages revealed that most of the HcCOL genes were expressed in floral organs and might be involved in the growth, development, and senescence of the floral organs of H. citrina. This study lays a foundation for the further elucidation of the function of the HcCOL gene in H. citrina and provides a theoretical basis for the molecular design breeding of H. citrina. Full article

Disrupted in Schizophrenia 1 (DISC1) is a scaffold protein implicated in major mental illnesses including schizophrenia, with a significant negative impact on social life. To investigate if DISC1 affects social interactions in Drosophila melanogaster, we created transgenic flies with second or third chromosome insertions of the human full-length DISC1 (hflDISC1) gene fused to a UAS promotor (UAS-hflDISC1). Initial characterization of the insertion lines showed unexpected endogenous expression of the DISC1 protein that led to various behavioral and neurochemical phenotypes. Social interaction network (SIN) analysis showed altered social dynamics and organizational structures. This was in agreement with the altered levels of the locomotor activity of individual flies monitored for 24 h. Together with a decreased ability to climb vertical surfaces, the observed phenotypes indicate altered motor functions that could be due to a change in the function of the motor neurons and/or central brain. The changes in social behavior and motor function suggest that the inserted hflDISC1 gene influences nervous system functioning that parallels symptoms of DISC1-related mental diseases in humans. Furthermore, neurochemical analyses of transgenic lines revealed increased levels of hydrogen peroxide and decreased levels of glutathione, indicating an impact of DISC1 on the dynamics of redox regulation, similar to that reported in transgenic mammals. Future studies are needed to address the localization of DISC1 expression and to address how the redox parameter changes correlate with the observed behavioral changes. Full article

Fibroblast growth factor 21 (FGF21) is a hormone involved in regulating the metabolism, energy balance, and glucose homeostasis, with new studies demonstrating its beneficial effects on the heart. This study investigated the relationship between FGF21 levels and clinical, biochemical, and echocardiographic parameters in patients with acute coronary syndromes (ACSs). This study included 80 patients diagnosed with ACS between May and July 2023, categorized into four groups based on body mass index (BMI): Group 1 (BMI 18.5–24.9 kg/m²), Group 2 (BMI 25–29.9 kg/m²), Group 3 (BMI 30–34.9 kg/m²), and Group 4 (BMI ≥ 35 kg/m²). Serum FGF21 levels were measured by ELISA (Abclonal Catalog NO.: RK00084). Serum FGF21 levels were quantifiable in 55 samples (mean ± SD: 342.42 ± 430.17 pg/mL). Group-specific mean FGF21 levels were 238.98 pg/mL ± SD in Group 1 (n = 14), 296.78 pg/mL ± SD in Group 2 (n = 13), 373.77 pg/mL ± SD in Group 3 (n = 12), and 449.94 pg/mL ± SD in Group 4 (n = 16), with no statistically significant differences between groups (p = 0.47). Based on ACS diagnoses, mean FGF21 levels were 245.72 pg/mL for STEMI (n = 21), 257.89 pg/mL for NSTEMI (n = 9), and 456.28 pg/mL for unstable angina (n = 25), with no significant differences observed between these diagnostic categories. Significant correlations were identified between FGF21 levels and BMI, diastolic blood pressure, and serum chloride. Regression analyses revealed correlations with uric acid, chloride, and creatinine kinase MB. This study highlights the complex interplay between FGF21, BMI, and acute coronary syndromes. While no significant differences were found in FGF21 levels between the different BMI and ACS diagnostic groups, correlations with clinical and biochemical parameters suggest a multifaceted role of FGF21 in cardiovascular health. Further research with a larger sample size is warranted to elucidate these relationships. Full article

Recent studies reported that circulating microRNAs (miRNAs) can target different metalloproteases (MMPs) involved in matrix remodeling and plaque vulnerability. Consequently, they might have a role in the diagnosis and prognosis of coronary artery disease. To quantify circulating miRNAs (miRNA126, miRNA146, and miRNA21) suggested to have possible cardiovascular implications, as well as levels of MMP-1 and MMP-9, and to determine their association with left ventricular (LV) function and with arterial function, in patients with either ST-segment elevation acute myocardial infarction (STEMI) or stable ischemic heart disease (SIHD). A total of 90 patients with coronary artery disease (61% men, 58 ± 12 years), including 60 patients with STEMI and 30 patients with SIHD, were assessed within 24 h of admission, by measuring serum microRNAs, and serum MMP-1 and MMP-9. LV function was assessed by measuring ejection fraction (EF) by 2D and 3D echocardiography, and global longitudinal strain (GLS) by speckle tracking. Arterial function was assessed by echo tracking, CAVI, and peripheral Doppler. Circulating levels of miRNA146, miRNA21, and MMP1 were significantly increased in patients with STEMI vs. SIHD (p = 0.0001, p = 0.0001, p = 0.04, respectively). MiRNA126 negatively correlated with LVEF (r = −0.33, p = 0.01) and LV deformation parameters (r = −0.31, p = 0.03) in patients with STEMI and negatively correlated with ABI parameters (r = −0.39, p = 0.03, r = −0.40, p = 0.03, respectively) in patients with SIHD. MiRNA146 did not have any significant correlations, while higher values of miRNA21 were associated with lower values of GLS in STEMI patients and with higher values of GLS in SIHD patients. Both MMP1 and MMP9 correlated negatively with LVEF (r = −0.27, p = 0.04, r = −0.40, p = 0.001, respectively) and GLS in patients with STEMI, and positively with arterial stiffness in patients with SIHD (r = 0.40 and r = 0.32, respectively; both p < 0.05). MiRNA126, miRNA21, and both MMP1 and MMP9 are associated with LV and arterial function parameters in patients with acute coronary syndrome. Meanwhile, they inversely correlate with arterial function in patients with chronic atherosclerotic disease. However, further studies are needed to establish whether these novel biomarkers have diagnosis and prognosis significance. Full article

Adeno-associated virus (AAV) is characterized by non-pathogenicity, long-term infection, and broad tropism and is actively developed as a vector virus for gene therapy products. AAV is classified into more than 100 serotypes based on differences in the amino acid sequence of the capsid protein. Endocytosis involves the uptake of viral particles by AAV and accessory receptors during AAV infection. After entry into the cell, they are transported to the nucleus through the nuclear pore complex. AAVs mainly use proteoglycans as receptors to enter cells, but the types of sugar chains in proteoglycans that have binding ability are different. Therefore, it is necessary to properly evaluate the primary structure of receptor proteins, such as amino acid sequences and post-translational modifications, including glycosylation, and the higher-order structure of proteins, such as the folding of the entire capsid structure and the three-dimensional (3D) structure of functional domains, to ensure the efficacy and safety of biopharmaceuticals. To further enhance safety, it is necessary to further improve the efficiency of gene transfer into target cells, reduce the amount of vector administered, and prevent infection of non-target cells. Full article

Copper (Cu) is a precious metal and one of the three most abundant trace elements in the body (50–120 mg). It is involved in a large number of cellular mechanisms and pathways and is an essential cofactor in the function of cellular enzymes. Both its excess and deficiency may be harmful for many diseases. Even small changes in Cu concentration may be associated with significant toxicity. Consequently, it can be damaging to any organ or tissue in our body, beginning with harmful effects already at the molecular level and then affecting the degradation of individual tissues/organs and the slow development of many diseases, such as those of the immunological system, skeletal system, circulatory system, nervous system, digestive system, respiratory system, reproductive system, and skin. The main purpose of this article is to review the literature with regard to both the healthiness and toxicity of copper to the human body. A secondary objective is to show its widespread use and sources, including in food and common materials in contact with humans. Its biological half-life from diet is estimated to range from 13 to 33 days. The retention or bioavailability of copper from the diet is influenced by several factors, such as age, amount and form of copper in the diet, lifestyle, and genetic background. The upper limit of normal in serum in healthy adults is approximately 1.5 mg Cu/L, while the safe upper limit of average intake is set at 10–12 mg/day, the reference limit at 0.9 mg/day, and the minimum limit at 0.6–0.7 mg/day. Cu is essential, and in the optimal dose, it provides antioxidant defense, while its deficiency reduces the body’s ability to cope with oxidative stress. The development of civilization and the constant, widespread use of Cu in all electrical devices will not be stopped, but the health of people directly related to its extraction, production, or distribution can be controlled, and the inhabitants of nearby towns can be protected. It is extremely difficult to assess the effects of copper on the human body because of its ubiquity and the increasing reports in the literature about its effects, including copper nanoparticles. Full article

Rett syndrome (RTT) is a paediatric neurodevelopmental disorder spanning four developmental stages. This multi-system disorder offers a unique window to explore genotype–phenotype relationships in a disease model. However, genetic prognosticators of RTT have limited clinical value due to the disorder’s heterogeneity on multiple levels. This case report used a precision medicine approach to better understand the clinical phenotype of RTT twins with an identical pathogenic MECP2 mutation and discordant neurodevelopmental profiles. Targeted genotyping, objective physiological monitoring of heart rate variability (HRV) parameters, and clinical severity were assessed in a RTT twin pair (5 years 7 months old) with an identical pathogenic MECP2 mutation. Longitudinal assessment of autonomic HRV parameters was conducted using the Empatica E4 wristband device, and clinical severity was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI) and the Multi-System Profile of Symptoms Scale (MPSS). Genotype data revealed impaired BDNF function for twin A when compared to twin B. Twin A also had poorer autonomic health than twin B, as indicated by lower autonomic metrics (autonomic inflexibility). Hospitalisation, RTT-CGI-S, and MPSS subscale scores were used as measures of clinical severity, and these were worse in twin A. Treatment using buspirone shifted twin A from an inflexible to a flexible autonomic profile. This was mirrored in the MPSS scores, which showed a reduction in autonomic and cardiac symptoms following buspirone treatment. Our findings showed that a combination of a co-occurring rs6265 BDNF polymorphism, and worse autonomic and clinical profiles led to a poorer prognosis for twin A compared to twin B. Buspirone was able to shift a rigid autonomic profile to a more flexible one for twin A and thereby prevent cardiac and autonomic symptoms from worsening. The clinical profile for twin A represents a departure from the disorder trajectory typically observed in RTT and underscores the importance of wider genotype profiling and longitudinal objective physiological monitoring alongside measures of clinical symptoms and severity when assessing genotype–phenotype relationships in RTT patients with identical pathogenic mutations. A precision medicine approach that assesses genetic and physiological risk factors can be extended to other neurodevelopmental disorders to monitor risk when genotype–phenotype relationships are not so obvious. Full article

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs’ cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients. Full article

Adipose-derived stem cells (ADSCs) comprise a promising therapy for osteoarthritis (OA). The therapeutic potential of ELIXCYTE^®, an allogeneic human ADSC (hADSC) product, was demonstrated in a phase I/II OA clinical trial. However, the exact mechanism underlying such effects is not clear. Moreover, studies suggest that interleukin-11 (IL-11) has anti-inflammatory, tissue-regenerative, and immune-regulatory functions. Our aim was to unravel the mechanism associated with the therapeutic effects of ELIXCYTE^® on OA and its relationship with IL-11. We cocultured ELIXCYTE^® with normal human articular chondrocytes (NHACs) in synovial fluid obtained from individuals with OA (OA-SF) to investigate its effect on chondrocyte matrix synthesis and degradation and inflammation by assessing gene expression and cytokine levels. NHACs exposed to OA-SF exhibited increased MMP13 expression. However, coculturing ELIXCYTE^® with chondrocytes in OA-SF reduced MMP13 expression in chondrocytes and downregulated PTGS2 and FGF2 expression in ELIXCYTE^®. ELIXCYTE^® treatment elevated anti-inflammatory cytokine (IL-1RA, IL-10, and IL-13) levels, and the reduction in MMP13 was positively correlated with IL-11 concentrations in OA-SF. These findings indicate that IL-11 in OA-SF might serve as a predictive biomarker for the ELIXCYTE^® treatment response in OA, emphasizing the therapeutic potential of ELIXCYTE^® to mitigate OA progression and provide insights into its immunomodulatory effects. Full article

Anesthetics are essential agents that are frequently used in clinical practice to induce a reversible loss of consciousness and sensation by depressing the central nervous system. The inhalational anesthetics isoflurane and sevoflurane are preferred due to their rapid induction and recovery times and ease of administration. Despite their widespread use, the exact molecular mechanisms by which these anesthetics induce anesthesia are not yet fully understood. In this study, the age-dependent effects of inhalational anesthetics on two demyelination models were investigated: congenital (B4galnt1-null) and chemically induced (cuprizone). Various motor and cognitive tests were used to determine sensitivity to isoflurane and sevoflurane anesthesia. B4galnt1-null mice, which exhibit severe motor deficits due to defects in ganglioside synthesis, showed significant impairments in motor coordination and balance in all motor tests, which were exacerbated by both anesthetics. Cuprizone-treated mice, which mimic the demyelination in B4galnt1-null mice, also showed altered, age-dependent sensitivity to anesthesia. The study showed that older mice exhibited more pronounced deficits, with B4galnt1-null mice showing the greatest susceptibility to sevoflurane. These differential responses to anesthetics suggest that age and underlying myelin pathology significantly influence anesthetic effects. Full article