International Journal of Molecular Sciences

Abstract

In amnestic mild cognitive impairment (aMCI), neuroinflammation evolves during disease progression, affecting microglial function and potentially accelerating the pathological process. Currently, no effective treatment exists, leading to explorations of various symptomatic approaches, though few target the underlying physiological mechanisms. Modulating inflammatory processes may [...] Read more.

In amnestic mild cognitive impairment (aMCI), neuroinflammation evolves during disease progression, affecting microglial function and potentially accelerating the pathological process. Currently, no effective treatment exists, leading to explorations of various symptomatic approaches, though few target the underlying physiological mechanisms. Modulating inflammatory processes may be critical in slowing disease progression. Cognitive stimulation (CS) and transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (l-DLPFC) show promise, but the results are heterogeneous. Thus, a randomized, double-blind, placebo-controlled clinical trial is currently underway. The first-stage results were examined after three weeks of intervention in two groups: active tDCS combined with CS and sham tDCS combined with CS. Twenty-two participants underwent two assessments: T0 (baseline) and T1 (after 15 sessions of tDCS, active or sham, and 9 sessions of CS). The results demonstrated that CS improved cognition, increased brain-derived neurotrophic factor (BDNF) levels, and reduced peripheral proinflammatory cytokine levels (interleukin IL-6 and chemokine CX3CL1) in serum. This decrease in IL-6 may promote microglial proliferation and survival as a modulatory effect response, while the increase in BDNF might suggest a regulatory mechanism in microglia–neuron interaction responses. However, tDCS did not enhance the cognitive or modulatory effects of CS, suggesting that longer interventions might be required to achieve substantial benefits. Full article

Abstract

Polybrominated biphenyls (PBBs) are commonly used flame retardants that pose severe risks to humans. However, there is a lack of systematic research on the transformation process and biological toxicities of PBBs in the environment, which is not conducive to the prevention and control [...] Read more.

Polybrominated biphenyls (PBBs) are commonly used flame retardants that pose severe risks to humans. However, there is a lack of systematic research on the transformation process and biological toxicities of PBBs in the environment, which is not conducive to the prevention and control of pollution risks of PBBs. Therefore, the transformation pathways (i.e., photodegradation, microbial degradation, combustion oxidation, and in vivo metabolism) of PBBs and previously designed PBB substitutes were deduced first. Then the potential rodent carcinogenicity, rodent toxicity, mutagenicity, developmental toxicity, skin and eye irritation, skin sensitization, and aquatic toxicity of the transformation products were evaluated using the toxicokinetics (TOPKAT) model. Finally, 3D quantitative structure activity relationship (3D-QSAR) models were constructed to assess the human toxicity (i.e., carcinogenicity, developmental toxicity, hepatotoxicity, epigenetic toxicity, neurotoxicity, and immunotoxicity) of PBBs, PBBs substitutes, and their transformation products. Results showed that the transformation products of PBBs and their substitutes exhibit high toxicity risks (i.e., potential carcinogenicity, mutagenicity, and developmental toxicity) to organisms. The D3-A1 molecule had the highest carcinogenic risk probability at 0.826. The dihydroxy metabolite 2,2′-OH-PBB-80 of the PBB-80 molecule presented the highest potential developmental toxicity risk (toxicity probability 0.713). Polybrominated dibenzofuran (PBDF) showed the strongest skin irritation (probability 0.995). The combustion oxidation products of PBBs exhibited higher potential ecological and human health risks than other transformation products. Among potential toxicity risks to humans, the developmental toxicity of the transformation products of PBBs and their substitutes was theoretically significant, with characterization values ranging from 70.53 to 100.87. This is the first study to comprehensively evaluate the ecological and human health risks of PBBs and their transformation products by combining the inference of transformation pathways with the prediction of transformation product toxicities, providing theoretical support for the design of environmentally friendly PBB substitutes in future studies. Full article

Abstract

Hypoxia-inducible factors (HIFs) are master regulators of cellular responses to low oxygen levels and modulate autophagy, a conserved process essential for maintaining homeostasis. Under hypoxic conditions, HIFs regulate the expression of autophagy-related genes and influence autophagic flux and cellular stress responses. Dysregulated hypoxia-induced [...] Read more.

Hypoxia-inducible factors (HIFs) are master regulators of cellular responses to low oxygen levels and modulate autophagy, a conserved process essential for maintaining homeostasis. Under hypoxic conditions, HIFs regulate the expression of autophagy-related genes and influence autophagic flux and cellular stress responses. Dysregulated hypoxia-induced autophagy promotes cancer cell survival, metabolism, and metastasis, thereby contributing to treatment resistance. Targeting HIF-mediated pathways or modulating autophagic processes offers the potential to improve traditional cancer therapies and overcome drug resistance. Pharmacological inhibitors of HIFs or autophagy, either alone or in combination with other treatments, may disrupt the pro-survival mechanisms within the hypoxic tumor microenvironment. Further research is needed to elucidate the intricate interplay between HIF signaling and the autophagy machinery in cancer cells. Understanding these processes could pave the way for novel therapeutic strategies to enhance treatment outcomes and combat drug resistance. This review highlights the complex relationship between HIFs and autophagy in cancer development and therapy, offering insights into how targeting these pathways may improve patient outcomes. Full article

Abstract

Post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as “Long COVID”, represents a significant clinical challenge characterized by persistent symptoms following acute COVID-19 infection. We conducted a comprehensive retrospective cohort study to identify serum autoantibody biomarkers associated with PASC. Initial screening using a [...] Read more.

Post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as “Long COVID”, represents a significant clinical challenge characterized by persistent symptoms following acute COVID-19 infection. We conducted a comprehensive retrospective cohort study to identify serum autoantibody biomarkers associated with PASC. Initial screening using a protein bead array comprising approximately 20,000 human proteins identified several candidate PASC-associated autoantibodies. Subsequent validation by enzyme-linked immunosorbent assay (ELISA) in an expanded cohort—consisting of PASC patients, non-PASC COVID-19 convalescents, and pre-pandemic healthy controls—revealed two promising biomarkers: autoantibodies targeting PITX2 and FBXO2. PITX2 autoantibodies demonstrated high accuracy in distinguishing PASC patients from both non-PASC convalescents (area under the curve [AUC] = 0.891) and healthy controls (AUC = 0.866), while FBXO2 autoantibodies showed moderate accuracy (AUC = 0.762 and 0.786, respectively). Notably, the levels of these autoantibodies were associated with several PASC symptoms, including fever, dyspnea, palpitations, loss of appetite, and brain fog. The identification of PITX2 and FBXO2 autoantibodies as biomarkers not only enhances our understanding of PASC pathophysiology but also provides promising candidates for further investigation. Full article

Abstract

Nonribosomal peptide synthetases (NRPS) are essential for the biosynthesis of therapeutically valuable molecules, including antibiotics, immunosuppressants, and anticancer agents. The assembly-line mechanism of NRPS offers significant potential for engineering novel natural products through reprogramming. However, the challenging purification of NRPS proteins has impeded [...] Read more.

Nonribosomal peptide synthetases (NRPS) are essential for the biosynthesis of therapeutically valuable molecules, including antibiotics, immunosuppressants, and anticancer agents. The assembly-line mechanism of NRPS offers significant potential for engineering novel natural products through reprogramming. However, the challenging purification of NRPS proteins has impeded the investigation of their assembly and catalytic mechanisms. In this study, we employed homologous recombination to insert a purification tag at the C-terminus of the NRPS gene within the chromosome. This genetic modification enabled efficient purification of NRPS proteins from the tagged mutant strain using a one-step affinity chromatography approach. Additionally, we discovered that MbtH-like proteins (MLPs) form stable complexes with all pyoverdine (PVD) NRPS subunits, allowing for the purification of the entire NRPS assembly line via tagged MLP. Negative stain electron microscopy analysis revealed that the purified PVD NRPS proteins exist as dynamically linear monomers. Our in-situ tag-based purification method enhances NRPS research in both biochemical and structural biology, providing a robust platform for further investigations into NRPS mechanisms and applications. Full article

Abstract

The articles featured in this Special Issue of the International Journal of Molecular Sciences, entitled “Recent Advances in Gluten-Related Disorders”, present significant advancements in the understanding of gluten hypersensitivity, offering valuable insights into mechanisms, diagnostics, and potential therapeutic strategies [...] Full article

Abstract

Benzo(a)pyrene (B(a)P) and pyrene, the most prominent subtypes of polycyclic aromatic hydrocarbons (PAHs), contaminate environments as organic pollutants. They adversely affect body systems, including degeneration of the central nervous system. This study investigated the in vitro toxic effects of B(a)P and pyrene on [...] Read more.

Benzo(a)pyrene (B(a)P) and pyrene, the most prominent subtypes of polycyclic aromatic hydrocarbons (PAHs), contaminate environments as organic pollutants. They adversely affect body systems, including degeneration of the central nervous system. This study investigated the in vitro toxic effects of B(a)P and pyrene on proliferation, endoplasmic reticulum (ER) stress induction, and autophagy in human astrocytes using U-87 MG human astrocytoma cells as a model. Both B(a)P and pyrene were toxic to U-87 MG cells in a concentration-dependent manner. Astrocytic proliferation was interfered with, enhancing S-phase cell cycle arrest. B(a)P promoted the presence of autophagic vesicles and the expression of autophagic markers LC3, beclin-1, and p62, suggesting activated autophagy. B(a)P enhanced the expression of ER stress markers BiP, PERK, and IRE1. ER stress appeared to be correlated with autophagy induction, as demonstrated by experiments using chloroquine, an autophagy inhibitor. Pyrene enhanced the expression of autophagic markers and ER stress primarily via PERK activation, although autophagic vesicles were not observed. The study demonstrates that B(a)P enhances ER stress-mediated autophagy more evidently than pyrene and affected toxicity to astrocytes. These results provide a basis for understanding the toxic effects of the main PAH substances affecting astrocytes. Full article

Abstract

Morphological changes in erythrocytes during disease, aging, or reactions to external agents are significant as they can influence disease progression. However, the exact mechanisms behind these temporary alterations and their potential to cause dysfunction remain unclear. Using a saponin-induced erythrocyte shape transition (EST) [...] Read more.

Morphological changes in erythrocytes during disease, aging, or reactions to external agents are significant as they can influence disease progression. However, the exact mechanisms behind these temporary alterations and their potential to cause dysfunction remain unclear. Using a saponin-induced erythrocyte shape transition (EST) model, we studied the gradual shift of erythrocytes towards echino-stomato-spherocytic forms and its link to hemolysis and thrombosis. We observed that different saponin concentrations elicited varying shape transformations. At low concentrations, erythrocytes transition from discocytic shapes to echinocytic, echino-stomatocytic, and ultimately stomatocytic forms. As the concentration moderately increases, the morphology evolves into stomato-spherocytic forms. At higher saponin concentrations, the erythrocytes completely transform into spherocytic forms. Regardless of the transformation degree, all forms showed increased phosphatidylserine exposure (PS) and microvesicle (MV) production, primarily due to increased scramblase and decreased flippase activity, which were influenced by elevated calcium levels and caspase 3 activity, effectively managing PS distribution and influencing cell membrane expansion and invagination. These alterations increased thrombin production, erythrocyte adhesion, and aggregation, promoting thrombosis in rats. Altogether, our findings indicate that the shift towards echino-stomato-spherocytic forms fosters a hypercoagulable state through PS externalization, heightening thrombotic risk. Full article

Abstract

Polyploidy, characterized by an increase in the number of whole sets of chromosomes in an organism, offers a promising avenue for cannabis improvement. Polyploid cannabis plants often exhibit altered morphological, physiological, and biochemical characteristics with a number of potential benefits compared to their [...] Read more.

Polyploidy, characterized by an increase in the number of whole sets of chromosomes in an organism, offers a promising avenue for cannabis improvement. Polyploid cannabis plants often exhibit altered morphological, physiological, and biochemical characteristics with a number of potential benefits compared to their diploid counterparts. The optimization of polyploidy induction, such as the level of antimitotic agents and exposure duration, is essential for successful polyploidization to maximize survival and tetraploid rates while minimizing the number of chimeric mixoploids. In this study, three classification-based machine learning algorithms—probabilistic neural network (PNN), support vector classification (SVC), and k-nearest neighbors (KNNs)—were used to model ploidy levels based on oryzalin concentration and exposure time. The results indicated that PNN outperformed both KNNs and SVC. Subsequently, PNN was combined with a genetic algorithm (GA) to optimize oryzalin concentration and exposure time to maximize tetraploid induction rates. The PNN-GA results predicted that the optimal conditions were a concentration of 32.98 µM of oryzalin for 17.92 h. A validation study testing these conditions confirmed the accuracy of the PNN-GA model, resulting in 93.75% tetraploid induction, with the remaining 6.25% identified as mixoploids. Additionally, the evaluation of morphological traits showed that tetraploid plants were more vigorous and had larger leaf sizes compared to diploid or mixoploid plants in vitro. Full article

Abstract

The prolonged use of pyrethroid insecticides for controlling the plant bug Lygus pratensis has led to upward resistance. This study aims to elucidate the molecular mechanisms and potential regulatory pathways associated with lambda-cyhalothrin resistance in L. pratensis. In this study, we constructed [...] Read more.

The prolonged use of pyrethroid insecticides for controlling the plant bug Lygus pratensis has led to upward resistance. This study aims to elucidate the molecular mechanisms and potential regulatory pathways associated with lambda-cyhalothrin resistance in L. pratensis. In this study, we constructed a regulatory network by integrating transcriptome RNA-Seq and proteome iTRAQ sequencing analyses of one lambda-cyhalothrin-susceptible strain and two resistant strains, annotating key gene families associated with detoxification, identifying differentially expressed genes and proteins, screening for transcription factors involved in the regulation of detoxification metabolism, and examining the metabolic pathways involved in resistance. A total of 82,919 unigenes were generated following the assembly of transcriptome data. Of these, 24,859 unigenes received functional annotations, while 1064 differential proteins were functionally annotated, and 1499 transcription factors belonging to 64 distinct transcription factor families were identified. Notably, 66 transcription factors associated with the regulation of detoxification metabolism were classified within the zf-C2H2, Homeobox, THAP, MYB, bHLH, HTH, HMG, and bZIP families. Co-analysis revealed that the CYP6A13 gene was significantly up-regulated at both transcriptional and translational levels. The GO and KEGG enrichment analyses revealed that the co-up-regulated DEGs and DEPs were significantly enriched in pathways related to sphingolipid metabolism, Terpenoid backbone biosynthesis, ABC transporters, RNA transport, and peroxisome function, as well as other signaling pathways involved in detoxification metabolism. Conversely, the co-down-regulated DEGs and DEPs were primarily enriched in pathways associated with Oxidative phosphorylation, Fatty acid biosynthesis, Neuroactive ligand–receptor interactions, and other pathways pertinent to growth and development. The results revealed a series of physiological and biochemical adaptations exhibited by L. pratensis during the detoxification metabolism related to lambda-cyhalothrin resistance. This work provided a theoretical basis for further analysis of the molecular regulation mechanism underlying this resistance. Full article

Abstract

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence [...] Read more.

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1–3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003–2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77–100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a “founder mutation” in Russia. Full article

Abstract

Cardiovascular disease remains a leading cause of global mortality, with many unresolved issues in current clinical treatment strategies despite years of extensive research. Due to the great progress in nanotechnology and gene therapy in recent years, the emerging gene therapy based on nanocarriers [...] Read more.

Cardiovascular disease remains a leading cause of global mortality, with many unresolved issues in current clinical treatment strategies despite years of extensive research. Due to the great progress in nanotechnology and gene therapy in recent years, the emerging gene therapy based on nanocarriers has provided a promising therapeutic alternative for cardiovascular diseases. This review outlines the status of nanocarriers as vectors in gene therapy for cardiovascular diseases, including coronary heart disease, pulmonary hypertension, hypertension, and valvular heart disease. It discusses challenges and future prospects, aiming to support emerging clinical treatments. This review is the first to summarize gene therapy using nanocarriers for valvular heart disease, highlighting their potential in targeting challenging tissues. Full article

Abstract

Epilepsy stands out as one of the most prevalent chronic neurological conditions affecting companion animals. Recent research has increasingly focused on exploring the role of gut microbiota in influencing neurological conditions, like epilepsy. This influence stems from the bidirectional communication pathways between gut [...] Read more.

Epilepsy stands out as one of the most prevalent chronic neurological conditions affecting companion animals. Recent research has increasingly focused on exploring the role of gut microbiota in influencing neurological conditions, like epilepsy. This influence stems from the bidirectional communication pathways between gut bacteria and the brain, which involve metabolic, neural, immunological, and endocrine mechanisms. In fact, a balanced and stable gut microbiota is essential to maintaining normal gut physiology and ensuring appropriate signaling along the gut–brain axis. Conversely, dysbiosis can have detrimental effects on gut physiology and may contribute to the development or exacerbation of neurological conditions, including epilepsy. Considering these findings, this review article aims to deepen the understanding of the mechanisms underlying the microbiota–gut–brain connection in the context of canine idiopathic epilepsy. Moreover, this review presents recent data on innovative gut-related therapeutic strategies for canine idiopathic epilepsy treatment. Full article

Abstract

Exercise plays a crucial role in maintaining metabolic health, enhancing muscle function, and improving insulin sensitivity, thereby preventing metabolic diseases such as type 2 diabetes. Emerging evidence highlights the significance of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H₂S) signaling pathway as a [...] Read more.

Exercise plays a crucial role in maintaining metabolic health, enhancing muscle function, and improving insulin sensitivity, thereby preventing metabolic diseases such as type 2 diabetes. Emerging evidence highlights the significance of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H₂S) signaling pathway as a pivotal regulator in the molecular and physiological adaptations induced by exercise. This review comprehensively examines the biosynthesis and metabolism of H₂S, its distribution in different muscle tissues, and the mechanisms by which CSE/H₂S influences muscle contraction, repair, and protein synthesis. Additionally, it explores how CSE/H₂S modulates insulin signaling pathways, glucose uptake, and lipid metabolism, thereby enhancing insulin sensitivity. The potential of H₂S donors as exercise supplements is also discussed, highlighting their ability to improve exercise performance and metabolic health. Current research advancements, including the application of multi-omics approaches, are reviewed to provide a deeper understanding of the complex molecular networks involved. Furthermore, the challenges and future directions in CSE/H₂S research are addressed, emphasizing the need for further mechanistic studies and clinical applications. This review underscores the therapeutic potential of targeting the CSE/H₂S pathway to optimize the benefits of exercise and improve metabolic health. Full article

Abstract

Kidney function parameters including estimated glomerular filtration rate (eGFR) and urine albumin excretion are commonly used to diagnose chronic kidney disease (CKD). However, these parameters are relatively insensitive, limiting their utility for screening and early detection of kidney disease. Studies have suggested that [...] Read more.

Kidney function parameters including estimated glomerular filtration rate (eGFR) and urine albumin excretion are commonly used to diagnose chronic kidney disease (CKD). However, these parameters are relatively insensitive, limiting their utility for screening and early detection of kidney disease. Studies have suggested that urinary proteomic profiles differ by eGFR stage, offering potential insights into kidney disease pathogenesis alongside opportunities to increase the sensitivity of current testing strategies. In this study, we characterized and compared the urinary proteome across different eGFR stages in a Black African cohort from rural Mpumalanga Province, South Africa. We stratified 81 urine samples by eGFR stage (mL/min/1.73 m²): Stage G1 (eGFR ≥ 90; n = 36), Stage G2 (eGFR 60–89; n = 35), and Stage G3–G5 (eGFR < 60; n = 10). Urine proteomic analysis was performed using an Evosep One liquid chromatography system coupled to a Sciex 5600 TripleTOF in data-independent acquisition mode. Nonparametric multivariate analysis and receiver operating characteristic (ROC) curves were used to assess the performance of differentially abundant proteins (DAPs). Pathway analysis was performed on DAPs. Creatinine-based eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. In this study, thirty-eight urinary proteins were differentially abundant for eGFR Stages 3–5 when compared to Stages G1 (AUC = 0.95; CI: 0.86–1) and G2 (AUC = 0.84; CI: 0.64–0.98). Notably, only six urinary proteins (Cystatin M (CST6), glutathione hydrolase 6 (GGT6), sushi domain containing 2 (SUSD2), insulin-like growth factor binding protein 6 (IGFBP6), heat shock protein 90 beta family member 1 (HSP90B1), and mannosidase alpha class 1A member 1 (MAN1A1)) were differentially abundant when comparing Stage G1 and Stage G2 with a modest AUC = 0.81 (CI: 0.67–0.92). Pathway analysis indicated that DAPs were associated with haemostasis and fibrin clot formation. In a rural cohort from South Africa, the urinary proteome differed by eGFR stage, and we identified six differentially abundant proteins which, in combination, could help to differentiate earlier eGFR stages with higher predictive accuracy than the currently available tests. Full article

Abstract

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, [...] Read more.

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of MGRN1 and the melanocyte-specific genes MLANA, PMEL, and TYRP1 provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of MGRN1-knockout cells confirmed these molecular features. Therefore, the simple MGRN1-MLANA-PMEL-TYRP1 combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome. Full article

Abstract

Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was [...] Read more.

Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures. Full article

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, with women being disproportionately affected in both prevalence and severity. A key feature of AD is synaptic loss, particularly around amyloid-β (Aβ) aggregates, which correlates strongly with the severity [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, with women being disproportionately affected in both prevalence and severity. A key feature of AD is synaptic loss, particularly around amyloid-β (Aβ) aggregates, which correlates strongly with the severity of dementia. Oligomeric Aβ is believed to be the primary driver of synaptic dysfunction by impairing excitatory neurotransmission through interactions with synaptic receptors, including N-methyl-D-aspartate (NMDA) receptors. However, the influence of sex on these synaptic changes and NMDA receptor mislocalization in AD is not well understood. This study examined potential sex-specific differences in synaptotoxicity and the role of extrasynaptic GluN2B-containing NMDA receptors in AD pathogenesis using the APP/PS1 double transgenic mouse model. Although both male and female mice showed a similar amyloid burden and cognitive impairments, synaptic alterations were slightly less severe in females, suggesting subtle sex differences in synaptic pathology. Both sexes exhibited the mislocalization of GluN2B subunits to extrasynaptic areas, which was linked to reduced PSD-95 levels and the synaptic accumulation of Aβ_1–42. Intrahippocampal injections of DL-TBOA confirmed the role of extrasynaptic GluN2B-containing NMDA receptors in memory dysfunction. These findings emphasize the importance of targeting synaptic receptor trafficking to address AD-related memory deficits, potentially offering a therapeutic approach for both sexes. Full article

Abstract

Ankrd2, a mechanoresponsive protein primarily studied in muscle physiology, is emerging as a player in cancer progression. This study investigates the functional role of Ankrd2 in osteosarcoma cells, revealing its critical involvement in cell proliferation and response to chemotherapeutic drugs. We showed that [...] Read more.

Ankrd2, a mechanoresponsive protein primarily studied in muscle physiology, is emerging as a player in cancer progression. This study investigates the functional role of Ankrd2 in osteosarcoma cells, revealing its critical involvement in cell proliferation and response to chemotherapeutic drugs. We showed that Ankrd2 knockdown impairs the activation of PI3K/Akt and ERK1/2 pathways, reduces levels of cell cycle regulators including cyclin D1 and cyclin B, and counteracts the expression of nuclear lamin A and lamin B, disrupting nuclear morphology and DNA integrity. Strikingly, the loss of Ankrd2 enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin, highlighting Ankrd2 potential as a therapeutic target to improve chemotherapeutic efficacy. Defining a novel mechanistic role for Ankrd2 in promoting tumor progression, we propose that Ankrd2 reduction could be exploited as an adjuvant strategy to enhance the efficacy of chemotherapy, offering new therapeutic opportunities for OS treatment. Full article