Myotonic dystrophy type 1 (DM1) is a rare and complex genetic disorder characterized by the expansion of CTG repeats within the 3' untranslated region of the dystrophia myotonic protein kinase (DMPK) gene. With a prevalence of approximately 10 per 100,000 people worldwide, DM1 presents with severe neuromuscular symptoms, including early-onset ataxia, dysarthria, muscle weakness, and exercise intolerance. The multisystemic nature of DM1 underscores the importance of exploring its molecular underpinnings to develop targeted therapeutic strategies.

In this study, I investigated the role of long non-coding RNAs (lncRNAs) in DM1 pathophysiology. Once dismissed as "genomic junk," lncRNAs are now recognized as pivotal regulators of gene expression and alternative splicing, making them key candidates for understanding the mechanisms underlying DM1. My research identified NUTM2A-AS1 as a critical lncRNA influencing splicing patterns in DM1-affected brains. Notably, NUTM2A-AS1 exhibited non-coding repeat expansions, implicating it in DM1's development and progression. Other lncRNAs were also found to be prevalent in splicing mechanisms in DM1.

Further, I identified additional lncRNAs, such as those associated with KHDRBS3 and HDAC2, that significantly impact alternative splicing. These findings provide unique insights into the regulatory networks involved in DM1. My analysis of differential gene expression highlighted several lncRNAs and their corresponding genes or proteins, including MAP6, FOSL2, and HLA-DQB1, all of which contribute to the disorder's multifaceted pathology.

These discoveries advance our understanding of the molecular mechanisms underlying DM1, emphasizing the intricate interplay of lncRNAs, genes, and proteins. This research lays the groundwork for future studies aimed at developing targeted therapies to address the diverse manifestations of this debilitating disorder.

Long COVID (L-C19) leads to significant consequences and affects the quality of life of patients and their families as well. Thus, the most common neurological symptoms are headache, brain fog, sleep disturbances, chronic fatigue, forgetfulness, and even more serious conditions, such as balance disorders, anxiety, and depression. Headache is the earliest and most common symptom of L-C19 and is sometimes accompanied by vomiting or nausea. Patients often report difficulties with concentration and learning and a reduced efficiency in daily activities. Even though this disorders may be caused by an acute illness, biochemical changes caused by SARS-CoV-2 in the nervous system can be an important factor. L-C19 also affects the peripheral nerves, leading to paraesthesia, muscle aches, and weakness throughout the body. The duration of these symptoms is often unknown, and the treatment is predominantly symptom-based and difficult to predict. Other dysfunctions may include dysautonomia, a condition affecting the autonomic nervous system, responsible for regulating automatic processes such as heart rate, blood pressure, and digestion. This disruption may lead to symptoms like dizziness and fatigue, is often accompanied by neuropsychiatric challenges, and can alter cerebral blood flow, contributing to light-headedness, trouble focusing, and emotional instability. Furthermore, the SARS-CoV-2 virus may disrupt mitochondrial function, an important component of cellular energy production. Mitochondrial dysfunction can manifest as fatigue, cognitive challenges, and mood disorders, given the brain's sensitivity to shifts in energy metabolism.
Acknowledgement: This work was supported by a grant of the Ministry of Research, Innovation and Digitization, under the Romania’s National Recovery and Resilience Plan Funded by the EU "Next Generation EU” program, project "Artificial intelligence-powered personalized health and genomics libraries for the analysis of long-term effects in COVID-19 patients (AI-PHGL-COVID)", number 760073/23.05.2023, code 285/30.11.2022, within Pillar III, Component C9, Investment 8.

Relevance. Previous studies have shown that transcutaneous vagus nerve stimulation (tVNS) can have a therapeutic effect similar to its invasive counterpart. However, an objective assessment of tVNS requires a reliable biomarker of successful vagus nerve activation.
The purpose of our study was to study the effect of short-term noninvasive stimulation of the auricular branch of the vagus nerve on heart-rate variability (HRV) parameters.
Methods. Patients were randomized into two groups according to the 1:1 scheme. Active tVNS was performed attached to the tragus of the left ear. Sham tVNS - was performed attached to the earlobe of the left ear. The stimulation frequency was 20 Hz with a pulse duration of 200 microseconds. The research algorithm included four five-minute time intervals for recording biological signals: (1) initially at rest, (2) during the first 5 minutes of stimulation, (3) during the next 5 minutes of stimulation, and (4) after the end of stimulation. HRV parameters evaluated in this study included the standard temporal and spectral characteristics of HRV. This clinical trial is registered with the ClinicalTrials database under a unique identifier: NCT05680337.
Results. A total of 111 patients were included in the study: 53- Active tVNS, 58- Sham tVNS. Initially, there were no differences in HRV parameters in the groups. After the start of stimulation, the parameters pNN50, NN50, RMSSD, VLF%, IC1, IC2, VLF%, HF%, and HF began to differ significantly in the groups. After the end of the stimulation, it was found that the RMSSD and HF% parameters became significantly lower in the Active tVNS group, and LF/HF became significantly higher than in the Sham tVNS group.
Conclusions. After the start of tVNS, there is a decrease in the levels of HRV parameters, reflecting the activity of the parasympathetic nervous system in the Active tVNS group. At the same time, there are no statistically significant dynamics in the Sham tVNS group.

Introduction: Rheumatoid arthritis (RA) is a chronic and complex inflammatory disorder characterized by inflammation of the synovial membrane (synovitis), leading to cartilage and bone damage of articular joints. Given the adverse effects and different and non-affective responses of patients to synthetic disease-modifying anti-rheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), it is of interest to use medicinal plants exhibiting encouraging therapeutic results and fewer side effects. Objective: This study aimed to investigate the anti-arthritic effect of Inula viscosa (I. viscosa) on the progression of arthritis in an NMRI mouse model. Methods: Mice were divided into six groups (n=6) as follows: normal control, disease control, Diclofenac group (10 mg/kg, p.o. daily), and three groups who were treated daily with 50, 100, and 200 mg/kg IVME (p.o.). Formaldehyde models were obtained by means of sub-plantar administration of 20 µL of formaldehyde (3.75% v/v) into the right hind paws of NMRI albino mice on the first and third of the ten experimental days. Joint diameters were measured; arthritis severity was evaluated by means of inhibition of the paw oedema; histological changes, synovial hyperplasia, and immune cell infiltration were evaluated using histological and immunohistochemical analyses of CD3+, CD20+, and CD68+; and staining markers of ankle joint tissue sections were analyzed with the QuPath v0.5.1 software tool using adaptive thresholding to quantify the percentage staining of positive cells. Results: The administration of I. visocsa (at a low dose of 50 mg/kg) significantly (***p <0.001) ameliorated the induced arthritis severity, resulting in the restoration of the paw diameter, (*p <0.05), reduced hyperplasia of the synovial membrane, and bone erosion, and significantly (*p <0,1) decreased CD68+-staining immune cell infiltration. Conclusion: These findings suggest that I. viscosa leaves have an anti-arthritic property, which is due to the anti-inflammatory effect, probably through cytokine regulation.

Metabolic diseases, including diabetes, obesity, and insulin resistance, have emerged as significant global health challenges with profound implications for liver health. As a central organ in glucose and lipid metabolism, the liver is particularly vulnerable to disruptions caused by these diseases. Such disturbances often result in complications like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are major contributors to liver-related morbidity. This study develops a mathematical model to explore the progression of these conditions and evaluate the role of interferon therapy in controlling disease dynamics.

The analysis focuses on two key equilibrium states: the disease-free equilibrium (DFE), which represents the absence of disease, and the endemic equilibrium (EE), where the disease persists in the population. A critical component of the study is the basic reproduction number (R₀), which serves as a threshold indicator of whether the disease will spread or die out. By comparing scenarios with and without interferon therapy, the study demonstrates how the therapy significantly reduces R₀, shifting the system from an endemic state to a disease-free state under specific conditions.

The findings highlight the potential of interferon therapy to stabilize liver health and reduce the prevalence of liver-related complications associated with metabolic diseases. This research provides valuable insights into the conditions under which interferon therapy is most effective, offering practical guidance for optimizing treatment strategies and public health interventions. By addressing the underlying dynamics of these diseases, this study contributes to a deeper understanding of their progression and supports global efforts to alleviate their impact.

Neurodegenerative diseases (NDDs), including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, are progressive disorders characterized by neuronal dysfunction and structural instability. Central to their pathology are aberrations in extracellular matrix (ECM) remodeling and chronic neuroinflammation, processes regulated by the ADAMTS family of metalloproteinases. Dysregulated activity of specific ADAMTS isoforms, such as ADAMTS-4 and ADAMTS-5, contributes to pathological ECM degradation, triggering neuroinflammatory cascades, synaptic disruption, and neuronal loss. This article proposes a novel therapeutic approach: the development of partial agonists targeting ADAMTS enzymes. Unlike broad-spectrum inhibitors, which can suppress essential protease functions, partial agonists offer a balanced strategy by selectively modulating enzymatic activity. These agents aim to mitigate pathological ECM degradation while preserving physiological ECM dynamics, addressing both neuroinflammation and ECM imbalance.

The design of partial agonists leverages bioisosteric principles to create isoform-specific targeting agents with high therapeutic precision. Structural scaffolds inspired by protease–substrate interactions are central to this approach. Additionally, innovative drug delivery systems, including nanoparticle encapsulation and prodrug strategies, are explored to overcome the formidable challenge of crossing the blood–brain barrier and ensure sustained drug release in the central nervous system. Advanced delivery platforms enhance therapeutic efficacy while minimizing systemic side effects, which is a critical consideration for chronic neurodegenerative disease management and therapy and developing potential curative strategies.

This research highlights the potential of ADAMTS-targeting partial agonists to transform NDD therapeutics by restoring ECM integrity and reducing neuroinflammation. Through these mechanisms, partial agonists can enhance neuronal resilience, stabilize synaptic networks, and significantly improve clinical outcomes, offering new hope for individuals affected by debilitating neurodegenerative conditions.

Abstract

Alzheimer's, Parkinson's, and Huntington's are neurodegenerative diseases currently incurable but uniquely defined by the deposition of neurotoxic proteins. They are intrinsically disordered proteins with very high causality for neurodegeneration. Tremendous advances have been realized in molecular pathogenesis with a view toward establishing causative genes and proteins. However, two important elements related to neurotoxic conformation and neuronal vulnerability remain unidentified. The prevailing hypothesis has been that pathogenic cascades are initiated by the conformational changes in the monomeric forms, and hence, these could be good targets for therapy. Single-molecule techniques, especially single-molecule force spectroscopy, have advanced the nanomechanics and conformational polymorphism of neurotoxic proteins. It has been shown that such polymorphism at the level of monomers is very strongly correlated with amyloidogenesis and neurotoxicity. Such polymorphism is, importantly, entirely absent in fibrillization-incompetent mutants but is enhanced by familial-disease mutations. There is also the case of pharmacological agents that inhibit β-conformational changes in monomers, dramatically reducing their polymorphism and associated neurotoxicity, indicating common molecular mechanisms for these diseases.

Advances in the manipulation and analysis of single molecules have dramatically enhanced our understanding of neurotoxic protein dynamics. Despite such advances, major questions remain about specific neurotoxic conformations and their role in selective neuronal degeneration. The solution to these challenges is crucial for the development of novel diagnostic, preventive, and therapeutic strategies against these devastating disorders, which carry significant social and clinical impact.

This abstract encapsulates the emerging potential of single-molecule studies to pave the way for innovative solutions in managing amyloidogenic neurodegenerative diseases.

Title:

The Role of Insulin Resistance in Congestive Heart Failure, Impaired Glucose Tolerance, and Hypertension

Aim:
The aim of this study was to explore the role of insulin resistance and compensatory hyperinsulinemia in glucose intolerance, hypertension, and CVD across conditions such as congestive heart failure (CHF) and non-insulin-dependent diabetes mellitus (NIDDM).

Background:
Insulin resistance is a characteristic feature of congestive heart failure (CHF), non-insulin-dependent diabetes mellitus (NIDDM), and essential hypertension. Hyperinsulinemia, increased plasma norepinephrine, and disturbed glucose metabolism contribute to these conditions. Although compensatory hyperinsulinemia maintains glucose homeostasis, it may enhance cardiovascular risks by promoting endothelial dysfunction and dyslipidaemia.

Methodology:
The analysis synthesizes findings from the following:

1. A case–control study of congestive heart failure patients and controls, using oral glucose tolerance tests and euglycemic clamps.
2. Longitudinal studies of insulin-mediated glucose uptake and β-cell function in NIDDM and hypertension.
3. Population-based studies of fasting insulin, norepinephrine, and free fatty acids (FFA).

Results and Discussion:

CHF patients presented with increased levels of norepinephrine, insulin, and FFA. These resulted in impaired glucose clearance and hepatic glucose regulation via insulin. NIDDM required hyperinsulinemia to counteract insulin resistance and maintain glucose tolerance, ultimately failing as the function of the β-cells declined. Hypertension linked insulin resistance with dyslipidaemia and CVD, characterized by high triglycerides and low HDL cholesterol. Insulin resistance in CHF and hypertension further exacerbates metabolic derangement and increases CVD risk.

Conclusion:
The mechanisms of insulin resistance and compensatory hyperinsulinemia are central to the pathogenesis of glucose intolerance, hypertension, and CVD in CHF, NIDDM, and related disorders. Addressing these disturbances may help mitigate disease progression and improve cardiovascular outcomes.

Phytochemicals are increasingly studied for their potential to inhibit HMG-CoA reductase (HMGR) and alpha-amylase enzymes, which are key targets in managing hypercholesterolemia and diabetes. The inhibition of HMGR reduces cholesterol synthesis, while alpha-amylase inhibition helps control postprandial blood glucose levels. This study used computational techniques, including molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions, to evaluate the potential of five Ginkgo biloba biflavonoids—amentoflavone, bilobetin, ginkgetin, isoginkgetin, and sciadopitysin—as dual inhibitors of these enzymes. The molecular docking results demonstrated that amentoflavone (-10.1 kcal/mol) and bilobetin (-9.8 kcal/mol) exhibited stronger binding affinities to HMGR than the reference drug atorvastatin (-9.3 kcal/mol). Similarly, for α-amylase, amentoflavone (-11.5 kcal/mol), bilobetin (-11.3 kcal/mol), and ginkgetin (-11.1 kcal/mol) surpassed the binding affinity of the reference drug acarbose (-10.5 kcal/mol). These consistently strong binding affinities indicate that both amentoflavone and bilobetin have the potential to act as dual inhibitors of these two enzymes. Our ADMET analysis revealed that bilobetin demonstrated favorable drug-like properties, adhering to Lipinski’s rule of five, which predicts good oral bioavailability. Although bilobetin exhibited low gastrointestinal absorption, it was predicted to be non-mutagenic and non-hepatotoxic and demonstrated no significant toxicity risks, making it a highly promising candidate for further drug development. These important findings underscore the potential of Ginkgo biloba biflavonoids for addressing metabolic disorders. Future in vitro and in vivo studies are essential to validate these in silico results, providing deeper insights into their therapeutic applications and contributing to the development of novel dual-action drugs targeting hypercholesterolemia and diabetes.

The carob tree (Ceratonia siliqua L), a traditional Mediterranean plant, stands out as a promising natural solution in the fight against obesity and diabetes, two major public health issues worldwide. This plant is rich in dietary fiber, polyphenols, and various bioactive compounds that act synergistically to prevent and reduce the metabolic imbalances associated with these pathologies. Among its assets, carob promotes satiety, reduces fat absorption, and positively modulates intestinal microbiota, key mechanisms for improving weight management and blood-sugar regulation.
On the metabolic front, carob extracts help regulate blood sugar and insulin, thereby limiting the complications associated with obesity, such as type 2 diabetes and cardiovascular disease. The underlying biological mechanisms include the inhibition of the digestive enzymes responsible for the breakdown and absorption of carbohydrates and lipids, resulting in improved glycemic stability and a significant reduction in caloric intake. The dietary fibers contained in carob play an important satiety-enhancing role, reducing the sensation of hunger and promoting better food management.
In addition, the modulation of the intestinal microbiota by carob bioactive compounds improves carbohydrate and lipid metabolism, enhancing energy balance. Its powerful antioxidant properties reduce oxidative stress and chronic inflammation, two key factors in the pathophysiology of obesity and diabetes. Carob also acts on fat metabolism by stimulating lipolysis (the breakdown of stored fat) and inhibiting lipogenesis (the formation of new fat).
These multiple properties position the carob tree as an essential resource for the development of natural and sustainable therapies against obesity, diabetes, and their associated complications. This study highlights the potential biomedical applications of carob extracts, offering an innovative and ecological perspective for the prevention and management of these metabolic disorders in an integrative and sustainable approach.