Therapeutic Modulation Research Articles

MODERN ASPECTS OF THE ETIOPATHOGENESIS OF ISCHAEMIC STROKE

Introduction. According to WHO, stroke is the third leading cause of death in adults and one of the most important causes of disability and dementia in adults. According to GBD estimates, Ukraine remains one of the leaders among EU countries in terms of stroke morbidity and mortality, the prevalence of stroke in our country is 289.4 per 100 thousand population. Almost 130,000 strokes occur every year (more than a third of them in people of working age). They lead to 67% of all deaths; in addition, 20–40% of surviving patients become dependent on outside help and only about 10% return to a full life. Objective. The aim of our study is to analyse and summarise current scientific data on molecular mechanisms of development and to clarify their role in the pathogenesis of stroke as potential therapeutic targets for the treatment of such disorders. Results. Stroke is a heterogeneous and multifactorial condition, broadly classified into ischaemic and haemorrhagic types based on underlying cause, which presents challenges in accurate diagnosis. While both types manifest with neurological impairment, they differ significantly in their pathophysiological mechanisms. Each etiological subtype is associated with distinct risk factors, which are critical for both primary and secondary prevention strategies. Recent advances in understanding the molecular mechanisms of stroke have highlighted the role of microRNAs, inflammatory mediators, and pathways involved in neuronal injury and neuroprotection. Research into the use of molecular inhibitors and activators offers promising avenues for therapeutic modulation at the cellular level. Growing insight into these molecular processes has spurred the search for highly sensitive and specific biomarkers capable of facilitating early diagnosis, risk stratification, assessment of disease severity, and outcome prediction. Conclusions. In recent years, research has been focused on further understanding the mechanisms of ischaemic stroke, which has a huge impact on human health and quality of life. The transition of all life sciences to the molecular level of research requires the study of not only the molecular causes of pathological conditions, but also knowledge of the signalling pathways regulating these processes based on the specific pathophysiological role in excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation and cell death. These studies are needed to identify potential therapeutic targets against ischaemic stroke that would help preserve and restore brain functions.

Identification of genetically engineered strategies to manipulate nano-platforms presenting immunotherapeutic ligands for alleviating primary ovarian insufficiency progression

Primary ovarian insufficiency (POI) is a pathological condition characterized by the early loss of functional ovarian follicles, leading to infertility and systemic consequences affecting reproductive, skeletal, cardiovascular, and neurocognitive helath. Aberrant immune activation, particularly an augmented T cell response in the ovary, plays a critical role in POI pathogenesis. In this context, therapeutic modulation of immune responses through immune checkpoint ligands has garnered interest. In the present study, we identified Lamp2b as an optimal scaffold for engineering extracellular vesicles (EVs). By genetically modifying HEK-293 T-derived EVs to present PD-L1 and Gal-9, enabling them to suppress ovarian autoreactive T lymphocytes and protect ovarian cells from immune-mediated destruction. Functionally, the bioengineered nanoplatform demonstrated potent immunosuppressive effects by promoting apoptosis of effector T cells, reducing intraovarian CD8⁺ T cell infiltration and reinstating serum anti-Müllerian hormone (AMH) levels in POI models. These combined actions effectively halted disease progression, ultimately preventing POI progression and preserving ovarian function.Graphical

Success and Controversy of Natural Products as Therapeutic Modulators of Wnt Signaling and Its Interplay with Oxidative Stress: Comprehensive Review Across Compound Classes and Experimental Systems.

The highly conserved Wnt signaling pathway, a complex network critical for embryonic development and adult tissue homeostasis, regulates diverse cellular processes, ultimately influencing tissue organization and organogenesis; its dysregulation is implicated in numerous diseases, and it is known to be affected by oxidative pathways. This report reviews the recent literature on major classes of natural products with pronounced anti-oxidant properties, such as cardiac glycosides, steroid saponins, ecdysteroids, withanolides, cucurbitacins, triterpenes, flavonoids, and iridoids, that modulate its activity in various pathological conditions, summarizing and critically analyzing their effects on the Wnt pathway in various therapeutically relevant experimental models and highlighting the role of ROS-mediated crosstalk with Wnt signaling in these studies. Models reviewed include not only cancer but also stroke, ischemia, bone or kidney diseases, and regenerative medicine, such as re-epithelialization, cardiac maintenance, and hair loss. It highlights the paramount importance of modulating this signaling by natural products to define future research directions. We also discuss controversies identified in the mode of action of several compounds in different models and directions on how to further improve the quality and depth of such studies.

Steroid hormones and influence of therapeutic drugs in Chinese postmenopausal rheumatoid arthritis patients.

To investigate steroid hormone profiles and therapeutic modulation in Chinese postmenopausal rheumatoid arthritis (RA) patients. This cross-sectional study enrolled 138 postmenopausal women, including 88 RA patients stratified by treatment status (23 treatment-naïve, 35 on methotrexate [MTX] monotherapy, and 30 receiving MTX plus glucocorticoids [GC]) and 50 age-matched healthy controls. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we quantified 36 steroid hormones/metabolites to assess treatment-associated endocrine alterations. Group comparisons employed non-parametric Kruskal-Wallis test for multi-group comparisons, with post-hoc Mann-Whitney U tests and false discovery rate (FDR) correction for multiple comparisons. Statistical significance was defined as p<0.05 after FDR correction. Untreated RA patients demonstrated significant global steroid dysregulation, characterized by marked suppression of multiple adrenal steroids (including aldosterone, cortisol, and testosterone) compared to healthy controls (all FDR<0.05). This was accompanied by profound alterations in estrogen metabolism, notably a hyperactivated 2-hydroxylation pathway and depleted 16-hydroxylation metabolites (FDR<0.001). MTX treatment partially restored steroid homeostasis, significantly improving aldosterone and androgen profiles (FDR<0.05) toward levels observed in healthy controls. However, the addition of GC therapy further disrupted endocrine balance, significantly suppressing cortisol, testosterone, and total estrogens (FDR<0.05), while pathologically amplifying the 4-hydroxylation pathway (FDR<0.001), a process potentially linked to synovial inflammation. This study demonstrates that impaired steroidogenesis and estrogen pathway dysregulation are characteristic features of postmenopausal RA, with MTX showing unexpected hormone-restorative effects. While GC therapy provides symptomatic relief, it paradoxically exacerbates endocrine disruption, suggesting the need for personalized hormonal monitoring in long-term GC-treated patients.

Insights into the protein domains of C-VI TRIM subfamily in viral infection.

Tripartite motif (TRIM) proteins, defined by their conserved RBCC domain architecture, play key roles in various cellular processes and virus-host interactions. In this review, we focus on Class VI TRIM proteins, including TRIM24, TRIM28, and TRIM33, highlighting the distinct functional attributes of their RING, B-BOX1, B-BOX2, COILED COIL, PHD, and BRD domains in viral infection. Through multiple sequence alignment, we delineate both the conserved and divergent features within this subclass, underscoring the uniqueness of Class VI TRIM protein. Additionally, we explore the post-translational modifications (PTMs) of Class VI TRIM proteins including their functional differences in modulating viral infection. Moreover, we examine the C-VI TRIM protein complexes and their significant contributions to the antiviral response. Furthermore, we discuss small molecule ligands targeting Class VI TRIM domains, with a focus on druggable structural motifs. Understanding the multi-domain features of TRIM proteins is crucial for developing effective antiviral strategies and the therapeutic modulation of their activity.

The gut microbiota in menopause: Is there a role for prebiotic and probiotic solutions?

The gut microbiota, comprising a diverse array of microorganisms in the gastrointestinal tract, has emerged as a key player in human health. Emerging research indicates that this gut microbial composition is influenced by sex. These sex differences are not necessarily static and likely alter across the life course in response to several factors including changing hormone profile. As such, the menopause transition-a pivotal phase in female ageing in which the hormone profile changes dramatically is receiving increasing attention. Declining estrogen which occurs during menopause appears to influence the microbiota, which may in turn contribute to menopause-related conditions such as weight gain, bone health, cancer risk and cognitive health. The modulation of estrogen through the gut's 'estrobolome', a collection of bacterial genes involved in estrogen metabolism, may offer explanation for some of the interindividual differences observed during menopause (e.g. length, symptoms and disease risk). Therapeutic modulation of the gut microbiota therefore represents a potential approach towards managing menopausal symptoms. Indeed, prebiotics and probiotics such as Lactobacillus have been shown to increase bacterial diversity and improve metabolic and overall health in menopausal women. However, evidence remains limited regarding the specific underlying mechanisms, highlighting an urgent need for a research focus in the area. This review summarizes the current understanding of the gut microbiota's role in menopausal health and the potential of prebiotics and probiotics as therapeutic interventions. Further research into gut microbiota modulation may enable more effective, personalised treatments for menopause-associated health challenges, and supporting women's health into older ages.

RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.

RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.

Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action.

Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action.

Aquaporin 4 modulation drives amyloid burden and cognitive abilities in an APPPS1 mouse model of Alzheimer's disease.

Deficiency in the aquaporin-4 (AQP4) water channel has been linked to impaired amyloid beta (Aβ) clearance. However, a detailed morphopathological analysis of amyloid deposition following AQP4 therapeutic modulation remains unexplored. Two-month-old amyloid precursor protein presenilin 1 (APPPS1) mice were treated daily for 28 days with either the AQP4 facilitator N-(3-(Benzyloxy)pyridin-2-yl) benzene-sulfonamide (TGN-073) or the AQP4 inhibitor N-(1,3,4-thiadiazol-2-yl)pyridine-3-carboxamide dihydrochloride (TGN-020) (both at 200mg/kg). Controls included vehicle-treated APPPS1 and WT C57BL/6J mice. Comprehensive histopathological, biochemical, and behavioral analyses were conducted. Mice treated with AQP4 facilitator showed a significant reduction in total Aβ, fibrillar deposits, and soluble Aβ, while the AQP4 inhibitor caused a substantial increase in brain Aβ. AQP4-facilitator treatment also reduced Aβ40 levels and Aβ40/Aβ42 ratio, whereas the inhibitor treatment increased both Aβ40 and Aβ42. Additionally, facilitator-treated mice demonstrated reduced anxiety and improved memory performance. These findings suggest that AQP4 modulation is a promising strategy to enhance Aβ clearanceand a potential therapeutic target in Alzheimer's disease. Intramural periarterial drainage of the interstitial fluid mediated by aquaporin-4 (AQP4) is a key element that ensures clearance of catabolites/Aβ peptide from within the brain parenchyma. Inhibition of AQP4 in an APPPS1 mouse model of AD leads to increased amyloid deposition and deficient behavior compared to untreated transgenic animals. Pharmaceutical facilitation of AQP4 in the same APPPS1 mouse model leads to a massive decrease in amyloid burden and improves the behavioral performance of the animals compared to untreated control APPPS1 mice.

Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

IL-17 and IL-23 inhibitors dose spacing in adult psoriatic patients: a real-world pilot study.

De-escalation strategies of biologics in psoriasis treatment are widespread in clinical practice. Dose spacing consists of de-escalating the time range between biological drug injections. Major objectives were: to describe trends in mean PASI, PASI100, 90, and ≤1 from baseline to 12months after dose spacing, provide drug survival analysis of dose-spaced regimens, and concurrently describe phenotypic characteristics related to the selection of patient candidates for therapeutic dose spacing. A pre-post analysis was made between mean PASI at dose spacing and baseline, and after 3, 6, 9, and 12months following dose spacing. Of 1,144 patients treated with IL-23 or IL-17 inhibitors, 61 patients underwent dose spacing. They presented with lower mean baseline Body Mass Index (BMI) (p=0.011) and PASI (Psoriasis Area Severity Index) (p=0.044) and were more frequently bio-experienced (p=0.033). 12months after dose spacing 42.9%, 85.7%, and 92.9% of observed patients achieved PASI100, 90, and ≤1. There were no significant differences in mean PASI between dose spacing and subsequent time points. The dose spacing survival was 70% at 1 year. Therapeutic modulation, such as dose spacing, is an effective strategy for most psoriasis patients, resulting in a clear or almost clear skin response that is maintained over time.

Exploring the interplay between valvular and serum zinc and copper levels and disease markers in aortic stenosis.

Exploring the interplay between valvular and serum zinc and copper levels and disease markers in aortic stenosis.

The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.

Targeting dopaminergic neuronal death: Luteolin as a therapeutic modulator in Parkinson's disease.

Understanding the convoluted roles of dopamine in brain function is supreme for elucidating the pathophysiology and the therapeutic approach of movement disorders. Of which, Parkinson's disease (PD) is a progressive neurological ailment characterized by disturbed motor and non-motor functions. Luteolin, a plant-derived flavonoid, exhibits neuroprotective properties through its antioxidant and anti-inflammatory effects. In this study, we evaluated the therapeutic potential of luteolin in a rotenone-induced Wistar rat model of PD. Results of behavior assessment showed that luteolin (25mg/kg and 50mg/kg i.p.) treatment for 28days significantly and dose-dependently improved motor functions. Furthermore, biochemical analysis demonstrated that luteolin restored oxidative balance by elevating glutathione (GSH) levels and reducing nitrate content. Additionally, ELISA results indicated that luteolin modulated level of tumor necrosis factor-alpha (TNF-α) and Bax, thereby reducing inflammation and neuronal apoptosis. Moreover, dopamine levels were significantly increased in rat brain homogenate, corroborating the neuroprotective effects of luteolin. Histopathological analysis further confirmed dopaminergic neuronal preservation in the cortex. These findings suggest that luteolin may serve as a potential therapeutic candidate for PD by mitigating oxidative stress, neuroinflammation, and apoptosis.

Mechanism underlying the involvement of CXCR4/CXCL12 in diabetic wound healing and prospects for responsive hydrogel-loaded CXCR4 formulations.

Diabetes mellitus is a prevalent chronic disease, often leading to complications, with chronic wounds being among the most challenging. Impairment of the CXCR4/CXCL12 signaling pathway, which plays a key role in cell mobilization, migration, and angiogenesis, significantly hampers the wound healing process in diabetic patients. Modulation of this pathway using CXCR4-targeted agents has shown promise in restoring wound repair capabilities. Additionally, the development of responsive hydrogels capable of adapting to external stimuli offers a powerful platform for drug delivery in chronic wound management. These hydrogels, when loaded with CXCR4 agonists or antagonists, enable controlled drug release and real-time therapeutic modulation. Integrating such hydrogels with existing wound healing strategies may provide an innovative and effective solution for overcoming the challenges associated with diabetic wound treatment.

Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis.

Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis.

Tip60 HAT activators as therapeutic modulators for Alzheimer’s disease

Reduced histone acetylation in the brain causes transcriptional dysregulation and cognitive impairment that are key initial steps in Alzheimer’s disease (AD) etiology. Unfortunately, current treatment strategies primarily focus on histone deacetylase inhibition (HDACi) that causes detrimental side effects due to non-specific acetylation. Here, we test Tip60 histone acetyltransferase (HAT) activation as a therapeutic strategy for selectively restoring cognition-associated histone acetylation depleted in AD by developing compounds that enhance Tip60’s neuroprotective HAT function. Several compounds show high Tip60-binding affinity predictions in silico, enhanced Tip60 HAT action in vitro, and restore Tip60 knockdown mediated functional deficits in Drosophila in vivo. Furthermore, compounds prevent neuronal deficits and lethality in an AD-associated amyloid precursor protein neurodegenerative Drosophila model and remarkably, restore expression of repressed neuroplasticity genes in the AD brain, underscoring compound specificity and therapeutic effectiveness. Our results highlight Tip60 HAT activators as a promising therapeutic neuroepigenetic modulator strategy for AD treatment.

GSK3B inhibition partially reverses brain ethanol-induced transcriptomic changes in C57BL/6J mice: Expression network co-analysis with human genome-wide association studies.

Alcohol use disorder (AUD) is a chronic behavioral disease with greater than 50% of its risk due to complex genetic contributions. Existing pharmacological and behavioral treatments for AUD are minimally effective and underutilized. Animal model behavioral genetics and human genome-wide association studies have begun to identify individual genes contributing to the progressive compulsive consumption of ethanol that occurs with AUD, promising possible new therapeutic targets. Our laboratory has previously identified Gsk3b as a central member in a network of ethanol-responsive genes in mouse prefrontal cortex, which altered ethanol consumption with genetic manipulation and was also significantly associated with risk for alcohol dependence in human genome-wide association studies. Here we perform detailed brain RNA sequencing transcriptomic studies to characterize a highly specific and clinically available GSK3B pharmacological inhibitor, tideglusib, as a possible therapeutic for clinical trials on treatment of AUD. A model of chronic intermittent ethanol consumption was used to study gene expression changes in prefrontal cortex and nucleus accumbens in the presence or absence of tideglusib treatment. Multivariate analysis of differentially expressed genes showed that tideglusib largely reversed ethanol- induced expression changes for two prominent clusters of genes in both prefrontal cortex and nucleus accumbens. Bioinformatic analysis showed these genes to have prominent roles in neuronal functioning and synaptic activity. Additionally, mouse brain differential gene expression data was analyzed together with human protein-protein interaction and genome-wide association studies on AUD to derive networks responding to tideglusib and relevant to human genetic risk for alcohol dependence. These studies identified discrete networks significantly enriched with genes provisionally associated with AUD, and provide key information on central hubs of such networks. Together these studies document tideglusib as a major modulator of chronic ethanol consumption-evoked brain gene expression signatures, and identify possible new targets for therapeutic modulation of AUD.

CXCR4+ PD-L1+ neutrophils are increased in non-survived septic mice.

CXCR4+ PD-L1+ neutrophils are increased in non-survived septic mice.

Game-Based Learning Effects on Student Engagement and Outcomes in Clinical Therapeutics Courses.

Game-Based Learning Effects on Student Engagement and Outcomes in Clinical Therapeutics Courses.