A winding trajectory exists in developing cures, whereas gene therapy targeting genes responsible for aging is a thrilling research direction, promising immense potential. Various methods have been employed to study potential aging-related genes, encompassing multiple levels of biological complexity from cellular assays to organismal studies (such as those in mammals), and strategies ranging from boosting gene expression to precise gene modification. Further development of the TERT and APOE genes has progressed to clinical trial stages. Those showing only a nascent connection to diseases can nonetheless hold practical applications. The article summarizes the current leading gene therapy strategies and products, along with their clinical and preclinical uses. It also explores the foundational principles and breakthroughs that drive the field of gene therapy. Lastly, we consider representative target genes and their potential for treating conditions associated with aging and senescence.
The protective influence of erythropoietin on illnesses, specifically ischemic stroke and myocardial infarctions, is often a subject of scientific discussion and assumptions. A misconception regarding erythropoietin's (EPO) protective mechanism has, to some degree, been prevalent in the scientific community, with the common receptor (cR) within the heteroreceptor EPO receptor (EPOR)/cR system being wrongly posited as the main contributor to these protective properties. This article aims to raise concerns about the assumed importance of cR in EPO's protective action, and urge the need for further research to validate this association.
The underlying reasons for late-onset Alzheimer's disease (LOAD), which accounts for the overwhelming majority of Alzheimer's disease (AD) cases (over 95%), are currently unknown. Evidently, growing evidence suggests that cellular senescence could be a key player in the development of AD, but the underlying mechanisms governing brain cell aging, and the precise methods via which senescent cells contribute to neuro-pathology, still remain obscure. The current study, for the first time, identifies a positive correlation between increased plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, and the upregulation of cell cycle repressors p53 and p21 in the hippocampus/cortex of SAMP8 mice and LOAD patients. In astrocytes from the brains of LOAD patients and SAMP8 mice, double immunostaining demonstrates a greater expression of senescent markers and PAI-1, in comparison to the corresponding control astrocytes. Further in vitro research suggests that elevated PAI-1 expression, irrespective of cellular localization, prompted senescence, yet the reduction or silencing of PAI-1 expression diminished the senescence-inducing effects of H2O2 in primary astrocytes isolated from mice and humans. The administration of conditional medium (CM) from senescent astrocytes led to neuron apoptosis. MK-28 Significantly, senescent astrocytes deficient in PAI-1, and overexpressing a secretion-impaired form (sdPAI-1) of this protein, produce conditioned medium with a substantially reduced effect on neurons, when compared to conditioned medium from senescent astrocytes overexpressing wild-type PAI-1 (wtPAI-1), despite similar degrees of senescence induction by both sdPAI-1 and wtPAI-1. Our study's results point towards a potential correlation between elevated PAI-1 levels, whether inside or outside brain cells, and brain cell aging in LOAD. Senescent astrocytes, in this context, may trigger neuron death by releasing pathologically active molecules, including PAI-1.
Due to its widespread prevalence and debilitating effects, osteoarthritis (OA), the most common degenerative joint condition, places a tremendous socioeconomic burden. Recent studies highlight osteoarthritis as a pervasive joint issue encompassing cartilage degeneration, synovial membrane inflammation, meniscal tears, and modifications in the subchondral bone. Endoplasmic reticulum (ER) stress results from the accumulation of misfolded or unfolded proteins inside the ER. Further investigation into the mechanisms of osteoarthritis has revealed that ER stress impacts the physiological function and survival of key cell types, including chondrocytes, fibroblast-like synoviocytes, synovial macrophages, meniscus cells, osteoblasts, osteoclasts, osteocytes, and bone marrow mesenchymal stem cells. As a result, the endoplasmic reticulum's stress response represents a compelling and promising target in the context of osteoarthritis treatment. While ER stress modulation has proven effective at reducing osteoarthritis progression in both in vitro and in vivo studies, therapeutic applications remain limited to preclinical phases, thus demanding further investigation and development.
The interplay between gut microbiome destabilization, dysbiosis reversal, and glucose-lowering drugs in elderly Type 2 Diabetes (T2D) patients is an unexplored research area. A six-month trial using a fixed combination of Liraglutide and Degludec assessed the influence of this therapy on the composition of the gut microbiome and its impact on quality of life, glucose regulation, cognitive function, depression, and markers of inflammation in a group of elderly Type 2 Diabetes (T2D) individuals (n=24, 5 women, 19 men, average age 82 years). Across the study participants (N=24, 19 men, mean age 82 years) who responded with decreased HbA1c levels (n=13) versus those who did not (n=11), we found no significant differences in microbiome biodiversity or community. However, the group with reduced HbA1c levels displayed a statistically significant elevation in Gram-negative Alistipes (p=0.013). Alistipes content modifications were directly linked to cognitive improvement (r=0.545, p=0.0062) and inversely correlated with TNF levels (r=-0.608, p=0.0036) in the group of respondents. The combined pharmacological intervention appears to have a substantial impact on both gastrointestinal microorganisms and cognitive abilities in elderly patients with type 2 diabetes, according to our results.
High morbidity and mortality rates are characteristic of the exceedingly common pathology, ischemic stroke. Intracellular calcium homeostasis and protein synthesis and trafficking are all key functions handled by the endoplasmic reticulum (ER). Emerging research strongly indicates that the stress response within the endoplasmic reticulum is implicated in stroke mechanisms. Moreover, a restricted blood flow to the brain after a stroke contributes to a decrease in ATP generation. Post-stroke, an important pathological process is the disruption of glucose metabolic function. Analyzing the connection between endoplasmic reticulum stress and stroke, this paper further investigates the therapeutic approaches and interventions for post-stroke ER stress. The matter of glucose metabolism, specifically glycolysis and gluconeogenesis, is also addressed in relation to the post-stroke period. From recent studies, we theorize a potential connection and crosstalk between the metabolic pathway of glucose and endoplasmic reticulum stress. multiple antibiotic resistance index To summarize, we examine ER stress, glycolysis, and gluconeogenesis within the context of stroke, analyzing how the intricate relationship between ER stress and glucose metabolism shapes the pathophysiology of stroke.
The etiology of Alzheimer's disease (AD) is closely related to the formation of cerebral amyloid plaques, formed largely from modified A molecules and metal ions. In amyloid plaques, the isomerization of A at the Asp7 residue (isoD7-A) is the most common occurrence. Medical technological developments We theorized that zinc-dependent oligomer formation by isoD7-A is responsible for its pathogenic effects, and that this process can be counteracted by the rationally designed tetrapeptide HAEE. Our demonstration of Zn2+-dependent isoD7-A oligomerization, alongside the formation of a stable isoD7-AZn2+HAEE complex that resists oligomerization, used surface plasmon resonance, nuclear magnetic resonance, and molecular dynamics simulations. To demonstrate the biological significance of zinc-dependent isoD7-A oligomerization and HAEE's impact on this process at the organism level, we utilized nematodes that had been genetically modified to overexpress human A. We found that the introduction of isoD7-A into the medium results in substantial amyloidosis, a zinc-dependent process, along with enhanced paralysis and reduced lifespan in the animals. Exogenous HAEE's action completely reverses the pathological impact of isoD7-A. IsoD7-A and Zn2+ interaction leads to A aggregation, and small molecules such as HAEE, capable of inhibiting such aggregation, are promising candidates for anti-amyloid therapy.
Since the initial outbreak, coronavirus disease-19 (COVID-19) has maintained its global spread for more than two years. Even though various vaccine types exist presently, the appearance of new variants, coupled with spike protein mutations and the ability of the virus to evade the immune system, has intensified challenges. Respiratory infections pose a particular threat to pregnant women, whose altered immune defenses and surveillance mechanisms make them more susceptible. In addition, the advisability of administering COVID-19 vaccines to pregnant women continues to be a point of discussion, given the limited dataset regarding the vaccine's effectiveness and safety in this specific population. The high-risk status of pregnant women with respect to infection is a result of their physiological features and the lack of adequate preventive measures. Pregnancy's potential to ignite pre-existing neurological ailments is a significant concern, showcasing symptoms strikingly similar to those caused by COVID-19 in pregnant women. These overlapping characteristics hinder accurate diagnosis and delay the implementation of prompt and effective treatment strategies. Thus, the provision of prompt emergency assistance for expectant mothers experiencing neurological symptoms induced by COVID-19 presents a challenge for both neurologists and obstetricians. To elevate the efficiency and efficacy of diagnosis and treatment in pregnant women experiencing neurological symptoms, we propose a structured framework for emergency management, drawing on the practical experience of clinicians and accessible resources.