Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review.

Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.

Signatures and Discriminative Abilities of Multi-Omics between States of Cognitive Decline.

Dementia poses a substantial global health challenge, warranting an exploration of its intricate pathophysiological mechanisms and potential intervention targets. Leveraging multi-omic technology, this study utilizes data from 2251 participants to construct classification models using lipidomic, gut metabolomic, and cerebrospinal fluid (CSF) proteomic markers to distinguish between the states of cognitive decline, namely, the cognitively unimpaired state, mild cognitive impairment, and dementia. The analysis identifies three CSF proteins (apolipoprotein E, neuronal pentraxin-2, and fatty-acid-binding protein), four lipids (DEDE.18.2, DEDE.20.4, LPC.O.20.1, and LPC.P.18.1), and five serum gut metabolites (Hyodeoxycholic acid, Glycohyodeoxycholic acid, Hippuric acid, Glyceric acid, and Glycodeoxycholic acid) capable of predicting dementia prevalence from cognitively unimpaired participants, achieving Area Under the Curve (AUC) values of 0.879 (95% CI: 0.802-0.956), 0.766 (95% CI: 0.700-0.835), and 0.717 (95% CI: 0.657-0.777), respectively. Furthermore, exclusively three CSF proteins exhibit the potential to predict mild cognitive impairment prevalence from cognitively unimpaired subjects, with an AUC of 0.760 (95% CI: 0.691-0.828). In conclusion, we present novel combinations of lipids, gut metabolites, and CSF proteins that showed discriminative abilities between the states of cognitive decline and underscore the potential of these molecules in elucidating the mechanisms of cognitive decline.

The Genetic Architecture of Biological Age in Nine Human Organ Systems.

Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture1 - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine.

The genetic architecture of biological age in nine human organ systems.

Investigating the genetic underpinnings of human aging is essential for unraveling the etiology of and developing actionable therapies for chronic diseases. Here, we characterize the genetic architecture of the biological age gap (BAG; the difference between machine learning-predicted age and chronological age) across nine human organ systems in 377,028 participants of European ancestry from the UK Biobank. The BAGs were computed using cross-validated support vector machines, incorporating imaging, physical traits and physiological measures. We identify 393 genomic loci-BAG pairs (P < 5 × 10-8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary and renal systems. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system (organ specificity) while exerting pleiotropic links with other organ systems (interorgan cross-talk). We find that genetic correlation between the nine BAGs mirrors their phenotypic correlation. Further, a multiorgan causal network established from two-sample Mendelian randomization and latent causal variance models revealed potential causality between chronic diseases (for example, Alzheimer's disease and diabetes), modifiable lifestyle factors (for example, sleep duration and body weight) and multiple BAGs. Our results illustrate the potential for improving human organ health via a multiorgan network, including lifestyle interventions and drug repurposing strategies.

Targeting Options of Tumor-Associated Macrophages (TAM) Activity in Gliomas.

Tumor-associated macrophages (TAMs), the most plastic cells of the hematopoietic system, exhibit increased tumor-infiltrating properties and functional heterogeneity depending on tumor type and associated microenvironment. TAMs constitute a major cell type of cancer-related inflammation, commonly enhancing tumor growth. They are profoundly involved in glioma pathogenesis, contributing to many cancer hallmarks such as angiogenesis, survival, metastasis, and immunosuppression. Efficient targeting of TAMs presents a promising approach to tackle glioma progression. Several targeting options involve chemokine signaling axes inhibitors and antibodies, antiangiogenic factors, immunomodulatory molecules, surface immunoglobulins blockers, receptor and transcription factor inhibitors, as well as microRNAs (miRNAs), administered either as standalone or in combination with other conventional therapies. Herein, we provide a critical overview of current therapeutic approaches targeting TAMs in gliomas with the promising outcome.