Trends in molecular medicine最新文献

Over the past 30 years, significant progress has been made in understanding the genetic causes of obesity. In the coming years, catalogs that map each genetic variant to its genomic function are expected to accelerate variant-to-function (V2F) translation. Given that obesity is a heterogeneous disease, research will have to move beyond body mass index (BMI). Gene discovery efforts for more refined adiposity traits are poised to reveal additional genetic loci, pointing to new biological mechanisms. Obesity genetics research is reaching unprecedented heights and, along with a renewed interest in the development of weight-loss medication, it holds the potential to identify new drug targets. Polygenic scores (PGSs) that predict obesity risk are expected to further improve and will be particularly valuable early in life for timely prevention.

Translational medicine is crucial for addressing health issues and translating research findings to improve population health. This Science and Society article highlights the potential of translational medicine in Mexico. It discusses the obstacles and challenges encountered in the translation process, instilling a sense of optimism for the future of healthcare in Mexico.

The increasing prevalence and poor prognosis of central nervous system (CNS) metastases pose a significant challenge in oncology, necessitating improved therapeutic strategies. Recent research has shed light on the complex genomic landscape of brain metastases, identifying unique and potentially actionable genetic alterations. These insights offer new avenues for targeted therapy, highlighting the potential of precision medicine approaches in treating CNS metastases. However, translating these discoveries into clinical practice requires overcoming challenges such as availability of tissue for characterization, access to molecular testing, drug delivery across the blood-brain barrier (BBB) and addressing intra- and intertumoral genetic heterogeneity. This review explores novel insights into the evolution of CNS metastases, the molecular mechanisms underlying their development, and implications for therapeutic interventions.

Proteasome functional insufficiency (PFI) is implicated in neurodegeneration and heart failure, where aberrant protein aggregation is common and impairs the ubiquitin (Ub)-proteasome system (UPS), exacerbating increased proteotoxic stress (IPTS) and creating a vicious circle. Breaking this circle represents a key to treating these diseases. Protein kinase (PK)-A and PKG can activate the proteasome and promote proteasomal degradation of misfolded proteins. PKA does so by phosphorylating Ser14-RPN6/PSMD11, but how PKG activates the proteasome remains unknown. Emerging evidence supports a strategy to treat diseases with IPTS by augmenting cAMP/PKA and cGMP/PKG. Conceivably, targeted activation of PKA and PKG at proteasome nanodomains would minimize the undesired effects from their actions on other targets. In this review, we discuss PKA and PKG regulation of proteostasis via the UPS.

Osteoarthritis (OA) is a prevalent articular disorder characterized by joint degeneration and persistent pain; it imposes a significant burden on both individuals and society. While OA has traditionally been viewed as a localized peripheral disorder, recent preclinical and clinical studies have revealed the crucial interconnections between the bone and the brain, highlighting the systemic nature of OA. The neuronal pathway, molecular signaling, circadian rhythms, and genetic underpinnings within the bone-brain axis play vital roles in the complex interplay that contributes to OA initiation and progression. This review explores emerging evidence of the crosstalk between the bone and brain in OA progression, and discusses the potential contributions of the bone-brain axis to the development of effective interventions for managing OA.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α₄β₇ antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), characterized by propagation of blood cell clones carrying somatic mutations in specific driver genes, is increasingly recognized as a critical factor in the development of hematological malignancies. This phenomenon, which often emerges with age, underscores the complex interplay between genetic predisposition and environmental influences in cancer initiation and progression. Recent years have witnessed significant advances in our understanding of the link between CHIP and hematological diseases. In this review, we provide a comprehensive overview of the features of CHIP and explore its role in promoting tumorigenesis and influencing treatment outcomes for blood cancers. Finally, we summarize current available tools for risk stratification and discuss management strategies for patients with CHIP.

Seven primary familial brain calcification genes have been identified but their role in disease mechanisms has been less explored. Cheng et al. recently demonstrated that astrocyte-mediated regulation of brain phosphate (P_i) involves direct and functional interactions among three of these proteins, paving the way for new strategies to combat brain calcification.