Trends in molecular medicine最新文献

Despite the dramatic decrease in HIV-associated neurocognitive impairment (NCI) in the combined antiretroviral treatment (cART) era, subtler neuropsychological complications remain prevalent. In this review, we discuss the changing pathophysiology of HIV-associated NCI, considering recent evidence of HIV neuropathogenesis, and the pivotal role of cART. Furthermore, we address the multifactorial nature of NCI in people living with HIV, including legacy and ongoing insults to the brain, as well as host-specific factors. We also summarize the ongoing debate about the refinement of diagnostic criteria, exploring the strengths and limitations of these recent approaches. Finally, we present current research in NCI management in people living with HIV and highlight the need for using both pharmacological and nonpharmacological pathways toward a holistic approach.

Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium-calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid-calcium-collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification.

The ability of the gut microbiome to adapt to a new environment and utilize a new metabolite or dietary compound by inducing structural variations (SVs) in the genome has an important role in human health. Here, we discuss recent data on host genetic regulation of SV induction and its use as a new therapeutic approach.

Type 1 diabetes (T1D), a severe disease requiring intensive insulin treatment, carries an increased risk for complications and reduced lifespan. Certain viruses have been implicated in T1D's etiology, with 'live', replicating enteroviruses (EVs) recently found in the pancreas at diagnosis. This discovery prompted a trial to slow down disease progression using antiviral drugs. A 6-month treatment combining pleconaril and ribavirin in new-onset T1D patients preserved residual insulin production after 1 year, unlike placebo. The results support the theory that viruses may cause T1D in genetically susceptible individuals. A low-grade, persistent viral infection may initiate a cascade of pathogenic mechanisms initially involving the innate immune system, inducing β-cell stress and neoantigen release, leading to autoimmunity, and eventually the destruction of insulin-producing β-cells.

The development of checkpoint antibodies for cancer therapy has been guided by the principle of blocking T cell inhibitory signals. Recognition of the role of the Fc domain in therapeutic activities, through the depletion of immunosuppressive populations and myeloid cell activation, prompts a shift toward the development of optimized Fc-engineered checkpoint antibodies.

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.

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.

Coeliac disease (CeD) is an immune-mediated disorder characterised by gluten-triggered inflammation and damage in the small intestine, with lifelong gluten-free diet (GFD) as the only treatment. It is a multifactorial disease, involving genetic and environmental susceptibility factors, and its complexity and lack of comprehensive human model systems have hindered understanding of its pathogenesis and development of new treatments. Therefore, it is crucial to establish systems that recapitulate patient genetic background and the interactions between the small intestinal epithelial barrier, immune cells, and environment that contribute to CeD. In this review, we discuss disease complexity, recent advances in stem cell biology, organoids, tissue co-cultures, and organ-on-chip (OoC) systems that facilitate the development of comprehensive human model systems, and model applications in preclinical studies of potential treatments.