Trends in Molecular Medicine
Reviews journal by Cell Press publishes articles covering all aspects of human diseases, diagnostics, therapeutics, and disease prevention. Posts are by the editor, Dr. Aliki Perdikari. Explore more at: cell.com/trends/molecular-me…
- ICYMI: ONLINE NOW: Stratification of immunotherapy responses by adaptive immune receptor repertoires
Stratification of immunotherapy responses by adaptive immune receptor repertoires
A growing number of diseases are now treated with immunotherapies, which consist of interventions that suppress or stimulate the patient’s immune system. Because individual humans express a unique repertoire of adaptive immune receptors, the efficacy of immunotherapies typically varies from person to person. Next generation sequencing of adaptive immune receptor repertoires, combined with machine learning or statistical analysis, has emerged as a sensitive means of stratifying patients based on their immune status, particularly in the fields of cancer and autoimmune disease therapy. The sensitivity and specificity of these approaches rely heavily on the methods of deriving features from each individual repertoire. Here, we review recent trends in stratification methods and highlight their limitations, including the need for data standardization and sharing.dlvr.it - ONLINE NOW: Stratification of immunotherapy responses by adaptive immune receptor repertoires
Stratification of immunotherapy responses by adaptive immune receptor repertoires
A growing number of diseases are now treated with immunotherapies, which consist of interventions that suppress or stimulate the patient’s immune system. Because individual humans express a unique repertoire of adaptive immune receptors, the efficacy of immunotherapies typically varies from person to person. Next generation sequencing of adaptive immune receptor repertoires, combined with machine learning or statistical analysis, has emerged as a sensitive means of stratifying patients based on their immune status, particularly in the fields of cancer and autoimmune disease therapy. The sensitivity and specificity of these approaches rely heavily on the methods of deriving features from each individual repertoire. Here, we review recent trends in stratification methods and highlight their limitations, including the need for data standardization and sharing.dlvr.it - ICYMI: ONLINE NOW: Hypoxia in MASLD: a spatial determinant of the pathogenesis
Hypoxia in MASLD: a spatial determinant of the pathogenesis
The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.dlvr.it - ICYMI: ONLINE NOW: Mapping clinical CAR-T cells: insights from scRNA-seq
Mapping clinical CAR-T cells: insights from scRNA-seq
Single cell RNA sequencing (scRNA-seq) has revolutionized the field of biology and become the most powerful tool for evaluating transcriptional profiles of a biological sample. Given its power, it is widely utilized across multiple disciplines, including chimeric antigen receptor (CAR)-T cell therapy. In this review, we provide a comprehensive summary of published studies that have used scRNA-seq to analyze clinical CAR-T cells, focusing on T cell exhaustion, cytotoxicity, memory, expansion, clonal diversity, and cytokines. We also highlight findings on activation, CD4+/CD8+ ratios, proliferation, regulatory T cells (Tregs) and metabolism, and their relevance to patient response across diseases. Finally, we discuss the limitations and future directions of scRNA-seq in CAR-T cell research, providing key insights for clinicians and researchers.dlvr.it - ONLINE NOW: Hypoxia in MASLD: a spatial determinant of the pathogenesis
Hypoxia in MASLD: a spatial determinant of the pathogenesis
The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.dlvr.it - ONLINE NOW: Mapping clinical CAR-T cells: insights from scRNA-seq
Mapping clinical CAR-T cells: insights from scRNA-seq
Single cell RNA sequencing (scRNA-seq) has revolutionized the field of biology and become the most powerful tool for evaluating transcriptional profiles of a biological sample. Given its power, it is widely utilized across multiple disciplines, including chimeric antigen receptor (CAR)-T cell therapy. In this review, we provide a comprehensive summary of published studies that have used scRNA-seq to analyze clinical CAR-T cells, focusing on T cell exhaustion, cytotoxicity, memory, expansion, clonal diversity, and cytokines. We also highlight findings on activation, CD4+/CD8+ ratios, proliferation, regulatory T cells (Tregs) and metabolism, and their relevance to patient response across diseases. Finally, we discuss the limitations and future directions of scRNA-seq in CAR-T cell research, providing key insights for clinicians and researchers.dlvr.it - ICYMI: ONLINE NOW: Polycystic kidney disease
Polycystic kidney disease
Polycystic kidney disease (PKD) is a genetic disorder characterized by increased kidney volume and declining renal function due to formation and expansion of cysts. Two main types exist: autosomal dominant PKD (ADPKD) (common, adult onset) and autosomal recessive PKD (ARPKD) (rare, childhood onset). Mutated genes regulate cilia function and trafficking, and PKD is a ciliopathy. A cilia-driven procystic pathway inhibited by the polycystins (PC-1, PC-2) or by cilia removal defines the aggressiveness of disease.dlvr.it - ONLINE NOW: Polycystic kidney disease
Polycystic kidney disease
Polycystic kidney disease (PKD) is a genetic disorder characterized by increased kidney volume and declining renal function due to formation and expansion of cysts. Two main types exist: autosomal dominant PKD (ADPKD) (common, adult onset) and autosomal recessive PKD (ARPKD) (rare, childhood onset). Mutated genes regulate cilia function and trafficking, and PKD is a ciliopathy. A cilia-driven procystic pathway inhibited by the polycystins (PC-1, PC-2) or by cilia removal defines the aggressiveness of disease.dlvr.it - ICYMI: ONLINE NOW: Major depressive disorder: susceptibility, underlying mechanisms, and emerging therapies
Major depressive disorder: susceptibility, underlying mechanisms, and emerging therapies
Genetic predisposition, chronic stress, childhood trauma, high-fat diet, chronic diseases, or substance use disorders increase major depressive disorder (MDD) risk. Biochemically, MDD is characterized by reduced dopamine, serotonin, and noradrenaline levels, hypothalamic–pituitary–adrenal (HPA) axis overactivation with elevated cortisol, and peripheral/central inflammation. Impaired synaptic plasticity (reduced neurotrophic signaling and neurogenesis, glutamate dysregulation) causes structural atrophy in mood-regulating brain regions.dlvr.it - ONLINE NOW: Major depressive disorder: susceptibility, underlying mechanisms, and emerging therapies
Major depressive disorder: susceptibility, underlying mechanisms, and emerging therapies
Genetic predisposition, chronic stress, childhood trauma, high-fat diet, chronic diseases, or substance use disorders increase major depressive disorder (MDD) risk. Biochemically, MDD is characterized by reduced dopamine, serotonin, and noradrenaline levels, hypothalamic–pituitary–adrenal (HPA) axis overactivation with elevated cortisol, and peripheral/central inflammation. Impaired synaptic plasticity (reduced neurotrophic signaling and neurogenesis, glutamate dysregulation) causes structural atrophy in mood-regulating brain regions.dlvr.it - ICYMI: ONLINE NOW: Lymph node microenvironment rewires ferroptosis redox defenses
Lymph node microenvironment rewires ferroptosis redox defenses
Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from ferroptosis. This highlights the importance of the microenvironment in shaping ferroptosis defenses and supports FSP1 as a targetable vulnerability for lymph node metastases.dlvr.it - ICYMI: ONLINE NOW: GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach
GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach
Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration.dlvr.it - ONLINE NOW: Lymph node microenvironment rewires ferroptosis redox defenses
Lymph node microenvironment rewires ferroptosis redox defenses
Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from ferroptosis. This highlights the importance of the microenvironment in shaping ferroptosis defenses and supports FSP1 as a targetable vulnerability for lymph node metastases.dlvr.it - ONLINE NOW: GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach
GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach
Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration.dlvr.it - ICYMI: ONLINE NOW: Harnessing patient autophagy flux to transform tuberculosis treatment
Harnessing patient autophagy flux to transform tuberculosis treatment
Tuberculosis (TB) remains a major global health burden, prompting heightened efforts towards host-directed therapies (HDT). Autophagy, a key antimicrobial and immunomodulatory process, is a promising candidate for HDT. However, despite encouraging preclinical results, autophagy-targeting strategies have shown limited clinical success, in part due to the lack of accurate profiling of patient-derived autophagy flux across the TB spectrum. This gap limits our understanding of baseline autophagy dynamics and hinders the rational design of HDT. This review highlights patient-derived autophagic flux as a dynamic, quantitative readout of autophagy activity and an underutilized element in TB biomarker and therapeutic research. We examine autophagy flux assessment methodologies and propose its role as a biomarker for TB diagnosis, prognosis, and patient stratification in personalized HDT strategies.dlvr.it - ONLINE NOW: Harnessing patient autophagy flux to transform tuberculosis treatment
Harnessing patient autophagy flux to transform tuberculosis treatment
Tuberculosis (TB) remains a major global health burden, prompting heightened efforts towards host-directed therapies (HDT). Autophagy, a key antimicrobial and immunomodulatory process, is a promising candidate for HDT. However, despite encouraging preclinical results, autophagy-targeting strategies have shown limited clinical success, in part due to the lack of accurate profiling of patient-derived autophagy flux across the TB spectrum. This gap limits our understanding of baseline autophagy dynamics and hinders the rational design of HDT. This review highlights patient-derived autophagic flux as a dynamic, quantitative readout of autophagy activity and an underutilized element in TB biomarker and therapeutic research. We examine autophagy flux assessment methodologies and propose its role as a biomarker for TB diagnosis, prognosis, and patient stratification in personalized HDT strategies.dlvr.it - ICYMI: ONLINE NOW: Lipedema: a chronic adipose tissue disease
Lipedema: a chronic adipose tissue disease
Lipedema is a non-inflammatory disorder of subcutaneous fat mainly affecting women, manifesting as non-pitting, diffuse fat accumulation in legs, hips, and upper arms. It progresses through stages: stage 1 has even skin with small, rice-grain-sized fat nodules; stage 2 features uneven, larger fat nodules and fibrosis; stage 3 causes skin deformity from massive fat extrusions. Genome-wide association studies (GWAS) link polymorphisms in VEGFA, GRB14-COBLL1, and other loci related to increased waist-to-hip ratio, and functionally connect vessel formation and lipid storage.dlvr.it - ONLINE NOW: Lipedema: a chronic adipose tissue disease
Lipedema: a chronic adipose tissue disease
Lipedema is a non-inflammatory disorder of subcutaneous fat mainly affecting women, manifesting as non-pitting, diffuse fat accumulation in legs, hips, and upper arms. It progresses through stages: stage 1 has even skin with small, rice-grain-sized fat nodules; stage 2 features uneven, larger fat nodules and fibrosis; stage 3 causes skin deformity from massive fat extrusions. Genome-wide association studies (GWAS) link polymorphisms in VEGFA, GRB14-COBLL1, and other loci related to increased waist-to-hip ratio, and functionally connect vessel formation and lipid storage.dlvr.it - ICYMI: ONLINE NOW: Cholesterol metabolism: a new checkpoint in cancer immunity
Cholesterol metabolism: a new checkpoint in cancer immunity
Immunotherapy resistance, orchestrated largely by the tumor microenvironment (TME), remains a major clinical challenge. Recent advances highlight metabolic reprogramming as a key driver of this resistance. In this review we focus on cholesterol metabolism, a central hub that profoundly reshapes the tumor immune landscape. We dissect how dysregulated cholesterol pathways fortify tumor cells against immune attack while simultaneously suppressing effector immune cells. We conceptualize cholesterol metabolism as a critical metabolic–immune checkpoint, a novel framework for understanding this tumor–immune crosstalk. Finally, we comprehensively review emerging therapeutic strategies targeting this checkpoint, illuminating a promising translational path to dismantle metabolic barriers and overcome immunotherapy resistance.dlvr.it - ICYMI: ONLINE NOW: Microvascular hypoxia and inflammation in chronic pain syndromes
Microvascular hypoxia and inflammation in chronic pain syndromes
In this opinion, we propose that compromised microvascular perfusion and inflammation are fundamental drivers of chronic pain syndromes, with many of these conditions sharing a common etiology involving suboptimal blood flow and inflammatory cascades. This hypothesis links capillary constriction, hypoxia, inflammation, and nociceptor activation into a unified framework for understanding pain mechanisms. For each example syndrome, we explore specific nuances, molecular mechanisms, and therapeutic opportunities, focusing on the interplay between hypoxia and inflammation. Current treatments often emphasize anti-angiogenic or broad-spectrum approaches, which may neglect the microvascular and hypoxic origins. We review studies investigating microvascular hypoperfusion and inflammation in pain and suggest that targeted therapies addressing vascular deficits and inflammatory responses could better disrupt the hypoxia–inflammation cycle, offering novel avenues for treatment.dlvr.it - ONLINE NOW: Cholesterol metabolism: a new checkpoint in cancer immunity
Cholesterol metabolism: a new checkpoint in cancer immunity
Immunotherapy resistance, orchestrated largely by the tumor microenvironment (TME), remains a major clinical challenge. Recent advances highlight metabolic reprogramming as a key driver of this resistance. In this review we focus on cholesterol metabolism, a central hub that profoundly reshapes the tumor immune landscape. We dissect how dysregulated cholesterol pathways fortify tumor cells against immune attack while simultaneously suppressing effector immune cells. We conceptualize cholesterol metabolism as a critical metabolic–immune checkpoint, a novel framework for understanding this tumor–immune crosstalk. Finally, we comprehensively review emerging therapeutic strategies targeting this checkpoint, illuminating a promising translational path to dismantle metabolic barriers and overcome immunotherapy resistance.dlvr.it - ONLINE NOW: Microvascular hypoxia and inflammation in chronic pain syndromes
Microvascular hypoxia and inflammation in chronic pain syndromes
In this opinion, we propose that compromised microvascular perfusion and inflammation are fundamental drivers of chronic pain syndromes, with many of these conditions sharing a common etiology involving suboptimal blood flow and inflammatory cascades. This hypothesis links capillary constriction, hypoxia, inflammation, and nociceptor activation into a unified framework for understanding pain mechanisms. For each example syndrome, we explore specific nuances, molecular mechanisms, and therapeutic opportunities, focusing on the interplay between hypoxia and inflammation. Current treatments often emphasize anti-angiogenic or broad-spectrum approaches, which may neglect the microvascular and hypoxic origins. We review studies investigating microvascular hypoperfusion and inflammation in pain and suggest that targeted therapies addressing vascular deficits and inflammatory responses could better disrupt the hypoxia–inflammation cycle, offering novel avenues for treatment.dlvr.it - ICYMI: ONLINE NOW: The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency
The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency
To date, research on premature ovarian insufficiency (POI) primarily centers on ovarian dysfunction and systemic hormonal imbalances, with limited attention given to associated endometrial alterations. Given the critical role of the endometrium in reproductive function and its potential contribution to POI-related infertility, in this review, we bridge the knowledge gap regarding endometrial aspects of POI. We discuss the physiology and pathophysiology alterations in the POI endometrium, the multilevel endometrial changes spanning histological architecture, molecular signatures, and functional capacity, and clinical ramifications for fertility potential. In addition, we critically evaluate both established and novel therapeutic interventions targeting these endometrial abnormalities, paying particular attention to their potential to restore reproductive function.dlvr.it - ONLINE NOW: The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency
The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency
To date, research on premature ovarian insufficiency (POI) primarily centers on ovarian dysfunction and systemic hormonal imbalances, with limited attention given to associated endometrial alterations. Given the critical role of the endometrium in reproductive function and its potential contribution to POI-related infertility, in this review, we bridge the knowledge gap regarding endometrial aspects of POI. We discuss the physiology and pathophysiology alterations in the POI endometrium, the multilevel endometrial changes spanning histological architecture, molecular signatures, and functional capacity, and clinical ramifications for fertility potential. In addition, we critically evaluate both established and novel therapeutic interventions targeting these endometrial abnormalities, paying particular attention to their potential to restore reproductive function.dlvr.it - ICYMI: ONLINE NOW: Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications
Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications
Microbial pathogens have developed diverse strategies to exploit the host immune system because of their long period of coevolution with the target hosts. A deeper understanding of these mechanisms, particularly the role of microbial virulence proteins (MPs) in modulating host immune defense mechanisms, has opened new avenues for devising innovative therapeutic strategies. Several MPs are now being repurposed for the treatment of a range of clinical conditions including anti-inflammatory, anticancer, antimicrobial, antithrombotic, antidiabetic, and kidney-related diseases. Some of these therapies are currently in clinical trials or in clinical use. This review highlights recent advances in repurposing MPs as therapeutics and their growing clinical relevance.dlvr.it - ICYMI: ONLINE NOW: Neuroendocrine timekeepers: changes in normal and premature aging
Neuroendocrine timekeepers: changes in normal and premature aging
The hypothalamus is a central regulator of circadian rhythms, metabolism, and endocrine function, integrating internal and external cues to maintain physiological homeostasis. Aging impairs hypothalamic function, leading to metabolic changes, sleep disturbances, and a higher risk of age-related disease. Laminopathies – rare genetic disorders marked by premature aging – exhibit profound neuroendocrine and circadian rhythm dysfunction, offering insights into mechanisms of hypothalamic aging. The complex interplay between the hypothalamus, circadian rhythms, and systemic aging highlights the critical role of neuroendocrine crosstalk in the regulation of health span and life span. This review summarizes emerging molecular and physiological insights into hypothalamic aging and circadian misalignment, and highlights potential interventions, such as chronotherapy and caloric restriction, that may alleviate hypothalamic alterations and promote healthy aging.dlvr.it - ONLINE NOW: Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications
Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications
Microbial pathogens have developed diverse strategies to exploit the host immune system because of their long period of coevolution with the target hosts. A deeper understanding of these mechanisms, particularly the role of microbial virulence proteins (MPs) in modulating host immune defense mechanisms, has opened new avenues for devising innovative therapeutic strategies. Several MPs are now being repurposed for the treatment of a range of clinical conditions including anti-inflammatory, anticancer, antimicrobial, antithrombotic, antidiabetic, and kidney-related diseases. Some of these therapies are currently in clinical trials or in clinical use. This review highlights recent advances in repurposing MPs as therapeutics and their growing clinical relevance.dlvr.it - ONLINE NOW: Neuroendocrine timekeepers: changes in normal and premature aging
Neuroendocrine timekeepers: changes in normal and premature aging
The hypothalamus is a central regulator of circadian rhythms, metabolism, and endocrine function, integrating internal and external cues to maintain physiological homeostasis. Aging impairs hypothalamic function, leading to metabolic changes, sleep disturbances, and a higher risk of age-related disease. Laminopathies – rare genetic disorders marked by premature aging – exhibit profound neuroendocrine and circadian rhythm dysfunction, offering insights into mechanisms of hypothalamic aging. The complex interplay between the hypothalamus, circadian rhythms, and systemic aging highlights the critical role of neuroendocrine crosstalk in the regulation of health span and life span. This review summarizes emerging molecular and physiological insights into hypothalamic aging and circadian misalignment, and highlights potential interventions, such as chronotherapy and caloric restriction, that may alleviate hypothalamic alterations and promote healthy aging.dlvr.it - ICYMI: ONLINE NOW: Predicting healthspan and disease risks through biological age
Predicting healthspan and disease risks through biological age
Aging is the gradual decline in physiological function essential for survival and reproduction. Unlike age-associated diseases, aging affects all individuals within a species, causing progressive impairments across multiple systems. Research shows that altering specific genes or dietary factors can extend lifespan, implicating molecular pathways in controlling senescence. Chronological age (CA) is a common measure of aging, but other hallmarks like telomere shortening better quantify functional decline. Identifying age-related hallmarks can help manipulate aging, spurring interest in aging clocks. These clocks predict biological age (BA) more precisely than CA, reflecting actual physiological health. As global life expectancy continues to rise, aging clocks hold promise for developing therapies to extend healthspan and improve life quality during aging.dlvr.it - ICYMI: ONLINE NOW: The right drug at the right time: key to IBD success
The right drug at the right time: key to IBD success
Despite revolutionary molecular targeting therapies introduced over the past two decades for the management of inflammatory bowel disease (IBD), there remains significant variability in drug efficacy, which likely reflects the multifactorial basis and the complex and dynamic nature of the disorder. The presence of different molecular mechanisms and the diversity of cytokine expression profiles that drive distinct subtypes or different phases of IBD could affect the response to current pharmacological treatments. In this review we discuss the distinct roles of cytokines across different disease phases, and emphasize the importance of tailored drug use based on available biomarkers to deliver molecular targeted agents suited to the condition of each patient.dlvr.it - ONLINE NOW: Predicting healthspan and disease risks through biological age
Predicting healthspan and disease risks through biological age
Aging is the gradual decline in physiological function essential for survival and reproduction. Unlike age-associated diseases, aging affects all individuals within a species, causing progressive impairments across multiple systems. Research shows that altering specific genes or dietary factors can extend lifespan, implicating molecular pathways in controlling senescence. Chronological age (CA) is a common measure of aging, but other hallmarks like telomere shortening better quantify functional decline. Identifying age-related hallmarks can help manipulate aging, spurring interest in aging clocks. These clocks predict biological age (BA) more precisely than CA, reflecting actual physiological health. As global life expectancy continues to rise, aging clocks hold promise for developing therapies to extend healthspan and improve life quality during aging.dlvr.it - ONLINE NOW: The right drug at the right time: key to IBD success
The right drug at the right time: key to IBD success
Despite revolutionary molecular targeting therapies introduced over the past two decades for the management of inflammatory bowel disease (IBD), there remains significant variability in drug efficacy, which likely reflects the multifactorial basis and the complex and dynamic nature of the disorder. The presence of different molecular mechanisms and the diversity of cytokine expression profiles that drive distinct subtypes or different phases of IBD could affect the response to current pharmacological treatments. In this review we discuss the distinct roles of cytokines across different disease phases, and emphasize the importance of tailored drug use based on available biomarkers to deliver molecular targeted agents suited to the condition of each patient.dlvr.it - ICYMI: ONLINE NOW: Tryptophan metabolites at the service of neuroimmune sensing of microbes
Tryptophan metabolites at the service of neuroimmune sensing of microbes
Hosts have evolved multifaceted, intricate mechanisms to sense and respond to the microbes they coexist with, and these mechanisms play an important role in health and disease. The co-metabolism of dietary components by hosts and their microbiomes produces a myriad of signaling molecules, which are increasingly recognized in pathophysiology regulation via their engagement with the neuro-immune network. In this review, we focus on the emerging role of tryptophan (Trp) metabolites in host–microbe crosstalk through the lens of neuroimmune sensing in the gut and beyond. We highlight how Trp metabolites orchestrate the immune and neural networks to mediate the local and trans-organ effects of the microbiome. We also consider how a neuroimmunometabolic perspective could offer valuable insights into the pathogenesis of, and treatment strategies for, chronic diseases.dlvr.it - ICYMI: ONLINE NOW: Emerging innovative treatments for leptomeningeal metastatic tumors
Emerging innovative treatments for leptomeningeal metastatic tumors
Leptomeningeal metastasis (LM) represents a devastating and terminal complication of advanced solid tumors, characterized by the dissemination of malignant cells within the leptomeninges and cerebrospinal fluid. Conventional therapies have demonstrated limited efficacy due to substantial toxicity and poor drug penetration. Recent advances in targeted therapy, immunotherapy, and intrathecal drug delivery are reshaping the therapeutic landscape for LM. Brain-penetrant agents have shown improved outcomes, and intrathecal administration of antibodies and immune checkpoint inhibitors (ICIs) further expands therapeutic options. Immunotherapies, notably chimeric antigen receptor T cells (CAR-T cells) and mesenchymal stem-cell-based therapies offer promise in counteracting LM’s immunosuppressive microenvironment. These innovations represent a paradigm shift in the management of LM and offer a renewed therapeutic potential for patients with LM. This review highlights key preclinical and clinical advances that are reshaping the management of LM.dlvr.it - ONLINE NOW: Tryptophan metabolites at the service of neuroimmune sensing of microbes
Tryptophan metabolites at the service of neuroimmune sensing of microbes
Hosts have evolved multifaceted, intricate mechanisms to sense and respond to the microbes they coexist with, and these mechanisms play an important role in health and disease. The co-metabolism of dietary components by hosts and their microbiomes produces a myriad of signaling molecules, which are increasingly recognized in pathophysiology regulation via their engagement with the neuro-immune network. In this review, we focus on the emerging role of tryptophan (Trp) metabolites in host–microbe crosstalk through the lens of neuroimmune sensing in the gut and beyond. We highlight how Trp metabolites orchestrate the immune and neural networks to mediate the local and trans-organ effects of the microbiome. We also consider how a neuroimmunometabolic perspective could offer valuable insights into the pathogenesis of, and treatment strategies for, chronic diseases.dlvr.it - ONLINE NOW: Emerging innovative treatments for leptomeningeal metastatic tumors
Emerging innovative treatments for leptomeningeal metastatic tumors
Leptomeningeal metastasis (LM) represents a devastating and terminal complication of advanced solid tumors, characterized by the dissemination of malignant cells within the leptomeninges and cerebrospinal fluid. Conventional therapies have demonstrated limited efficacy due to substantial toxicity and poor drug penetration. Recent advances in targeted therapy, immunotherapy, and intrathecal drug delivery are reshaping the therapeutic landscape for LM. Brain-penetrant agents have shown improved outcomes, and intrathecal administration of antibodies and immune checkpoint inhibitors (ICIs) further expands therapeutic options. Immunotherapies, notably chimeric antigen receptor T cells (CAR-T cells) and mesenchymal stem-cell-based therapies offer promise in counteracting LM’s immunosuppressive microenvironment. These innovations represent a paradigm shift in the management of LM and offer a renewed therapeutic potential for patients with LM. This review highlights key preclinical and clinical advances that are reshaping the management of LM.dlvr.it - ICYMI: ONLINE NOW: Molecular advances and therapeutic potential in leveraging hepcidin
Molecular advances and therapeutic potential in leveraging hepcidin
Iron, regulated by the hormone hepcidin, is essential for cellular function and diverse biological processes. In this forum, we examine emerging therapeutic approaches targeting the hepcidin–iron axis, with applications across three key areas: cancer treatment, polycythemia vera (PV) and anemia, and infectious disease.dlvr.it - ICYMI: ONLINE NOW: Androgen receptor and its coregulators in sex-biased diseases
Androgen receptor and its coregulators in sex-biased diseases
Men have a higher incidence of specific types of cancer and neurodegenerative disease. Mounting evidence suggests that androgen receptor (AR)-mediated androgen signaling is a key determinant at the core of this sex discrepancy. Herein we review the role of androgens in disorders characterized by altered AR activity, focusing on transcriptional coregulators that shape receptor specificity. In particular, we highlight the roles of protein arginine methyltransferase 6 (PRMT6) and lysine-specific demethylase 1 (LSD1), enzymes associated with epigenetic repression, yet functioning as AR coactivators. By enhancing AR transcriptional output, PRMT6 and LSD1 contribute to malignant transformation and progression across multiple cell types. We further explore how these insights inform combinatorial therapeutic strategies targeting AR, PRMT6, and LSD1, with implications for both cancer and neurodegeneration.dlvr.it - ONLINE NOW: Molecular advances and therapeutic potential in leveraging hepcidin
Molecular advances and therapeutic potential in leveraging hepcidin
Iron, regulated by the hormone hepcidin, is essential for cellular function and diverse biological processes. In this forum, we examine emerging therapeutic approaches targeting the hepcidin–iron axis, with applications across three key areas: cancer treatment, polycythemia vera (PV) and anemia, and infectious disease.dlvr.it - ONLINE NOW: Androgen receptor and its coregulators in sex-biased diseases
Androgen receptor and its coregulators in sex-biased diseases
Men have a higher incidence of specific types of cancer and neurodegenerative disease. Mounting evidence suggests that androgen receptor (AR)-mediated androgen signaling is a key determinant at the core of this sex discrepancy. Herein we review the role of androgens in disorders characterized by altered AR activity, focusing on transcriptional coregulators that shape receptor specificity. In particular, we highlight the roles of protein arginine methyltransferase 6 (PRMT6) and lysine-specific demethylase 1 (LSD1), enzymes associated with epigenetic repression, yet functioning as AR coactivators. By enhancing AR transcriptional output, PRMT6 and LSD1 contribute to malignant transformation and progression across multiple cell types. We further explore how these insights inform combinatorial therapeutic strategies targeting AR, PRMT6, and LSD1, with implications for both cancer and neurodegeneration.dlvr.it - The November issue of Trends in Molecular Medicine is now online! www.cell.com/trends/molec... Special thanks to all the authors and reviewers for their contribution! I am happy to receive your feedback and ideas for topics so please get in touch!
- ICYMI: ONLINE NOW: Transcriptional landscape of skeletal muscle in cancer patients
Transcriptional landscape of skeletal muscle in cancer patients
Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.dlvr.it - ONLINE NOW: Transcriptional landscape of skeletal muscle in cancer patients
Transcriptional landscape of skeletal muscle in cancer patients
Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.dlvr.it - ICYMI: ONLINE NOW: ANGPTL3/8: one target, multiple lipid disorders
ANGPTL3/8: one target, multiple lipid disorders
The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL–cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning.dlvr.it - ICYMI: ONLINE NOW: Precision medicine for sodium channelopathy-related autism and epilepsy
Precision medicine for sodium channelopathy-related autism and epilepsy
Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder, most (ASD) notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.dlvr.it - ONLINE NOW: ANGPTL3/8: one target, multiple lipid disorders
ANGPTL3/8: one target, multiple lipid disorders
The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL–cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning.dlvr.it - ONLINE NOW: Precision medicine for sodium channelopathy-related autism and epilepsy
Precision medicine for sodium channelopathy-related autism and epilepsy
Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder, most (ASD) notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.dlvr.it - ICYMI: ONLINE NOW: The biology of congenital urinary bladder outflow obstruction
The biology of congenital urinary bladder outflow obstruction
Congenital urinary bladder outflow obstruction (BOO) is a major cause of kidney failure in children. Sometimes, it is caused by anatomical obstruction of the urethra. In other cases, functional failure of voiding occurs without anatomical obstruction. Bladder development is driven by genes expressed in smooth muscle, neural and urothelial cell lineages. Variants in the coding regions of such genes cause a subset of BOO. In other cases, such as posterior urethral valves (PUV), noncoding variants may influence susceptibility. By modelling BOO in mutant mice, combined with viral vector mediated gene therapy, steps are being made to ameliorate the pathobiology of these diseases. Translation of such strategies to humans may require prenatal gene therapy.dlvr.it - ONLINE NOW: The biology of congenital urinary bladder outflow obstruction
The biology of congenital urinary bladder outflow obstruction
Congenital urinary bladder outflow obstruction (BOO) is a major cause of kidney failure in children. Sometimes, it is caused by anatomical obstruction of the urethra. In other cases, functional failure of voiding occurs without anatomical obstruction. Bladder development is driven by genes expressed in smooth muscle, neural and urothelial cell lineages. Variants in the coding regions of such genes cause a subset of BOO. In other cases, such as posterior urethral valves (PUV), noncoding variants may influence susceptibility. By modelling BOO in mutant mice, combined with viral vector mediated gene therapy, steps are being made to ameliorate the pathobiology of these diseases. Translation of such strategies to humans may require prenatal gene therapy.dlvr.it - ICYMI: ONLINE NOW: Renin–angiotensin system: a novel target for brain health
Renin–angiotensin system: a novel target for brain health
Emerging evidence highlights the brain renin–angiotensin system (RAS) as a key regulator of reward, memory, and stress. While these discoveries established the brain RAS as a promising therapeutic target for interventions in neurological and neuropsychiatric disorders, translational progress is hampered by the lack of an integrative mechanistic framework. Here, we consolidate accumulating evidence on the molecular and system-level roles of the brain RAS in reward, memory, and stress pathways, and its dual regulatory architecture. Pharmacological RAS modulation regulates domain-specific signaling in frontostriatal reward circuits, hippocampal–prefrontal memory networks, and frontolimbic fear networks. We evaluate the transdiagnostic therapeutic potential in neurological and neuropsychiatric disorders (e.g., dementia and depression), identify translational barriers, and conclude with strategic research priorities to facilitate clinical translation.dlvr.it
