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International Journal of Molecular... Sep 2023Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by... (Review)
Review
Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by changes in bone homeostasis, which lead to reduced bone mass, impaired bone quality, and an increased risk of fractures. The pathophysiology of osteoporosis is complex and multifactorial, involving imbalances in hormones, cytokines, and growth factors. Understanding the cellular and molecular mechanisms underlying osteoporosis is essential for appropriate diagnosis and management of the condition. This paper provides a comprehensive review of the normal cellular and molecular mechanisms of bone homeostasis, followed by an in-depth discussion of the proposed pathophysiology of osteoporosis through the osteoimmunological, gut microbiome, and cellular senescence models. Furthermore, the diagnostic tools used to assess osteoporosis, including bone mineral density measurements, biochemical markers of bone turnover, and diagnostic imaging modalities, are also discussed. Finally, both the current pharmacological and non-pharmacological treatment algorithms and management options for osteoporosis, including an exploration of the management of osteoporotic fragility fractures, are highlighted. This review reveals the need for further research to fully elucidate the molecular mechanisms underlying the condition and to develop more effective therapeutic strategies.
Topics: Humans; Pathology, Molecular; Osteoporosis; Osteoporotic Fractures; Bone Density; Bone and Bones
PubMed: 37834025
DOI: 10.3390/ijms241914583 -
BMJ (Clinical Research Ed.) Oct 2023Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an... (Review)
Review
Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.
Topics: Humans; Amyotrophic Lateral Sclerosis; Pathology, Molecular; Disease Progression
PubMed: 37890889
DOI: 10.1136/bmj-2023-075037 -
Cell Reports Sep 2023Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by...
Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
Topics: Ceramides; HSP27 Heat-Shock Proteins; Mitochondria; Mitophagy; Sphingolipids; Humans
PubMed: 37689067
DOI: 10.1016/j.celrep.2023.113081 -
Cell Reports Aug 2023Biomolecular condensates have been shown to interact in vivo, yet it is unclear whether these interactions are functionally meaningful. Here, we demonstrate that...
Biomolecular condensates have been shown to interact in vivo, yet it is unclear whether these interactions are functionally meaningful. Here, we demonstrate that cooperativity between two distinct condensates-germ granules and P bodies-is required for transgenerational gene silencing in C. elegans. We find that P bodies form a coating around perinuclear germ granules and that P body components CGH-1/DDX6 and CAR-1/LSM14 are required for germ granules to organize into sub-compartments and concentrate small RNA silencing factors. Functionally, while the P body mutant cgh-1 is competent to initially trigger gene silencing, it is unable to propagate the silencing to subsequent generations. Mechanistically, we trace this loss of transgenerational silencing to defects in amplifying secondary small RNAs and the stability of WAGO-4 Argonaute, both known carriers of gene silencing memories. Together, these data reveal that cooperation between condensates results in an emergent capability of germ cells to establish heritable memory.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; RNA, Small Interfering; Gene Silencing; RNA Interference; Germ Cells; RNA Nucleotidyltransferases
PubMed: 37505984
DOI: 10.1016/j.celrep.2023.112859 -
Current Issues in Molecular Biology Jun 2023Almost every death in young patients with an advanced skin tumor is caused by melanoma. Today, with the help of modern treatments, these patients survive longer or can... (Review)
Review
Almost every death in young patients with an advanced skin tumor is caused by melanoma. Today, with the help of modern treatments, these patients survive longer or can even achieve a cure. Advanced stage melanoma is frequently related with poor prognosis and physicians still find this disease difficult to manage due to the absence of a lasting response to initial treatment regimens and the lack of randomized clinical trials in post immunotherapy/targeted molecular therapy settings. New therapeutic targets are emerging from preclinical data on the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of malignant transformation. In the current paper, we present the diagnostic challenges, molecular biology and genetics of malignant melanoma, as well as the current therapeutic options for patients with this diagnosis.
PubMed: 37504268
DOI: 10.3390/cimb45070352 -
International Journal of Molecular... Dec 2023Cancer is rooted in genetic background, with the expression of oncogenesis playing a pivotal role in the early stages of tumor formation [...].
Cancer is rooted in genetic background, with the expression of oncogenesis playing a pivotal role in the early stages of tumor formation [...].
Topics: Humans; Neoplasms; Molecular Biology; Carcinogenesis; Cell Transformation, Neoplastic; Biology
PubMed: 38139014
DOI: 10.3390/ijms242417187 -
ELife Feb 2024A new in vitro system called Rec-Seq sheds light on how mRNA molecules compete for the machinery that translates their genetic sequence into proteins.
A new in vitro system called Rec-Seq sheds light on how mRNA molecules compete for the machinery that translates their genetic sequence into proteins.
Topics: Protein Biosynthesis; Ribosomes; RNA, Messenger
PubMed: 38393777
DOI: 10.7554/eLife.96304 -
Neuro-oncology Oct 2023In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS...
In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, "histomolecular" diagnosis is required. A variety of approaches exists for determining the status of the underlying molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analyses, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter methylation status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory, and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
Topics: Humans; Brain Neoplasms; Pathology, Molecular; Mutation; Glioma; World Health Organization
PubMed: 37279174
DOI: 10.1093/neuonc/noad100 -
International Journal of Molecular... Sep 2023The Special Issue State-of-the-Art Molecular Genetics and Genomics in Germany focuses on German researchers and their international peers, covering their recent advances...
The Special Issue State-of-the-Art Molecular Genetics and Genomics in Germany focuses on German researchers and their international peers, covering their recent advances in genetics, genomics, epigenetics, and cytogenetics/cytogenomics in relation to prokaryotic and eukaryotic multicellular to mammalian organisms in arras ranging from basic to medical research [...].
Topics: Animals; Genomics; Epigenomics; Germany; Biomedical Research; Molecular Biology; Mammals
PubMed: 37762398
DOI: 10.3390/ijms241814096