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Genetic and Plasma Proteomic Approaches to Identify Therapeutic Targets for Graves' Disease and Graves' Ophthalmopathy.

BackgroundThe blood proteome is a major source of biomarkers and therapeutic targets. We aimed to identify the causal proteins and potential targets for Graves' disease (GD) and Graves' ophthalmopathy (GO) via systematic genetic analyses.MethodsGenome-wide association studies (GWASs) on the UK Biobank- Pharma Proteomics Project (UKB-PPP) collected 2923 Olink proteins from 54,219 participants. We conducted a proteome-wide Mendelian randomization (MR) study with cis-pQTLs to identify candidate proteins for GD and GO risk. Colocalization analysis and the Heidi test were used to examine whether th

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… inflammatory response occurs. 38 A previous study revealed that CXCL10 was associated with the risk of GD; however, compared with those in euthyroid thyroid autoantibody-negative patients, CXCL10 levels in patients with newly diagnosed GD were significantly greater. 39 In the presence of IFNγ+ TNFα, fenofibrate …

Drug repurposing for breast cancer therapy: Old weapon for new battle.

Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process o

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… Other drugs such as L-NMMA (tilarginine acetate, a nitric oxide synthase inhibitor) [ 138 ], pro-viral integration moloney virus kinase (PIM)-1 inhibitors (olaparib) [ 139 ], L-asparginase [ 140 ], and fenofibrate [ 141 ] are being repurposed for breast cancer. …

Computational proteomics to enhance personalized treatment of COVID-19 and Long COVID.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to significant global health burden, including both acute infections and persistent post-acute sequelae, also known as Long COVID (LC) in survivors. While clinical management has reduced case-fatality rates, a substantial proportion of patients develop LC, a heterogeneous syndrome with long-term symptoms. This complex continuum requires therapeutic strategies for both the acute and chronic phases. Plasma proteomics has emerged as a powerful tool in precision medicin

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… COVID-19 patients | Not applicable | Not applicable | [ 245 ] Fluvoxamine | Obsessive-compulsive disorder (OCD) | Sigma-1 receptor | Repurposed: Reduces inflammation; prevents clinical deterioration | Promising results in early trials; further studies ongoing | Not applicable | Not applicable | [ 246 ] Fenofibrate …

The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.

The cGAS-STING pathway acts as a critical molecular hub connecting genomic instability with cellular senescence. Functioning as a key regulator of the innate immune system, this pathway detects aberrant cytoplasmic DNA to activate downstream inflammatory responses, thereby playing a pivotal role in aging-related diseases. This review systematically explores the core mechanisms by which the cGAS-STING pathway regulates cellular senescence, emphasizing its role in triggering senescence through the recognition of DNA damage signals (e.g., oxidative stress, telomere dysfunction) and promoting para

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… ATM/Chk1/p53 pathway | Tert overexpression | Blocks DNA damage signal transduction | [ 300 ] Modulates OGG1/FEN1 expression balance, reduces mtDNA-mediated signaling | 6-Shogaol | Reduces mtDNA-mediated cGAS-STING signaling activation in the GI tract | [ 301 ] Reduces ROS generation, restores MMP | Fenofibrate … For example, the lipid-lowering agent fenofibrate demonstrates dual efficacy by reducing ROS production and restoring MMP, thereby inhibiting mtDNA release and alleviating corneal inflammation [ 302 ]. …

Cancer Metabolism as a Therapeutic Target and Review of Interventions.

Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and

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… Atorvastatin and Fenofibrate Modulate Certain Steroidal Hormones, Vitamin D and Bile Acids in Diabetic Dyslipidemic Rats Int. J. Pharm. Clin. Res. 2015 7 426 434 120. Waters D.D. Safety of high-dose atorvastatin therapy Am. J. Cardiol. 2005 96 69 75 10.1016/j.amjcard.2005.06.028 16126026 121. …

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients.

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are au

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… It was reported that fenofibrate, the peroxisome proliferator-activated receptor alpha (PPARα) agonist, [ 9 ] could revert the ketogenic potentiality back to what it was originally in a tumor-bearing experimental animal model. … Fenofibrate prevents skeletal muscle loss in mice with lung cancer. Proc. Natl. Acad. Sci. USA. 2018;115:E743–E752. doi: 10.1073/pnas.1714703115. 10. Fearon K.C., Barber M.D., Falconer J., McMillan D.C., Ross J.A., Preston T. …

The updated landscape of tumor microenvironment and drug repurposing.

Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Nonetheless, the clinical efficacy of therapeutic strategies targeting TME, especially the specific cells or pathways of TME, remains unsatisfactory. Classifying the chemopathological characteristics of TME and crosstalk among one another can greatly b

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… Completed DC vaccine and cisplatin Ovarian cancer NCT02432378 Recruiting Gemcitabine and gene therapy (rAd-IFN) Malignant pleural mesothelioma NCT03710876 Recruiting Chemotherapy (carboplatin, gemcitabine) and 5-LOX inhibitor zileuton Advanced NSCLC NCT00070486 Completed Etoposide, CTX, thalidomide, fenofibrate … vaccine and cisplatin | Ovarian cancer | NCT02432378 | Recruiting Gemcitabine and gene therapy (rAd-IFN) | Malignant pleural mesothelioma | NCT03710876 | Recruiting Chemotherapy (carboplatin, gemcitabine) and 5-LOX inhibitor zileuton | Advanced NSCLC | NCT00070486 | Completed Etoposide, CTX, thalidomide, fenofibrate …

Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022.

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Unraveling Obesity and Multiple Myeloma: Insights from Epidemiology and Molecular Mechanisms.

Purpose of reviewThe global incidence of obesity has risen dramatically in recent decades, with consequent detrimental health effects. Extensive studies have demonstrated that obesity significantly affects the risk, prognosis, and progression of various cancers, including multiple myeloma (MM). As an established modifiable risk factor for both MM and its precursor stages -monoclonal gammopathy of unknown significance (MGUS) and smoldering MM (SMM)- the association between obesity and disease onset has become a compelling area of research. This review presents a comprehensive overview of the cu

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… Sha et al. demonstrated that the efficacy of lenalidomide can be significantly altered when co-administered with PPAR ligands (e.g. the PPARα agonist fenofibrate, the PPARβ/δ agonist GW501516 , and the PPARγ agonist troglitazone), which modulate the transcriptional activity of the shallow hydrophobic … In line with these findings, another study evaluated the clinical outcomes in MM patients with concurrent diabetes and/or dyslipidemia who were treated with both IMiDs and PPAR agonists (fenofibrate, GW5015016 and troglitazone), indicating better PFS, and OS in patients treated with both drug classes …

Mitochondrial biogenesis: pharmacological approaches.

Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and div … ility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mito …

Role of mitochondria in physiological activities, diseases, and therapy.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of

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… Combination therapy NCT00088413 Colorectal cancer CPI-613 + Fluorouracil Phase I Combination therapy NCT02232152 CPI-613 + mFOLFIRINOX Phase I Combination therapy NCT05070104 Prostate cancer GnRH agonist Not applicable Gonadotropin-releasing hormone agonist NCT03867357 Symptomatic multiple myeloma Fenofibrate … Sodium-glucose cotransporter 2 inhibitor | NCT03919656 | Semaglutide + Dieting | Phase IV | Combination therapy | NCT04854083 | Isoleucine | Not applicable | Accelerate branched-chain amino acids oxidation | NCT04461236 | Metformin | Phase IV | Reduce blood sugar | NCT01813929 Diabetic nephropathy | Fenofibrate …

Pancreatitis: TIGAR-O Version 2 Risk/Etiology Checklist With Topic Reviews, Updates, and Use Primers.

The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive (TIGAR-O) Pancreatitis Risk/Etiology Checklist (TIGAR-O_V1) is a broad classification system that lists the major risk factors and etiologies of recurrent acute pancreatitis, chronic pancreatitis, and overlapping pancreatic disorders with or without genetic, immunologic, metabolic, nutritional, neurologic, metaplastic, or other features. New discoveries and progressive concepts since the 2001 TIGAR-O list relevant to understanding and managing complex pancreatic disorders require an up

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… More than 100 drugs have been implicated in AP and RAP, such as methylprednisolone, fenofibrate, angiotensin-converting enzyme inhibitors, statins, estrogens, and valproic acid, although direct, mechanistic cause-effect relationships are typically lacking and underlying cofactors such as genetic factors …

New insight into adiponectin role in obesity and obesity-related diseases.

Obesity is a major health problem strongly increasing the risk for various severe related complications such as metabolic syndrome, cardiovascular diseases, respiratory disorders, diabetic retinopathy, and cancer. Adipose tissue is an endocrine organ that produces biologically active molecules defined "adipocytokines," protein hormones with pleiotropic functions involved in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, cell proliferation, and so forth. In obesity, fat accumulation causes dysregulation of adipokine production tha

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… angiotensin receptor blocker, independently on PPAR- γ activation Biochemical and Biophysical Research Communications 2007 356 4 1024 1030 2-s2.0-34047170834 17399685 10.1016/j.bbrc.2007.03.084 149 Hiuge A Tenenbaum A Maeda N Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate …

Nanomedicine: Principles, Properties, and Regulatory Issues.

Several scientific areas have benefited significantly from the introduction of nanotechnology and the respective evolution. This is especially noteworthy in the development of new drug substances and products. This review focuses on the introduction of nanomedicines in the pharmaceutical market, and all the controversy associated to basic concepts related to these nanosystems, and the numerous methodologies applied for enhanced knowledge. Due to the properties conferred by the nanoscale, the challenges for nanotechnology implementation, specifically in the pharmaceutical development of new dru

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… lymphoblastic leukemia Nanocrystals | Paliperidone palmitate Xeplion® | Prolonged release suspension for injection | Schizophrenia | Olanzapine pamoate Zypadhera® | Powder and solvent for prolonged release suspension for injection | Schizophrenia | Aprepitant Emend® | Capsule | Nausea and vomiting | Fenofibrate …

Chronic pruritus: a narrative review.

Chronic pruritus encompasses a manifestation of several cutaneous, allergic, infectious, neurological, psychological, and systemic conditions, whose etiological investigation and therapeutic strategy can be challenging. This comprehensive review aims to enhance the understanding of pruritus by highlighting important elements in its pathogenesis, including keratinocytes, Merkel cells and mast cells, nerve fibers, histaminergic and nonhistaminergic pathways, and the interaction of itch signals with the central nervous system. Diagnostic evaluation of chronic pruritus may require a meticulous app

PPARs in Irradiation-Induced Gastrointestinal Toxicity.

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. Although the benefits of this treatment are well established, many patients experience distressing complications due to injury to normal tissue. These side effects are related to inflammatory processes, and they decrease therapeutic benefit by increasing the overall treatment time. Emerging evidence indicates that PPARs and their ligands are important in the modulation of immune and inflammatory reactions. This paper discusses the effects of abdominal irradiation on PPARs, their role and functions in i

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… The best-studied synthetic PPAR- α ligands are the fibrate class of hypolipidemic drugs (bezafibrate, clofibrate, and fenofibrate), which have been used therapeutically in humans for many years [ 16 ]. 3. …

Monitoring concentration and lipid signature of plasma extracellular vesicles from HR+ metastatic breast cancer patients under CDK4/6 inhibitors treatment.

Extracellular vesicles (EVs) are cell-derived small membrane structures that transport various molecules. They have emerged as potential circulating biomarkers for monitoring responses to cancer therapies. This study aimed to comprehensively characterize plasma-carried EVs in hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients treated with first-line CDK4/6 inhibitors (iCDK4/6) combined with endocrine therapy. MBC patients were classified into three groups based on their response to therapy: resistant, intermediate or sensitive. In a prospective cohort, we monitored the con

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… Fenofibrate decreases plasma ceramide in type 2 diabetes patients: A novel marker of CVD? . …

The interplay of mitochondrial dysfunction and altered metabolic pathways in glioblastoma.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, characterized by rapid progression, treatment resistance, and poor prognosis, with a survival rate of less than five years despite advances in medical interventions. A hallmark of GBM is metabolic reprogramming, which supports tumor growth and progression. Mitochondrial dysfunction plays a critical role in this metabolic shift by altering energy production and disrupting key cellular pathways. However, the precise molecular mecha-nisms underlying these alterations remain inadequately understood. This review highlights th

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… NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells . …

Molecular and cellular mechanisms of skeletal muscle atrophy: an update.

Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic pr

Student Summer Research Awards - SSRAAbstracts of the SSRA September 2022 meeting, UCD School of Medicine.

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