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Ketosis Suppression and Ageing (KetoSAge): The Effects of Suppressing Ketosis in Long Term Keto-Adapted Non-Athletic Females.

Most studies on ketosis have focused on short-term effects, male athletes, or weight loss. Hereby, we studied the effects of short-term ketosis suppression in healthy women on long-standing ketosis. Ten lean (BMI 20.5 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9) maintaining nutritional ketosis (NK) for > 1 year (3.9 years ± 2.3) underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Adherence to each phase was confirmed with daily capillary D-beta-hydroxybutyrate (BHB) tests (P1 = 1.9 ± 0.7; P2 = 0.1 ± 0.1; an

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… Chronically elevated IGF-1, and/or increased IGF-1 bioavailability and sensitivity, receptor expression, and amount of Ras protein prenylation [ 51 ] are strongly implicated in neoplasia and ageing [ 48 , 53 , 54 , 55 , 56 ], whilst IGF-1 knockdown within in vivo models show improved longevity [ 56 , … Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia Endocrinology 2000 141 1310 1316 10.1210/endo.141.4.7411 10746633 51. Goalstone M.L. Draznin B. What does insulin do to Ras? Cell. …

Old Drugs, New Battles: Unleashing Repurposed Drug Classes in Triple-Negative Breast Cancer Treatment.

Cancer remains a major global health challenge, with triple-negative breast cancer (TNBC) representing one of the most aggressive and difficult-to-treat subtypes, characterized by poor prognosis and limited therapeutic options. Current treatments, including chemotherapy, are hindered by high recurrence rates, drug resistance, and severe side effects, highlighting the urgent need for novel therapeutic strategies to address these challenges. Drug repurposing, which involves the application of existing FDA-approved (Food and administration) drugs for new oncological uses, offers a cost-effective

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… Statins, known for their cholesterol-lowering properties, also exhibit anticancer activity by inhibiting the mevalonate pathway, which is crucial for the prenylation of oncogenic proteins, such as Ras and Rho [ 62 ]. …

Bisphosphonate Use in Acute Spinal Cord Injury: A Focused Systematic Review on Zoledronic Acid.

Spinal cord injury (SCI) causes significant bone loss as a long-term complication, increasing fracture risk and healthcare costs. Bisphosphonates are widely studied for mitigating bone loss since they can prevent fractures and preserve rehabilitation potential in acute SCI patients. Zoledronic acid, in particular, stands out due to its high potency, dosing convenience, and better patient adherence. This review aims to evaluate the efficacy of bisphosphonates, particularly zoledronic acid, in mitigating bone loss in acute SCI. A systematic review was conducted following the Preferred Reporting

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… This inhibition prevents protein prenylation, which is required for small GTPase signaling proteins essential for cytoskeletal organization and vesicular trafficking in osteoclasts. Consequently, this disruption leads to loss of osteoclast function and induces apoptosis [ 26 ]. …

Emerging strategies to target RAS signaling in human cancer therapy.

RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target d

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… The final four amino acids, CAAX, of the C-terminal are the targets of posttranslational modifications, including iso-prenylation, proteolysis, and methylation which mediate RAS shift and binding to the cell membrane [ 21 ]. Fig. 1 Structure and switch of RAS. … The three molecules, NHTD, deltarasin, and deltazinone, competitively bind the prenyl-binding pocket of PDEδ, exhibiting the ability to impair the RAS protein stimulation at the membrane and further suppressing oncogenic KRAS signaling [ 77 – 79 ]. …

Bisphosphonate-Related Osteonecrosis of the Jaw and Oral Microbiome: Clinical Risk Factors, Pathophysiology and Treatment Options.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesio

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… This leads to the suppression of protein prenylation, causing osteoclast apoptosis [ 45 ]. Further research into the complex interplay between the chemical structure of BPs, their binding properties, and bacterial interactions is key to understanding the pathogenesis of BRONJ. 4.3. …

Treatment of Stage 2 Medication-Induced Osteonecrosis of the Jaw: A Case Series.

Medication-induced jaw osteonecrosis (MRONJ) is a rare and serious disease with a negative impact on patients' quality of life, whose exact cause remains unclear and which may have a multifactorial origin. Although there are different therapeutic protocols, there is still no consensus. This case series evaluated three patients diagnosed with staged 2 MRONJ treated at the University of Murcia dental clinic according to the protocols described by the Spanish Society of Oral and Maxillofacial Surgery and the American Association of Oral and Maxillofacial Surgeons. Within 12 months of the applicat

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… However, those that present nitrogen has been shown to be more potent and bind and inhibit key enzymes of the intracellular mevalonate pathway, thus preventing the prenylation and activation of small GTPases that are essential for bone resorption activity and survival. osteoclasts [ 28 ]. …

Alterations in macrophage polarization in the craniofacial and extracranial skeleton after zoledronate application and surgical interventions - an in vivo experiment.

PURPOSE: Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions. MATERIALS AN

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… The actual theory is that nitrogen-containing BPs have a high affinity to hydroxylapatite crystals in the bone and initiate apoptosis of osteoclasts by intervening in the mevalonate pathway and therefore the protein prenylation ( 13 ). …

Anti-Tumor Effects of Low Dose Zoledronate on Lung Cancer-Induced Spine Metastasis.

Zoledronate (Zol) is an anti-resorptive/tumoral agent used for the treatment of many cancers including spinal bone metastasis. High systemic administration of a single dose is now the standard clinical care, yet it has been associated with several side effects. Here, we aimed to evaluate the effects of lower doses Zol on lung cancer and lung cancer-induced bone metastasis cells over a longer time period. Human lung cancer (HCC827) and three bone metastases secondary to lung cancer (BML1, BML3 and BML4) cells were treated with Zol at 1, 3 and 10 µM for 7 days and then assessed for cell prolifer

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… The study of Kenessey et al. suggested that Zol inhibited the mevalonate pathway leading to the prevention of post-translational modification i.e prenylation of small G-proteins involved in motility signaling (such as Rho, Rac, Cdc42) and consequently resulted in an impaired migratory capacity [ 45 ] …

Anti-tumour activity of bisphosphonates in preclinical models of breast cancer.

There is increasing evidence of anti-tumour effects of bisphosphonates from pre-clinical studies, supporting a role for these drugs beyond their traditional use in treatment of cancer-induced bone disease. A range of model systems have been used to investigate the effects of different bisphosphonates on tumour growth, both in bone and at peripheral sites. Most of these studies conclude that bisphosphonates cause a reduction in tumour burden, but that early intervention and the use of high and/or repeated dosing is required. Successful eradication of cancer may only be achievable by targeting t

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… of zoledronic acid by inhibition of endothelial progenitor cell differentiation J Surg Res 2009 151 115 120 10.1016/j.jss.2008.01.031 18619615 Luckman SP Hughes DE Coxon FP Graham R Russell G Rogers MJ Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation …

Revolutionizing ovarian cancer therapy by drug repositioning for accelerated and cost-effective treatments.

Drug repositioning, the practice of identifying novel applications for existing drugs beyond their originally intended medical indications, stands as a transformative strategy revolutionizing pharmaceutical productivity. In contrast to conventional drug development approaches, this innovative method has proven to be exceptionally effective. This is particularly relevant for cancer therapy, where the demand for groundbreaking treatments continues to grow. This review focuses on drug repositioning for ovarian cancer treatment, showcasing a comprehensive exploration grounded in thorough in vitro

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… Lonafarnib also inhibits protein prenylation in the mevalonate pathway, inhibiting cell proliferation with higher efficiency than 6-fluoromevalonate and YM-53601 ( 108 ). … Mechanistically, zoledronic acid and fluvastatin treatment enhance the effects that involved Ras prenylation. …

Bone metastases in thyroid cancer.

Whereas preemptive screening for the presence of lymph node and lung metastases is standard-of-care in thyroid cancer patients, bone metastases are less well studied and are often neglected in thyroid cancer patient surveillance. Bone metastases in thyroid cancer are, however, independently associated with poor/worse prognosis with a median overall survival from detection of only 4 years despite an otherwise excellent prognosis for the vast majority of thyroid cancer patients. In this review we summarize the state of current knowledge as pertinent to bony metastatic disease in thyroid cancer,

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… Nitrogen-containing bisphosphonates (zoledronic acid, pamidronate, ibandronate) also inhibit farnesyl diphosphate synthase, an enzyme in the mevalonate pathway, thereby attenuating prenylation of small GTPase signaling proteins in osteoclasts as required for normal cellular function. … Non-nitrogen-containing bisphosphonates such as clodronate do not inhibit farnesyl diphosphate synthase or protein prenylation, but instead trigger formation of cytotoxic metabolites in osteoclasts that can lead to osteoclast dysfunction [82] . …

Oxidative Stress in Multiple Myeloma: Pathogenic Mechanisms, Biomarkers, and Redox-Targeted Therapeutic Strategies.

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor ery

Протеиновая пальмитиоляция в гематологическое облучение: механистические связи с липидным метаболическим перепрограммированием и резистентностью к терапии.

Протеиновая пальмитиолация стала центральным постпереходным механизмом, регулирующим локализацию белков, стабильность и трансдукцию сигналов. В гематологических галактиках эта динамическая модификация находится на пересечении липидного метаболического перепрограммирования, взаимодействия между опухолью и иммуном и терапевтического сопротивления. Здесь мы рассматриваем вопрос о том, как дисрегулированные пальмитоилпереносазы и депальмитолазы изменяют метаболические ферменты, липидные переносчики, липидно-дрофтовые белки, онкогенные сигнальные компоненты и молекулы иммунного регулирования, созда

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… Unlike myristoylation or prenylation, palmitoylation’s reversibility allows for rapid cycling of proteins between membrane compartments, critically regulating their stability, trafficking, and function ( 25 , 26 ). …

A Tailored Approach for Appendicular Impending and Pathologic Fractures in Solid Cancer Metastases.

Advances in medical and surgical treatment have played a major role in increasing the survival rates of cancer patients with metastatic bone disease. The clinical course of patients with bone metastases is often impaired by bone complications, such as bone fractures, which have a substantial negative impact on clinical outcomes. To optimize clinical results and prevent a detrimental impact on patients' health, a tailored approach should be defined for any given patient. The optimal management of impending or pathologic fractures is unknown and relies on a multidisciplinary approach to tailor c

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… Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res. 1998;13:581–589. doi: 10.1359/jbmr.1998.13.4.581. 125. …

Gambogic Acid as a Candidate for Cancer Therapy: A Review.

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form mice

Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?

Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteo

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… Nitrogen-containing BPs (alkyl-amino BPs: pamidronate, alendronate, ibandronate; heterocyclic BPs: risendronate, ZA) impair the mevalonate pathway by inhibiting the farnesyl diphosphate synthase (FPP synthase), ultimately preventing prenylation of small GTPase signaling proteins vital for normal cellular …

Treatment and Prevention of Bone Metastases from Breast Cancer: A Comprehensive Review of Evidence for Clinical Practice.

Bone is the most common site of metastasis from breast cancer. Bone metastases from breast cancer are associated with skeletal-related events (SREs) including pathological fractures, spinal cord compression, surgery and radiotherapy to bone, as well as bone pain and hypercalcemia, leading to impaired mobility and reduced quality of life. Greater understanding of the pathophysiology of bone metastases has led to the discovery and clinical utility of bone-targeted agents such as bisphosphonates and the receptor activator of nuclear factor kappa-B ligand (RANK-L) antibody, denosumab. Both are now

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… Nitrogen-containing bisphosphonates, including pamidronate, ibandronate and zoledronic acid, also inhibit farnesyl diphosphate synthase, a rate-limiting enzyme of the mevalonate pathway, preventing protein prenylation of small guanosine triphosphatase (GTPase) such as Ras, Rho and Rab, which are important …

Trial watch: beta-blockers in cancer therapy.

Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catech

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… factors including nuclear factor kappa B (NF-kB), activator protein 1 (AP1), and cAMP response element-binding protein (CREB) in the context of lung and pancreatic adenocarcinoma development. 51 Additionally, β-AR activation results in enhanced retinoblastoma protein phosphorylation and suppresses Rap1B prenylation … Wilson JM, Lorimer E, Tyburski MD, Williams CL. β-adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells. Cancer Biol Ther. 2015;16(9):1364–1374. doi: 10.1080/15384047.2015.1070988. 43. …

Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies.

Polyphenols are one of the largest plant-derived natural product and they play an important role in plants' defense as well as in human health and disease. A number of them are pleiotropic molecules and have been shown to regulate signaling pathways, immune response and cell growth and proliferation which all play a role in cancer development. Hematological malignancies on the other hand, are cancers of the blood. While current therapies are efficacious, they are usually expensive and with unwanted side effects. Thus, the search for newer less toxic agents. Polyphenols have been reported to po

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… They do exist as aglycones or glycosidic conjugates and can be further processed by methylation, glucosylation and prenylation ( 92 ). Like isoflavones, stilbenoids are regarded as plant phytoalexins ( 92 , 93 ). … In the treatment of multiple myeloma cells with bortezomib and gambogenic acid, a prenylated xanthone was observed to induce apoptosis via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression ( 172 ). …

Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer.

BackgroundPatients with prostate cancer are at risk of impaired bone health. Prostate cancer has a propensity to metastasize to bone, after which patients are at risk of skeletal-related events (SREs). These complications are associated with increased mortality, substantial pain, and reduced quality of life. Patients are also at risk of bone loss due to androgen deprivation therapy (ADT), which can be compounded in elderly patients with reduced bone density. It is essential, therefore, that aspects of bone health and therapies able to prevent the occurrence of SREs are considered throughout th

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… Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13:581–9. doi: 10.1359/jbmr.1998.13.4.581. 44. Parker C, Gillessen S, Heidenreich A, Horwich A, Committee EG. …