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Metal-on-Metal Total Hip Resurfacing Arthroplasty: An Evidence-Based Analysis.

OBJECTIVE: The objective of this review was to assess the safety and effectiveness of metal on metal (MOM) hip resurfacing arthroplasty for … these patients revealed markedly abnormal changes in myofibrils (heart muscles), mitochondria, and sarcoplasmic reticulum. In Belgium, a similar epidemic was reported in 1966, in which, cobalt was used in some Belgian beers. (ABSTRACT TRUNCATED)

Lifestyle and Pharmacological Interventions to Prevent Anthracycline-Related Cardiotoxicity in Cancer Patients.

Anthracyclines remain a cornerstone of cancer therapy but are associated with a significant risk of cardiotoxicity, which can lead to overt heart failure. The risk is modulated by cumulative dose, pre-existing cardiovascular disease, and patient-specific factors. As cancer survival improves, the long-term cardiovascular consequences of anthracycline exposure have become a growing concern, underscoring the need for effective preventive strategies. This narrative review examines lifestyle and pharmacological interventions aimed at mitigating anthracycline-induced cardiotoxicity. Evidence suggest

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… Simultaneously, they activate ryanodine receptor 2 (RyR2) channels, promoting uncontrolled calcium release from the sarcoplasmic reticulum (SR) into the cytosol [ 27 , 31 ]. …

Сердечная недостаточность с сохранившейся фракцией выброса: синергия между кардиологическими и экстракардиальными механизмами и эффекты новых методов лечения.

Сердечная недостаточность с консервированной фракцией выброса (HFFEF) является системным заболеванием, в котором метаболические коморбиды ожирение, тип 2 диабет (T2D) и хронические заболевания почек (CKD) сходятся, вызывая системное воспаление, эндотелиальную дисфункцию и миокардный фиброз. Микроваскулярная дисфункция представляет собой важную связь между этими коморбидами и аномалиями внутри и за пределами сердца, хотя ее причинно-следственная связь с ГФФФ по-прежнему не до конца установлена. Помимо поощрения миокардной жесткости и диастотической дисфункции, поврежденная микроваскулярная функ

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… Human left ventricular cardiomyocytes exhibiting HFpEF-like phenotypes demonstrated improved contractility following GLP-1 RA treatment, mediated by reduced diastolic sarcoplasmic reticulum calcium leak and enhanced systolic calcium handling [ 83 ]. …

Liposomal Doxorubicin in the treatment of breast cancer patients: a review.

Drug delivery systems can provide enhanced efficacy and/or reduced toxicity for anticancer agents. Liposome drug delivery systems are able to modify the pharmacokinetics and biodistribution of cytostatic agents, increasing the concentration of the drug released to neoplastic tissue and reducing the exposure of normal tissue. Anthracyclines are a key drug in the treatment of both metastatic and early breast cancer, but one of their major limitations is cardiotoxicity. One of the strategies designed to minimize this side effect is liposome encapsulation. Liposomal anthracyclines have achieved hi

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… Early histological changes secondary to anthracyclines include cytoplasmic vacuolization and loss of muscle fibres from myocytes due to dilated sarcoplasmic reticulum. In more advanced stages, changes occur in cellular remodelling leading to left ventricular failure [ 26 ]. …

Bone targeted nano-drug and nano-delivery.

There are currently no targeted delivery systems to satisfactorily treat bone-related disorders. Many clinical drugs consisting of small organic molecules have a short circulation half-life and do not effectively reach the diseased tissue site. This coupled with repeatedly high dose usage that leads to severe side effects. With the advance in nanotechnology, drugs contained within a nano-delivery device or drugs aggregated into nanoparticles (nano-drugs) have shown promises in targeted drug delivery. The ability to design nanoparticles to target bone has attracted many researchers to develop n

Cellular and molecular mechanisms of muscle atrophy.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of co

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… Dysfunction of mitochondria and sarcoplasmic reticulum in the pathogenesis of collagen VI muscular dystrophies . Ann. N. Y. Acad. Sci. 1147 , 303 – 311 19076452 10.1196/annals.1427.009 Bertaggia E. Coletto L. Sandri M. ( 2012 ). …

2,4 Dinitrophenol as Medicine.

In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescri

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… It is believed that with the loss of dystrophin, the mechanism of muscle loss is largely due to a significant elevation of free cytosolic Ca 2+ from the sarcoplasmic reticulum (endoplasmic reticulum of myotubes) which destroys the mitochondrial population (lowering ATP availability) and cascades into …

G Protein-Coupled Receptor Signaling: Implications and Therapeutic Development Advances in Cancers.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of membrane proteins, mediating cellular responses to a wide range of extracellular stimuli. GPCRs initiate complex intracellular signaling networks that regulate vital physiological functions and are associated with numerous diseases, including various types of cancer. Their conserved seven-transmembrane (7TM) structure enables these signaling networks by allowing interactions with multiple ligands and intracellular effectors. In several types of tumors, abnormal GPCR signaling promotes carcinogenesis by supporting imm

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… The sarcoplasmic reticulum and nuclear envelope include intracellular Ca2+ release channels called cardiomyocyte IP3 receptors, which are activated by IP3. … The sarcoplasmic reticulum Ca2+ATPase pump that controls protein phospholamban is dephosphorylated when diacylglycerol and intracellular Ca2+ activate protein kinase C‐alpha (PKC‐α), which controls cardiac contractility by upregulating type 1 protein phosphatase [ 77 ]. …

Novel Therapeutics for Anthracycline Induced Cardiotoxicity.

Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing

Muscle and Bone Defects in Metastatic Disease.

PURPOSE OF REVIEW: The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. RECENT FINDINGS: Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism ha

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… As RyR1 channels are required for muscle contraction by releasing calcium from sarcoplasmic reticulum stores into cytoplasm, their oxidation results in intracellular calcium leakage, which leads to muscle weakness. …

Prevention of Anthracycline-Induced Cardiotoxicity: The Good and Bad of Current and Alternative Therapies.

Doxorubicin (Dox)-induced cardiotoxicity (DIC) remains a serious health burden, especially in developing countries. Unfortunately, the high cost of current preventative strategies has marginalized numerous cancer patients because of socio-economic factors. In addition, the efficacy of these strategies, without reducing the chemotherapeutic properties of Dox, is frequently questioned. These limitations have widened the gap and necessity for alternative medicines, like flavonoids, to be investigated. However, new therapeutics may also present their own shortcomings, ruling out the idea of "natur

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… Considering cellular biology, several enzymes like NADPH oxidases (NOXs), NOSs, XOs and peroxisomes, which are located in the sarcoplasmic reticulum, mitochondria, and cytoplasm, account for a significant amount of ROS production ( 34 – 36 ). …

Polydatin: Pharmacological Mechanisms, Therapeutic Targets, Biological Activities, and Health Benefits.

Polydatin is a natural potent stilbenoid polyphenol and a resveratrol derivative with improved bioavailability. Polydatin possesses potential biological activities predominantly through the modulation of pivotal signaling pathways involved in inflammation, oxidative stress, and apoptosis. Various imperative biological activities have been suggested for polydatin towards promising therapeutic effects, including anticancer, cardioprotective, anti-diabetic, gastroprotective, hepatoprotective, neuroprotective, anti-microbial, as well as health-promoting roles on the renal system, the respiratory s

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… Polydatin protects cardiac function against burn injury by inhibiting sarcoplasmic reticulum Ca2+ leak by reducing oxidative modification of ryanodine receptors Free Radic. Biol. Med. 2013 60 292 299 10.1016/j.freeradbiomed.2013.02.030 23499836 136. Yousef A.I. Shawki H.H. El-Shahawy A.A. …

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers.

Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical cancer. This aberra

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… These include VEGF, bFGF, IL-1α, IL-2, IL-4, IL-6, and IL-8, and TNF α. 73 vGPCR modulates the nuclear factor of activated T-cells (NFAT) pathway by elevating cytosolic calcium through sarcoplasmic reticulum calcium ATPase. 77 The ability of vGPCR to control multiple pathways including the PLC, PKC, …

Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activati

Cardiotoxicity Induced by Anticancer Therapies: A Call for Integrated Cardio-Oncology Practice.

The introduction of novel oncologic therapies, including targeted agents, immunotherapies, and antibody-drug conjugates, has transformed the therapeutic landscape of cancer care. This evolution has resulted in a dual clinical scenario; while survival outcomes have markedly improved, leading to a growing population of long-term cancer survivors, an increasing incidence of previously unrecognized treatment-related toxicities has emerged. Among these, cardiovascular adverse events represent some of the most prevalent and clinically significant complications observed in both conventional chemother

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… These include patchy interstitial fibrosis, proliferation of fibroblasts, infiltration by monocyte-derived histiocytes, myofibril loss, distension of the sarcoplasmic reticulum, and vacuolization of cardiomyocytes adjacent to fibrotic areas [ 23 ]. …

The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is

Cancer Therapy and Exercise Intolerance: The Heart Is But a Part: JACC: CardioOncology State-of-the-Art Review.

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond th

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates.

As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In thi

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… Regarding impaired mitochondrial metabolism, we were able to find some molecules involved in this phenotype, such as OXPHOS proteins, uncoupling proteins (UCP) 2/3, sarcoplasmic reticulum calcium ATPases (SERCA), and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, among others. …

Pre-clinical Research on Bladder Toxicity After Radiotherapy for Pelvic Cancers: State-of-the Art and Challenges.

Despite the dramatic advancements in pelvic radiotherapy, urinary toxicity remains a significant side-effect. The assessment of clinico-dosimetric predictors of radiation cystitis (RC) based on clinical data has improved substantially over the last decade; however, a thorough understanding of the physiopathogenetic mechanisms underlying the onset of RC, with its variegated acute and late urinary symptoms, is still largely lacking, and data from pre-clinical research is still limited. The aim of this review is to provide an overview of the main open issues and, ideally, to help investigators in

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… Thanks activation of muscarinic M3 receptor by acetylcholine, intracellular calcium is released by the opening of membrane nifedipine-sensitive L-type Ca2+ channels, by the increase in inositol 1,4,5-trisphosphate (IP3) production with consequent release of calcium from the sarcoplasmic reticulum, and …

Adeno-associated virus as a delivery vector for gene therapy of human diseases.

Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dos