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Novel Immunotherapies for Myasthenia Gravis.

Myasthenia gravis (MG), a prototype autoimmune neurological disease, had its therapy centred on corticosteroids, non-steroidal broad-spectrum immunotherapy and cholinesterase inhibitors for several decades. Treatment-refractory MG and long-term toxicities of the medications have been major concerns with the conventional therapies. Advances in the immunology and pathogenesis of MG have ushered in an era of newer therapies which are more specific and efficacious. Complement inhibitors and neonatal Fc receptor blockers target disease-specific pathogenic mechanisms linked to myasthenia and have pr

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… In contrast, late onset MG often occurs in males, has no HLA association and may display anti-striational antibodies despite harbouring atrophic thymus. 4 Thymoma occurs in 15–30% of MG and is commonly associated with co-existing anti-ryanodine receptor and anti-titin antibodies. 6 , 7 MuSK-MG tends …

The role of CD38 in HIV infection.

The widely-expressed molecule CD38 is a single-stranded type II transmembrane glycoprotein that is mainly involved in regulating the differentiation and activation state of the cell. CD38 has broad and complex functions, including enzymatic activity, intercellular signal transduction, cell activation, cytokine production, receptor function and adhesion activity, and it plays an important role in the physiological and pathological processes of many diseases. Many studies have shown that CD38 is related to the occurrence and development of HIV infection, and CD38 may regulate its progression thr

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… Frontrunners of T cell activation: initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor. Sci Signal. 2015;8(398):ra102. doi: 10.1126/scisignal.aab0863. 145. Rodríguez-Alba JC, Abrego-Peredo A, Gallardo-Hernández C, Pérez-Lara J, Santiago-Cruz W, Jiang W, et al. …

Abstracts of the 3rd International Conference on Cancer Cachexia, September 23–25, 2016 in Washington, DC, USA

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… TGF‐β upregulated NADPH oxidase 4 (Nox4) that oxidized skeletal muscle proteins, including the ryanodine receptor/calcium release channel (RyR1). Humans with breast or lung cancer bone metastases also had oxidized skeletal muscle RyR1. Oxidized RyR1 leaked calcium causing muscle weakness. …

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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… 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 by the activation of ryanodine …

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.

Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.

Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate card

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… CaMK2-dependent phosphorylation of the ryanodine receptor 2 in cardiomyocyte may impair intracellular calcium homeostasis and abnormal atrial electrical conductance, which may be linked with higher AF inducibility, increased left atrial mass and fibrosis ( 12 ). …

Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis.

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms' distribution, disease severity, age at onset, thymic histopathology and response to therapies. Cur

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… LOMG is more frequent in males, who often have a normally involuted thymus and antibodies to other muscle proteins, mainly titin or the ryanodine receptor (RyR) ( 1 , 14 ). …

mRNA vaccine in cancer therapy: Current advance and future outlook.

Messenger ribonucleic acid (mRNA) vaccines are a relatively new class of vaccines that have shown great promise in the immunotherapy of a wide variety of infectious diseases and cancer. In the past 2 years, SARS-CoV-2 mRNA vaccines have contributed tremendously against SARS-CoV2, which has prompted the arrival of the mRNA vaccine research boom, especially in the research of cancer vaccines. Compared with conventional cancer vaccines, mRNA vaccines have significant advantages, including efficient production of protective immune responses, relatively low side effects and lower cost of acquisitio

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… Allele‐specific silencing of mutant mRNA rescues ultrastructural and arrhythmic phenotype in mice carriers of the R4496C mutation in the ryanodine receptor gene (RYR2) . Circ Res . 2017 ; 121 ( 5 ): 525 ‐ 536 . 28620067 10.1161/CIRCRESAHA.117.310882 75 Lurie N , Sharfstein JM , Goodman JL . …

Targeting the two-pore channel 2 in cancer progression and metastasis.

The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions

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… Many different types of Ca 2+ -channels are found in cells; some are expressed on the plasma membrane [e.g., voltage-gated Ca 2+ channels, transient receptor potential (TRP) channels, and store-operated channels], whereas others are expressed on the membrane of intracellular organelles, such as ryanodine …

Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets.

Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc's involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc's cellular metabolism, particularly the functions of

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… Intracellular zinc can then modulate ryanodine receptor (RyR)-mediated calcium release from the SR. …

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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… The mechanism by which TGF-β contributes to skeletal muscle weakness was shown to be through NADPH oxidase 4 (NOX4)-mediated oxidation of skeletal muscle proteins such as ryanodine receptor/calcium (Ca2+) release channel (RyR1) [ 22 ]. …

Marine Natural Products as Potent Anticancer Agents (2020-2024): Structural Diversity, SARs and Target Prediction.

In recent years, Marine Natural Products (MNPs) have emerged as a significant source for anticancer drug discovery, as many natural products can offer structural diversity, unique mechanisms of action, and relatively low toxicity. This article provides a systematic review of MNPs with reported anticancer activities from 2020 to 2024. These compounds are classified into seven major categories: terpenoids, alkaloids, sterols, polyketides, peptides and proteins, polysaccharides, and macrolides. For each category, we elaborate on the marine sources, structural identification, in vitro anticancer a

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… Sequence alignment results indicated that this protein exhibits structural homology with the N-terminal region of the ryanodine receptor and defensin-like proteins. The research further completed the three-dimensional structural modeling of the protein using Phyre2. …

Research Progress in Pharmacological Targeted Therapy for Myasthenia Gravis.

Myasthenia gravis (MG) is a disorder of neuromuscular junction transmission that is mediated by autoantibodies and depends on T cell help, causing fatigable muscle weakness. Limitations of conventional first-line treatments, including long-term adverse effects and inadequate control of refractory disease, have driven targeted therapy to the forefront of MG research. This narrative review summarizes second-line and later-line targeted biological and cellular therapies, covering agents directedat B and T cells, complement inhibitors, neonatal Fc receptor (FcRn) antagonists and cytokine inhibitor

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… Pathogenesis of LRP4-Ab-positive and double-seronegative MG remains only partially elucidated, with possible roles for additional autoantibodies (agrin, cortactin, ryanodine receptors). 2 , 3 Additionally, CD4+ T helper cells can secrete proinflammatory cytokines (eg, interleukin-2, interferon-γ) to …

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research.

Lower urinary tract dysfunction (LUTD) is nearly ubiquitous in men of advancing age and exerts substantial physical, mental, social, and financial costs to society. While a large body of research is focused on the molecular, genetic, and epigenetic underpinnings of the disease, little research has been dedicated to the influence of environmental chemicals on disease initiation, progression, or severity. Despite a few recent studies indicating a potential developmental origin of male LUTD linked to chemical exposures in the womb, it remains a grossly understudied endpoint in toxicology research

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… Comparative analyses of the 12 most abundant PCB congeners detected in human maternal serum for activity at the thyroid hormone receptor and ryanodine receptor. Environ. Sci. Technol. 2019;53:3948–3958. doi: 10.1021/acs.est.9b00535. 82. Rude K.M., Keogh C.E., Gareau M.G. …

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution.

Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amo

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… The glutathione transferase structural family includes a nuclear chloride channel and a ryanodine receptor calcium release channel modulator J. Biol. Chem. 2001 276 3319 3323 10.1074/jbc.M007874200 11035031 29. Wu Y. Fan Y. Xue B. Luo L. Shen J. Zhang S. Jiang Y. Yin Z. …

Skeletal muscle dysfunction induced by cancer immunotherapy: mechanistics insights and surgical implications.

Cancer immunotherapy has revolutionized cancer treatment, yet its effects extend far beyond tumor eradication. Accumulating evidence indicates that immunotherapy-associated skeletal muscle dysfunction represents a complex, cross-organ pathological process driven by dynamic crosstalk between the tumor microenvironment and peripheral tissues. Rather than an isolated adverse event, muscle injury emerges from integrated mechanisms including inflammatory cytokine spillover, aberrant immune cell infiltration, metabolic reprogramming, vascular dysfunction, and impaired regenerative signaling. Central

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… ROS damage calcium channels on muscle fiber membranes (ryanodine receptors), disrupt calcium homeostasis, and directly reduce contractile efficiency. Immunotherapy exacerbates muscle damage by disrupting angiogenesis ( 81 ). …

Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects.

Resveratrol (RES), a naturally occurring polyphenolic compound, has garnered significant attention due to its diverse biological activities, which include anti-inflammatory, antioxidant, and antiaging properties. This review synthesizes current evidence concerning the molecular mechanisms, therapeutic efficacy, and safety profile of RES across a variety of pathologies, with an emphasis on the latest research conducted in recent years. Mechanistically, RES is known to modulate critical signaling pathways such as the activation of sirtuin 1. These actions collectively contribute to the attenuati

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… RES suppressed the proliferation and metastasis of pancreatic cancer cells by inhibiting the expression of ryanodine receptor type 2 and enhancing the expression of phosphatase and tensin homolog [ 123 ]. …

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

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. …

Cyclic Peptides in Modern Drug Discovery: Trends and Therapeutic Directions.

Peptide therapeutics are an important drug modality due to their high specificity, favorable safety, and expanding design potential. Among them, cyclic peptides occupy a space between small molecules and biologics, offering improved rigidity, stability, and target engagement. This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades. Results show a steady rise in academic publications and patents, reflecting growing interest across discovery and development. Notably, oral administration is gaining attention, indicating progress