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Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain.

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that regulates the transcription of many genes that are responsible for the adaptation and survival of tumor cells in hypoxic environments. Over the past few decades, tremendous efforts have been made to comprehensively understand the role of HIF-1 in tumor progression. Based on the pivotal roles of HIF-1 in tumor biology, many HIF-1 inhibitors interrupting expression, stabilization, DNA binding properties, or transcriptional activity have been identified as potential therapeutic agents for various cancers, yet none of these inhi

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… HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1. Biochem. Biophys. Res. Commun. 2015;458:14–20. doi: 10.1016/j.bbrc.2015.01.031. 61. Naik R., Han S., Lee K. …

Pulmonary and Hepatic Complications of Hematopoietic Cell Transplantation

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… The clinician initiating voriconazole or other antifungal “azole” therapy should be mindful of its impact on cytochrome p450-dependent drugs, including the calcineurin inhibitors tacrolimus and cyclosporine and the mTor inhibitor sirolimus. …

Novel therapeutic strategies targeting resistance mechanisms in hematologic malignancies: from BCL2 inhibition to immunomodulatory approaches.

BACKGROUND: Hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), are characterized by high relapse rates due to intrinsic and acquired drug resistance. Resistance mechanisms often involve dysregulation of apoptosis pathways, such as B-cell lymphoma 2 (BCL2) family overexpression, and immune evasion through microenvironment modulation. PURPOSE: This review synthesizes recent advances (2020-2025) in therapeutic strategies targeting these mechanisms, focusing on BCL2 inhibition and immunomodul

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… The degradation of these proteins leads to complex downstream effects including activation of pro-apoptotic pathways via GPR68/calcium/calpain signaling and inhibition of the RCAN1/calcineurin pro-survival pathway. …

Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the d

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… Voclosporin Voclosporin (VCS) is an oral calcineurin inhibitor, belonging to the same drug class as tacrolimus and cyclosporine. VCS was approved in January 2021, by the FDA, for the treatment of active lupus nephritis, in combination with conventional immunosuppressive therapy [ 176 ]. …

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies.

Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studie

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… Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–815. doi: 10.1016/0092-8674(91)90124-H. 53. Schreiber S.L. The Rise of Molecular Glues. Cell. 2021;184:3–9. doi: 10.1016/j.cell.2020.12.020. 54. …

Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation.

Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and

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… Structure-based design of an acyclic ligand that bridges FKBP12 and Calcineurin. J. Am. Chem. Soc . 115 10420–10421. 10.1021/ja00075a092 Bai L. C., Zhou H. B., Xu R. Q., Zhao Y. J., Chinnaswamy K., McEachern D., et al. (2019). …

Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools.

Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the op

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… Clinically, this is supported by the observation that calcineurin inhibition leads to an altered natural killer cell phenotype (a major contributor to immunosurveillance) and thus reduced immunosurveillance and persistence of senescent cells ( Hoffmann et al., 2015 ). …

UK clinical guideline for the prevention and treatment of osteoporosis.

UNLABELLED: The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. INTRODUCTION: The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope

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… .: Some immunosuppressants (calmodulin/calcineurine phosphatase inhibitors) (Excess) thyroid hormone treatment (levothyroxine and/or liothyronine). … .: Some immunosuppressants (calmodulin/calcineurine phosphatase inhibitors) (Excess) thyroid hormone treatment (levothyroxine and/or liothyronine). …

Lysosomal storage diseases.

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage ca

HDACs and Their Inhibitors on Post-Translational Modifications: The Regulation of Cardiovascular Disease.

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the

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… Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice. J. Physiol. 2009;587:3899–3910. doi: 10.1113/jphysiol.2009.173948. 57. Miska E.A., Karlsson C., Langley E., Nielsen S.J., Pines J., Kouzarides T. …

Uncommon Factors Leading to Nephrotic Syndrome.

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransfe

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… Symptomatic treatment may include dietary modification to reduce sodium and fluid intake, diuretics to relieve edema, intravenous albumin infusions to correct hypoalbuminemia, as well as immunosuppressive agents such as corticosteroids or calcineurin inhibitors. …

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimpose

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… Mycophenolate mofetil inhibits lymphocyte clonal expansion upon antigen exposure, while calcineurin inhibitors (cyclosporine and tacrolimus) primarily affect T-cells [ 58 ]. Anthracyclines can cause cardiotoxicity and long-term corticosteroid use can cause adrenal insufficiency. …

Chronic stress in solid tumor development: from mechanisms to interventions.

Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells.

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… Stimulation of beta(2)-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction. Brain Behav Immun. 2011;25(1):59–66. doi: 10.1016/j.bbi.2010.07.248. 99. McAlees JW, Smith LT, Erbe RS, Jarjoura D, Ponzio NM, Sanders VM. …

Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer.

Despite the clinical outcomes being extremely limited, blocking immune inhibitory checkpoint pathways has been in the spotlight as a promising strategy for treating gastrointestinal cancer. However, a distinct strategy for the successful treatment is obviously needed in the clinical settings. Myeloid cells, such as neutrophils, macrophages, dendritic cells, and mast cells, are the majority of cellular components in the human immune system, but have received relatively less attention for the practical implementation than T cells and NK cells in cancer therapy because of concentration of the int

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… TOX expression is induced by calcineurin and NFAT2, and orchestrates immune inhibitory signals, not only PD1 but also other IC molecules, in CD8 + T cells ( 137 ). …

Immune Dysfunction in Uremia 2020.

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failur

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… Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: Involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB Blood 2003 102 662 671 10.1182/blood-2002-09-2785 12663441 112. Martinez F. Pallet N. …

Targeting cancer stem cells in drug discovery: Current state and future perspectives.

In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic st

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… Increased Ca 2+ levels activate the protein kinases calmodulin-dependent protein kinase II (CaMK-II), protein kinase C, and calcineurin[ 41 ]. …

Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neur

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… Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflug. Arch. 1996;431:828–837. doi: 10.1007/s004240050074. 62. Mohapatra D.P., Nau C. …

Exercise-mobilized donor lymphocyte infusions enhanced with cytokine stimulation for the prevention and treatment of leukemic relapse after allogeneic hematopoietic cell transplantation.

Donor lymphocyte infusions (DLI) are a standard therapy following allogeneic hematopoietic cell transplantation (alloHCT) for preventing and treating leukemic relapse in high-risk patients, particularly those with myeloid malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). However, the efficacy of DLI remains suboptimal and is accompanied by a significant risk of life-threatening graft-versus-host disease (GvHD), highlighting the urgent need for strategies that enhance graft-versus-leukemia (GvL) effects while mitigating GvHD.

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… also be important to determine the effects of using DLI-X and DLI-XS in combination with other emerging therapies to bolster the GvL effects of DLI, including DNA hypomethylation agents, Bcl-2 inhibitors, FLT-3 inhibitors, and antibody-drug conjugates, as well as those designed to inhibit GvHD such as calcineurin …

Secondary antibody deficiencies: what's around the corner?

Secondary antibody deficiencies (SADs) are characterized by impaired humoral immunity, which can cause recurrent and severe infections. Several factors may contribute to SAD development, making it difficult to establish a clear etiological classification. This heterogeneity also leads to clinical variability, further complicating patient management and treatment strategies. Various diagnostic and therapeutic algorithms are often adapted from those used in primary antibody deficiencies, potentially resulting in under- or over-treatment. Key points include the decision to initiate Immunoglobulin

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… Depending on the mode of action, these drugs may be classified as antimetabolite agents (methotrexate, mofetil mycophenolate, azathioprine), calcineurin inhibitors (Cyclosporin A, Tacrolimus), and mTor Inhibitors (sirolimus, everolimus) ( 112 ). …

Systemic Sclerosis Association with Malignancy.

The association of systemic sclerosis (SSc) and cancer is well known from several decades suggesting common genetic and environmental risk factors involved in the development of both diseases. Immunosuppressive drugs widely used in SSc may increase the risk of cancer occurrence and different SSc clinical and serological features identify patients at major risk to develop malignancy. In this context, among serological features, presence of anti-RNA polymerase III and anti-topoisomerase I autoantibodies seems to increase cancer frequency in SSc patients (particularly lung and breast cancers). Lu

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… Crane GM Powell H Kostadinov R Rocafort PT Rifkin DE Burger PC Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage Oncotarget 2015 6 32 33849 33866 10.18632/oncotarget.5292.PMID:26460822;PMCID:PMC4741807 26460822 PMC4741807 92. …