Advances in understanding the role of P-gp in doxorubicin resistance: molecular pathways, therapeutic strategies, and prospects

SUMOylation dynamically conjugates SUMO molecules to the lysine residue of a substrate protein, which depends on the physiological state of the cell and the attached SUMO isoforms. A prominent role of SUMOylation in molecular pathways is to govern the cellular death process. Herein, we summarize the association between SUMOylation modification events and four types of cellular death processes: apoptosis, autophagy, senescence and pyroptosis. SUMOylation positively or negatively regulates a certain cellular death pattern depending on specific conditions including the attached SUMO isoforms, disease types, substrate proteins and cell context. Moreover, we also discuss the possible role of SUMOylation in ferroptosis and propose a potential role of the SUMOylated GPX4 in the regulation of ferroptosis. Mapping the exact SUMOylation network with cellular death contributes to develop novel SUMOylation-targeting disease therapeutic strategies.

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Is Immune Response Relevant in Interstitial Lung Disease?

Current Immunology Reviews ◽

10.2174/1573395516999200914143054 ◽

2020 ◽

Vol 16 (1) ◽

pp. 18-27

Author(s):

Manzoor M. Khan

Keyword(s):

Immune Response ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Lung Fibrosis ◽

Lymphocytic Infiltration ◽

Therapeutic Strategies ◽

Mediators Of Inflammation ◽

Acquired Immune Responses ◽

Novel Therapeutic Strategies

Interstitial lung disease, a term for a group of disorders, causes lung fibrosis, is mostly refractory to treatments and has a high death rate. After diagnosis the survival is up to 3 years but in some cases the patients live much longer. It involves a heterogenous group of lung diseases that exhibit progressive and irreversible destruction of the lung due to the formation of scars. This results in lung malfunction, disruption of gas exchange, and eventual death because of respiratory failure. The etiology of lung fibrosis is mostly unknown with a few exceptions. The major characteristics of the disease are comprised of injury of epithelial type II cells, increased apoptosis, chronic inflammation, monocytic and lymphocytic infiltration, accumulation of myofibroblasts, and inability to repair damaged tissue properly. These events result in abnormal collagen deposition and scarring. The inflammation process is mild, and the disease is primarily fibrotic driven. Immunosuppressants do not treat the disease but the evidence is evolving that both innate and acquired immune responses a well as the cytokines contribute to at least early progression of the disease. Furthermore, mediators of inflammation including cytokines are involved throughout the process of lung fibrosis. The diverse clinical outcome of the disease is due to different pattern of inflammatory markers. Nonetheless, the development of novel therapeutic strategies requires better understanding of the role of the immune response. This review highlights the role of the immune response in interstitial lung disease and considers the therapeutic strategies based on these observations. For this review several literature data sources were used to assess the role of the immune response in interstitial lung disease and to evaluate the possible therapeutic strategies for the disease.

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Targeting macrophages in cancer immunotherapy

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00506-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Zhaojun Duan ◽

Yunping Luo

Keyword(s):

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapeutic Strategies ◽

Cellular Immunotherapy ◽

Cancer Therapies ◽

Tumor Vaccines ◽

Development And Differentiation ◽

Promising Treatment ◽

Cancer Immunotherapies

AbstractImmunotherapy is regarded as the most promising treatment for cancers. Various cancer immunotherapies, including adoptive cellular immunotherapy, tumor vaccines, antibodies, immune checkpoint inhibitors, and small-molecule inhibitors, have achieved certain successes. In this review, we summarize the role of macrophages in current immunotherapies and the advantages of targeting macrophages. To better understand and make better use of this type of cell, their development and differentiation characteristics, categories, typical markers, and functions were collated at the beginning of the review. Therapeutic strategies based on or combined with macrophages have the potential to improve the treatment efficacy of cancer therapies.

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Endogenous Mammalian Cardiotonic Steroids—A New Cardiovascular Risk Factor?—A Mini-Review

Life ◽

10.3390/life11080727 ◽

2021 ◽

Vol 11 (8) ◽

pp. 727

Author(s):

Natalia Słabiak-Błaż ◽

Grzegorz Piecha

Keyword(s):

Adenosine Triphosphatase ◽

Therapeutic Strategies ◽

Structure And Function ◽

Sodium Potassium ◽

Sodium Homeostasis ◽

Cardiovascular Tissue ◽

Ancient Times ◽

And Function ◽

Regulation Of Blood Pressure

The role of endogenous mammalian cardiotonic steroids (CTS) in the physiology and pathophysiology of the cardiovascular system and the kidneys has interested researchers for more than 20 years. Cardiotonic steroids extracted from toads or plants, such as digitalis, have been used to treat heart disease since ancient times. CTS, also called endogenous digitalis-like factors, take part in the regulation of blood pressure and sodium homeostasis through their effects on the transport enzyme called sodium–potassium adenosine triphosphatase (Na/K-ATPase) in renal and cardiovascular tissue. In recent years, there has been increasing evidence showing deleterious effects of CTS on the structure and function of the heart, vasculature and kidneys. Understanding the role of CTS may be useful in the development of potential new therapeutic strategies.

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Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy

Cancers ◽

10.3390/cancers13040663 ◽

2021 ◽

Vol 13 (4) ◽

pp. 663

Author(s):

Yu Yuan ◽

Abdalla Adam ◽

Chen Zhao ◽

Honglei Chen

Keyword(s):

Immune Evasion ◽

Immune Checkpoint ◽

Poor Prognosis ◽

Target Therapy ◽

Acquired Resistance ◽

Immune Checkpoint Blockade ◽

Therapeutic Strategies ◽

Present Evidence ◽

Immunosuppressive Factor

Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.

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Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22115722 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5722

Author(s):

Alessandro de Sire ◽

Nicola Marotta ◽

Cinzia Marinaro ◽

Claudio Curci ◽

Marco Invernizzi ◽

...

Keyword(s):

Signaling Pathways ◽

Synergistic Effects ◽

Molecular Pathways ◽

Epigenetic Changes ◽

Pathological Features ◽

Oxidative Signaling ◽

Cartilage Extracellular Matrix ◽

Wide Range ◽

Comprehensive Picture

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

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Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22116071 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6071

Author(s):

Suzanne Gascon ◽

Jessica Jann ◽

Chloé Langlois-Blais ◽

Mélanie Plourde ◽

Christine Lavoie ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Growth Factors ◽

Signaling Pathways ◽

Brain Structures ◽

Therapeutic Strategies ◽

Native Proteins ◽

Receptor Sites ◽

The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

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Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211003983 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110039

Author(s):

Carlos A. Cañas ◽

Felipe Cañas ◽

Mario Bautista-Vargas ◽

Fabio Bonilla-Abadía

Keyword(s):

Tissue Factor ◽

Proinflammatory Cytokines ◽

Antiphospholipid Antibodies ◽

Therapeutic Strategies ◽

Prothrombotic State ◽

Pulmonary Epithelium ◽

Angiotensin Converting Enzyme 2 ◽

Patients With Heart Failure ◽

Inflammatory Effect

COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.

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Nutritional Optic Neuropathies: State of the Art and Emerging Evidences

Nutrients ◽

10.3390/nu12092653 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2653

Author(s):

Matilde Roda ◽

Natalie di Geronimo ◽

Marco Pellegrini ◽

Costantino Schiavi

Keyword(s):

Bariatric Surgery ◽

Optic Neuropathy ◽

Multidisciplinary Approach ◽

State Of The Art ◽

Signs And Symptoms ◽

Therapeutic Strategies ◽

Scientific Interest ◽

Optic Nerve Atrophy ◽

Prompt Diagnosis

Nutritional optic neuropathy is a cause of bilateral, symmetrical, and progressive visual impairment with loss of central visual acuity and contrast sensitivity, dyschromatopsia, and a central or centrocecal scotoma. The clinical features are not pathognomonic, since hereditary and toxic forms share similar signs and symptoms. It is becoming increasingly common due to the widespread of bariatric surgery and strict vegetarian or vegan diets, so even the scientific interest has recently increased. In particular, recent studies have focused on possible pathogenetic mechanisms, and on novel diagnostic and therapeutic strategies in order to prevent the onset, make a prompt diagnosis and an accurate nutritional supplementation, and to avoid irreversible optic nerve atrophy. Nowadays, there is clear evidence of the role of cobalamin, folic acid, thiamine, and copper, whereas further studies are needed to define the role of niacin, riboflavin, and pyridoxine. This review aims to summarize the etiology, diagnosis, and treatment of nutritional optic neuropathy, and it is addressed not only to ophthalmologists, but to all physicians who could come in contact with a patient with a possible nutritional optic neuropathy, being a fundamental multidisciplinary approach.

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Contribution of the CK2 Catalytic Isoforms α and α’ to the Glycolytic Phenotype of Tumor Cells

Cells ◽

10.3390/cells10010181 ◽

2021 ◽

Vol 10 (1) ◽

pp. 181

Author(s):

Francesca Zonta ◽

Christian Borgo ◽

Camila Paz Quezada Meza ◽

Ionica Masgras ◽

Andrea Rasola ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Cancer Cells ◽

Tumor Cells ◽

Therapeutic Strategies ◽

The Other ◽

Osteosarcoma Cell ◽

Monomeric Form ◽

New Information

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting.

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