Intracellular Ca2 + Imbalance Critically Contributes to Paraptosis

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process. Ca2+ transport has been shown to be important in the paraptosis induced by several natural products, metal complexes, and co-treatment with proteasome inhibitors and certain Ca2+-modulating agents. In particular, the Ca2+-mediated communication between the ER and mitochondria plays a crucial role in paraptosis. Mitochondrial Ca2+ overload from the intracellular Ca2+-flux system located at the ER–mitochondrial axis can induce mitochondrial dilation during paraptosis, while the accumulation of misfolded proteins within the ER lumen is believed to exert an osmotic force and draw water from the cytoplasm to distend the ER lumen. In this process, Ca2+ release from the ER also critically contributes to aggravating ER stress and ER dilation. This review focuses on the role of Ca2+ transport in paraptosis by summarizing the recent findings related to the actions of Ca2+-modulating paraptosis-inducing agents and discussing the potential cancer therapeutic strategies that may effectively induce paraptosis via Ca2+ signaling.

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Skin and Gut Microbiome in Psoriasis: Gaining Insight Into the Pathophysiology of It and Finding Novel Therapeutic Strategies

Frontiers in Microbiology ◽

10.3389/fmicb.2020.589726 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lihui Chen ◽

Jie Li ◽

Wu Zhu ◽

Yehong Kuang ◽

Tao Liu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Therapeutic Strategies ◽

Intestinal Microbiome ◽

Core Microbiome ◽

The Core ◽

The World ◽

Novel Therapeutic Strategies ◽

Insight Into ◽

Gaining Insight

Psoriasis affects the health of myriad populations around the world. The pathogenesis is multifactorial, and the exact driving factor remains unclear. This condition arises from the interaction between hyperproliferative keratinocytes and infiltrating immune cells, with poor prognosis and high recurrence. Better clinical treatments remain to be explored. There is much evidence that alterations in the skin and intestinal microbiome play an important role in the pathogenesis of psoriasis, and restoration of the microbiome is a promising preventive and therapeutic strategy for psoriasis. Herein, we have reviewed recent studies on the psoriasis-related microbiome in an attempt to confidently identify the “core” microbiome of psoriasis patients, understand the role of microbiome in the pathogenesis of psoriasis, and explore new therapeutic strategies for psoriasis through microbial intervention.

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Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and their Implications for Therapy

Cancers ◽

10.3390/cancers13174255 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4255

Author(s):

Rikke Sick Andersen ◽

Atul Anand ◽

Dylan Scott Lykke Harwood ◽

Bjarne Winther Kristensen

Keyword(s):

Poor Prognosis ◽

Therapeutic Strategy ◽

Treatment Strategies ◽

Treatment Resistance ◽

Standard Of Care ◽

Primary Brain Tumor ◽

Therapeutic Strategies ◽

The Poor ◽

Temozolomide Chemotherapy

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

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WNT and β-Catenin in Cancer: Genes and Therapy

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030419-033628 ◽

2020 ◽

Vol 4 (1) ◽

pp. 177-196 ◽

Cited By ~ 5

Author(s):

Rene Jackstadt ◽

Michael Charles Hodder ◽

Owen James Sansom

Keyword(s):

Tumor Microenvironment ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Pathway ◽

Therapeutic Strategy ◽

Wnt Signaling Pathway ◽

Therapeutic Strategies ◽

Tissue Homeostasis ◽

Cancer Genes

The WNT pathway is a pleiotropic signaling pathway that controls developmental processes, tissue homeostasis, and cancer. The WNT pathway is commonly mutated in many cancers, leading to widespread research into the role of WNT signaling in carcinogenesis. Understanding which cancers are reliant upon WNT activation and which components of the WNT signaling pathway are mutated is paramount to advancing therapeutic strategies. In addition, building holistic insights into the role of WNT signaling in not only tumor cells but also the tumor microenvironment is a vital area of research and may be a promising therapeutic strategy in multiple immunologically inert cancers. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Here, we review how the WNT pathway is activated in multiple cancers and discuss current strategies to target aberrant WNT signaling.

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Potential therapeutic strategies for targeting Y-box-binding protein 1 in cancers

Current Cancer Drug Targets ◽

10.2174/1568009621666210831125001 ◽

2021 ◽

Vol 21 ◽

Author(s):

Jia-Wei Yang ◽

Chao Sun ◽

Qiu-Yang Jin ◽

Xing-Hui Qiao ◽

Xiu-Li Guo

Keyword(s):

Nuclear Translocation ◽

Binding Protein ◽

Circular Rna ◽

Therapeutic Strategies ◽

Mrna Splicing ◽

Tumor Proliferation ◽

Normal Cells ◽

The Past ◽

Potential Cancer

: As one of the most conservative proteins in evolution, Y-box-binding protein 1 (YB-1) has long been considered as a potential cancer target. YB-1 is usually poorly expressed in normal cells and exerts cellular physiological functions such as DNA repair, pre-mRNA splicing and mRNA stabilizing. In cancer cells, the expression of YB-1 is up-regulated and undergoes nuclear translocation and contributes to tumorigenesis, angiogenesis, tumor proliferation, invasion, migration and chemotherapy drug resistance. During the past decades, a variety of pharmacological tools such as siRNA, shRNA, microRNA, circular RNA, lncRNA and various compounds have been developed to target YB-1 for cancer therapy. In this review, we describe the physiological characteristics of YB-1 in detail, highlight the role of YB-1 in tumors and summarize the current therapeutic methods for targeting YB-1 in cancer.

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Targeting hypoxia in tumor: a new promising therapeutic strategy

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1517-0 ◽

2020 ◽

Vol 39 (1) ◽

Cited By ~ 8

Author(s):

Maria Carla Bosco ◽

Gabriella D’Orazi ◽

Donatella Del Bufalo

Keyword(s):

Cardiovascular Disease ◽

Therapeutic Strategy ◽

Metabolic Diseases ◽

Therapeutic Strategies ◽

Low Oxygen ◽

Radio Therapy ◽

Oxygen Condition ◽

Negative Role ◽

Patient Prognosis

AbstractLow oxygen condition (hypoxia) is considered a hallmark of rapidly growing solid tumors. The presence of hypoxia renders tumor cells resistant to conventional chemo- and radio-therapy, selecting a more malignant and invasive phenotype and playing a negative role in patient prognosis. This commentary wishes to recognize the 2019 Nobel Prize in Medicine awarded to three physicians-scientists, Prof. William G. Kaelin Jr., Prof. Sir Peter J. Ratcliffe, and Prof. Gregg L. Semenza, for their discovery of the mechanisms mediating cell ability to sense and adapt to changes in oxygen availability. Their studies established the basis for our understanding of the role of hypoxia in a variety of diseases, including anemia, renal failure, cardiovascular disease, metabolic diseases, and cancer, paving the way for new promising therapeutic strategies through the development of drugs that can either activate or block the oxygen-sensing machinery.

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Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26

Biology ◽

10.3390/biology10010059 ◽

2021 ◽

Vol 10 (1) ◽

pp. 59

Author(s):

Laura Garcia-Vega ◽

Erin M. O’Shaughnessy ◽

Ahmad Albuloushi ◽

Patricia E. Martin

Keyword(s):

Therapeutic Strategies ◽

Connexin 26 ◽

Epithelial Tissue ◽

Mediated Communication ◽

Therapeutic Targeting ◽

Profound Impact ◽

Physiological Processes ◽

Functional Consequences ◽

And Function

Epithelial tissue responds rapidly to environmental triggers and is constantly renewed. This tissue is also highly accessible for therapeutic targeting. This review highlights the role of connexin mediated communication in avascular epithelial tissue. These proteins form communication conduits with the extracellular space (hemichannels) and between neighboring cells (gap junctions). Regulated exchange of small metabolites less than 1kDa aide the co-ordination of cellular activities and in spatial communication compartments segregating tissue networks. Dysregulation of connexin expression and function has profound impact on physiological processes in epithelial tissue including wound healing. Connexin 26, one of the smallest connexins, is expressed in diverse epithelial tissue and mutations in this protein are associated with hearing loss, skin and eye conditions of differing severity. The functional consequences of dysregulated connexin activity is discussed and the development of connexin targeted therapeutic strategies highlighted.

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Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Molecules ◽

10.3390/molecules25204831 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4831

Author(s):

Jiaqi Li ◽

Jie Qing Eu ◽

Li Ren Kong ◽

Lingzhi Wang ◽

Yaw Chyn Lim ◽

...

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Therapeutic Strategy ◽

Treatment Resistance ◽

Tumour Microenvironment ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Cancer Associated Fibroblasts ◽

Tumour Metabolism

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

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Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization

Cancers ◽

10.3390/cancers11101599 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1599 ◽

Cited By ~ 30

Author(s):

Marta Pérez-Hernández ◽

Alain Arias ◽

David Martínez-García ◽

Ricardo Pérez-Tomás ◽

Roberto Quesada ◽

...

Keyword(s):

Cancer Treatment ◽

Therapeutic Strategy ◽

Nutrient Recycling ◽

Clinical Results ◽

Therapeutic Strategies ◽

Combination Therapies ◽

Novel Therapeutic Strategies ◽

Cellular Components ◽

Catabolic Process

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic.

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p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function

Molecular Neurobiology ◽

10.1007/s12035-021-02715-0 ◽

2022 ◽

Author(s):

Juan R. Perea ◽

Marta Bolós ◽

Raquel Cuadros ◽

Esther García ◽

Vega García-Escudero ◽

...

Keyword(s):

Therapeutic Strategy ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Therapeutic Strategies ◽

Primary Microglia ◽

Chronic Inflammatory Response ◽

The Past ◽

The Central Nervous System ◽

Tau Aggregation

AbstractAlzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.

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Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00142.2014 ◽

2014 ◽

Vol 307 (6) ◽

pp. R571-R584 ◽

Cited By ~ 61

Author(s):

Georgi V. Petkov

Keyword(s):

Smooth Muscle ◽

Urinary Bladder ◽

Overactive Bladder ◽

Bk Channels ◽

Bk Channel ◽

Regulatory Mechanisms ◽

Bladder Smooth Muscle ◽

Intracellular Ca ◽

Urinary Bladder Smooth Muscle

The physiological functions of the urinary bladder are to store and periodically expel urine. These tasks are facilitated by the contraction and relaxation of the urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, which comprises the bladder wall. The large-conductance voltage- and Ca2+-activated K+ (BK, BKCa, MaxiK, Slo1, or KCa1.1) channel is highly expressed in UBSM and is arguably the most important physiologically relevant K+ channel that regulates UBSM function. Its significance arises from the fact that the BK channel is the only K+ channel that is activated by increases in both voltage and intracellular Ca2+. The BK channels control UBSM excitability and contractility by maintaining the resting membrane potential and shaping the repolarization phase of the spontaneous action potentials that determine UBSM spontaneous rhythmic contractility. In UBSM, these channels have complex regulatory mechanisms involving integrated intracellular Ca2+ signals, protein kinases, phosphodiesterases, and close functional interactions with muscarinic and β-adrenergic receptors. BK channel dysfunction is implicated in some forms of bladder pathologies, such as detrusor overactivity, and related overactive bladder. This review article summarizes the current state of knowledge of the functional role of UBSM BK channels under normal and pathophysiological conditions and provides new insight toward the BK channels as targets for pharmacological or genetic control of UBSM function. Modulation of UBSM BK channels can occur by directly or indirectly targeting their regulatory mechanisms, which has the potential to provide novel therapeutic approaches for bladder dysfunction, such as overactive bladder and detrusor underactivity.

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