Molecular Mechanisms, Proteinopathies and Therapeutic Strategies in Neurodegenerative Disorders

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

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Natural Products for Regulating Macrophages M2 Polarization

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190523093535 ◽

2020 ◽

Vol 15 (7) ◽

pp. 559-569 ◽

Cited By ~ 1

Author(s):

Zhen Chang ◽

Youhan Wang ◽

Chang Liu ◽

Wanli Smith ◽

Lingbo Kong

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Research Progress ◽

Cellular Mechanisms ◽

Pharmacological Activities ◽

Current Review ◽

M2 Polarization ◽

Macrophages Polarization ◽

Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

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Molecular Processes Involved in Pancreatic Cancer and Therapeutics

Current Chemical Biology ◽

10.2174/2212796814999201008130819 ◽

2020 ◽

Vol 14 ◽

Author(s):

Subhajit Makar ◽

Abhrajyoti Ghosh ◽

Divya ◽

Shalini Shivhare ◽

Ashok Kumar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Mechanisms ◽

Early Stage ◽

Locally Advanced ◽

Therapeutic Strategies ◽

Screening Methods ◽

Pancreatic Cancer Cells ◽

Systemic Treatments ◽

Cancer Initiation ◽

Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

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The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽

10.3390/biology9120485 ◽

2020 ◽

Vol 9 (12) ◽

pp. 485

Author(s):

Lorenzo Cuollo ◽

Fabrizio Antonangeli ◽

Angela Santoni ◽

Alessandra Soriani

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Senescent Cell ◽

Pharmacological Intervention ◽

Tissue Microenvironment ◽

Age Related ◽

Secretory Phenotype ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

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Immune Actions on the Peripheral Nervous System in Pain

International Journal of Molecular Sciences ◽

10.3390/ijms22031448 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1448

Author(s):

Jessica Aijia Liu ◽

Jing Yu ◽

Chi Wai Cheung

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Peripheral Nervous System ◽

Immune Cells ◽

Molecular Mechanisms ◽

Process Integration ◽

Current Knowledge ◽

Therapeutic Strategies ◽

Lipid Mediators ◽

Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

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Cannabidiol induces autophagy via ERK1/2 activation in neural cells

Scientific Reports ◽

10.1038/s41598-021-84879-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Talita A. M. Vrechi ◽

Anderson H. F. F. Leão ◽

Ingrid B. M. Morais ◽

Vanessa C. Abílio ◽

Antonio W. Zuardi ◽

...

Keyword(s):

Central Nervous System ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Cannabis Sativa ◽

Autophagic Flux ◽

Neural Cells ◽

Human Neuroblastoma ◽

Trpv1 Receptor ◽

The Central Nervous System ◽

Catabolic Process

AbstractAutophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

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Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Cells ◽

10.3390/cells10061411 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1411

Author(s):

Don Carlo Ramos Batara ◽

Moon-Chang Choi ◽

Hyeon-Uk Shin ◽

Hyunggee Kim ◽

Sung-Hak Kim

Keyword(s):

Brain Tumor ◽

Glioblastoma Multiforme ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Primary Brain Tumor ◽

Molecular Target ◽

Therapeutic Strategies ◽

Homeostatic Mechanism ◽

Cellular Context ◽

Cellular Components

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

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Epilepsy and Migraine Shared Genetic and Molecular Mechanisms: Focus on Therapeutic Strategies

Molecular Neurobiology ◽

10.1007/s12035-021-02386-x ◽

2021 ◽

Author(s):

Palvi Gotra ◽

Nidhi Bhardwaj ◽

Abhilash Ludhiadch ◽

Gagandeep Singh ◽

Anjana Munshi

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Shared Genetic

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Hypoxic tumor microenvironment: Implications for cancer therapy

Experimental Biology and Medicine ◽

10.1177/1535370220934038 ◽

2020 ◽

Vol 245 (13) ◽

pp. 1073-1086

Author(s):

Sukanya Roy ◽

Subhashree Kumaravel ◽

Ankith Sharma ◽

Camille L Duran ◽

Kayla J Bayless ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Metabolic Regulation ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Tumor Vasculature ◽

Therapeutic Strategies ◽

Therapeutic Resistance ◽

Low Oxygen ◽

Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

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