The Aging GABAergic System and Its Nutritional Support

Aging is associated with a decline in hormones and an associated decline in GABAergic function and calcium and ion current dysregulation. Neurosteroid hormones act as direct calcium channel blockers, or they can act indirectly on calcium channels through their interaction with GABA receptors. The calcium channel dysfunction associated with hormone loss further leads to an excitatory cell state, which can ultimately lead to cell death. The calcium theory of aging posits that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging and that sustained changes in Ca2+ homeostasis provide the final common pathway for age-associated brain changes. There is a link between hormone loss and calcium dysregulation. Loss of calcium regulation associated with aging can lead to an excitatory cell state, primarily in the mitochondria and nerve cells, which can ultimately lead to cell death if not kept in check. A decline in GABAergic function can also be specifically tied to declines in progesterone, allopregnanolone, and DHEA levels associated with aging. This decline in GABAergic function associated with hormone loss ultimately affects GABAergic inhibition or excitement and calcium regulation throughout the body. In addition, declines in GABAergic function can also be tied to vitamin status and to toxic chemicals in the food supply. The decline in GABAergic function associated with aging has an effect on just about every body organ system. Nutritional support of the GABAergic system with supportive foods, vitamins, and GABA or similar GABA receptor ligands may address some of the GABAergic dysfunction associated with aging.

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Tumor Microenvironment-Triggered In-Situ Cancer Vaccines with Dual Immunogenic Cell Death Inductions for Elevated Antitumor and Antimetastatic Therapy

Nanoscale ◽

10.1039/d1nr02018h ◽

2021 ◽

Author(s):

Jun Lin ◽

Binbin Ding ◽

Pan Zheng ◽

Dong Li ◽

Meifang Wang ◽

...

Keyword(s):

Cell Death ◽

Tumor Microenvironment ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Cancer Vaccines ◽

High Specificity ◽

The Body ◽

Immunogenic Cell Death ◽

Specific Antigens

Cancer vaccine is to make tumor-specific antigens into vaccines, which then are injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic...

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Norwegian or Crusted Sarcoptic Mange in Two Leishmanial Dogs

Journal of the American Animal Hospital Association ◽

10.5326/jaaha-ms-6445 ◽

2017 ◽

Vol 53 (6) ◽

pp. 326-330

Author(s):

Flora Kaltsogianni ◽

Rania Farmaki ◽

Alexander F. Koutinas

Keyword(s):

Complete Resolution ◽

Nutritional Support ◽

Antibody Test ◽

Skin Lesions ◽

The Body ◽

End Stage Kidney Disease ◽

Rare Type ◽

End Stage ◽

Crusted Scabies ◽

Immunofluorescent Antibody Test

ABSTRACT Norwegian or crusted scabies (N/CS) is a rare skin disease with very few cases reported in the dog or the cat. Two adult, stray dogs were admitted in our clinic with a generalized, multifocal to diffuse and nonpruritic dermatitis that was characterized by severe crusting, scaling, and ulceration. In both instances, leishmaniosis and N/CS were diagnosed by immunofluorescent antibody test serology, lymph node cytology, and skin scrapings in which high numbers of Sarcoptes mites were found. The combination of miticidal and antileishmanial treatment, supported by topical treatment and nutritional support, resulted in the complete resolution of the skin lesions and spectacular improvement of the body condition in both cases. Dog 1 eventually died from end-stage kidney disease attributed to leishmaniosis-associated glomerulonephritis, whereas the also proteinuric dog 2 remains clinically healthy. The manifestation of the rare type of N/CS in these dogs could be attributed to cell-mediated immunosuppression, which was most likely induced by leishmaniosis and malnutrition. The necessity of searching for leishmaniosis in those scabietic cases, especially in the endemic areas of leishmaniosis, is strongly recommended.

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Cytoplasmic Location of α1A Voltage-Gated Calcium Channel C-Terminal Fragment (Cav2.1-CTF) Aggregate Is Sufficient to Cause Cell Death

PLoS ONE ◽

10.1371/journal.pone.0050121 ◽

2013 ◽

Vol 8 (3) ◽

pp. e50121 ◽

Cited By ~ 7

Author(s):

Makoto Takahashi ◽

Masato Obayashi ◽

Taro Ishiguro ◽

Nozomu Sato ◽

Yusuke Niimi ◽

...

Keyword(s):

Cell Death ◽

Calcium Channel ◽

Voltage Gated ◽

Terminal Fragment ◽

Voltage Gated Calcium Channel ◽

Cytoplasmic Location

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Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

Cells ◽

10.3390/cells10102531 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2531

Author(s):

Amandine Grimm

Keyword(s):

Brain Metabolism ◽

Brain Aging ◽

Cognitive Impairments ◽

Tau Phosphorylation ◽

The Body ◽

Tau Pathology ◽

Age Related ◽

Energy Consuming ◽

Effects Of Aging ◽

The Brain

The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

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Myocardial Damage by SARS-CoV-2: Emerging Mechanisms and Therapies

Viruses ◽

10.3390/v13091880 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1880

Author(s):

Huyen Tran Ho ◽

Stefan Peischard ◽

Nathalie Strutz-Seebohm ◽

Karin Klingel ◽

Guiscard Seebohm

Keyword(s):

Immune Response ◽

Cell Death ◽

Energy Metabolism ◽

Programmed Cell Death ◽

Viral Replication ◽

Ion Homeostasis ◽

Membrane Vesicles ◽

Cardiac Cells ◽

The Body ◽

Double Membrane

Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.

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Lipids Nutrients in Parkinson and Alzheimer’s Diseases: Cell Death and Cytoprotection

International Journal of Molecular Sciences ◽

10.3390/ijms21072501 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2501 ◽

Cited By ~ 2

Author(s):

Thomas Nury ◽

Gérard Lizard ◽

Anne Vejux

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Cell Death ◽

Neurodegenerative Diseases ◽

The Body ◽

Protein Accumulation ◽

Common Features ◽

Apoptosis And Inflammation ◽

The Brain ◽

And Oxidative Stress

Neurodegenerative diseases, particularly Parkinson’s and Alzheimer’s, have common features: protein accumulation, cell death with mitochondrial involvement and oxidative stress. Patients are treated to cure the symptoms, but the treatments do not target the causes; so, the disease is not stopped. It is interesting to look at the side of nutrition which could help prevent the first signs of the disease or slow its progression in addition to existing therapeutic strategies. Lipids, whether in the form of vegetable or animal oils or in the form of fatty acids, could be incorporated into diets with the aim of preventing neurodegenerative diseases. These different lipids can inhibit the cytotoxicity induced during the pathology, whether at the level of mitochondria, oxidative stress or apoptosis and inflammation. The conclusions of the various studies cited are oriented towards the preventive use of oils or fatty acids. The future of these lipids that can be used in therapy/prevention will undoubtedly involve a better delivery to the body and to the brain by utilizing lipid encapsulation.

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The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Cancers ◽

10.3390/cancers11091313 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1313

Author(s):

Man Wang ◽

Shuai Jiang ◽

Yinfeng Zhang ◽

Peifeng Li ◽

Kun Wang

Keyword(s):

Cell Death ◽

Biological Significance ◽

Chemotherapeutic Agents ◽

The Body ◽

Cell Swelling ◽

Pathogen Invasion ◽

Membrane Rupture ◽

Cancer Management ◽

Cell Death Pathways ◽

Cancer Pathogenesis

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

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Effective Induction of Apoptosis by Mistletoe Plant Extracts in an Acute Lymphoblastic Leukemia Model.

Blood ◽

10.1182/blood.v108.11.1880.1880 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1880-1880

Author(s):

Georg Seifert ◽

Patrick Jesse ◽

Aram Prokop ◽

Tobias Reindl ◽

Stephan Lobitz ◽

...

Keyword(s):

Cell Death ◽

Body Weight ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

The Body ◽

Induction Of Apoptosis ◽

First Time ◽

Over Time

Abstract Mistletoe (Viscum album) is one of the most used alternative cancer therapies applied as monotherapy or in combination with conventional therapies. Anti-tumor effects of mistletoe (MT) extracts were related to cytostatic and immunomodulatory effects observed in vitro. Aqueous MT extracts contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. The MT lectins inhibit protein biosynthesis by inactivating the 60S ribosomal subunit. Mistletoe lectin-I (ML-I) is one important apoptosis inducing compound. It is a heterodimer that consists of a cytotoxic A-chain (ribosome inactivating protein, RIP type 1) linked by a carbohydrate binding B-chain for cellular lectin uptake. However, although MT is widely used, there is a lack of scientific preclinical and clinical data. Here, we describe for the first time efficacy and mechanism of MT extracts against lymphoblastic leukemia in vitro and in vivo. For this purpose, we first investigated both the cytotoxic effect and mechanism of action of two standardized aqueous MT extracts (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) and isolated ML-I, in three human acute lymphoblastic leukemia (ALL) cell lines (NALM-6, sup-B-15 and REH). MT-A, MT-P and ML-I clearly inhibited cell proliferation as determined by LDH reslease assays at very low concentrations (ML-I LD50 from 0,05 ng/ml to 10 ng/ml depending on the host tree) with MT-P being the most cytotoxic extract. The mechanism of cell death was determined by DNA-fragmentation assays. These indicated dose dependent induction of apoptosis as the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). For this purpose, mice (n=8/group) were injected i.v. with 1 × 106NALM6 cells and treated by intraperitoneal injections four times per week for 3 weeks (day 1–4; 7–11; 14–18) at varying doses (1, 5 and 50 mg/Kg (plant weight/body weight)). Mice (n=8) treated with PBS and cyclophosphamide (100 mg/kg, once on day 1) were used as negative and positive controls, respectively. Toxicity, peripheral blood counts, bodyweight and survival was determined over time. Interestingly, both MT extracts in all tested concentrations significantly improved survival (up to 55,4 days) in contrast to controls (34,6 days). Furthermore, no hematologic side effects were observed from this treatment as indicated by completely stable blood counts. Also the body weight of treated animals remained stable over time indicating a complete absence of systemic toxicity in the selected dose range. In summary, we demonstrate for the first time efficacy and mechanism of MT extracts against ALL in vitro and in vivo and hereby provide an important base line for the design of clinical trials with these compounds.

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