scholarly journals Insights into the COVID-19 pandemic from a rare neurodegenerative disease

2020 ◽  
Author(s):  
Stephen Sturley ◽  
Zsuzsa Márka ◽  
Szabolcs Márka ◽  
Natalie Hammond ◽  
Tamayanthi Rajakumar ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Unmet Need ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Therapeutic Strategies ◽  
Biological Conservation ◽  
Rapid Testing ◽  
Enveloped Viruses ◽  
Niemann Pick

The current justified furor regarding epidemic preparedness has emphasized an unmet need for therapeutic strategies that lead to rapid implementation. The prompt identification and sequencing of the COVID-19 genome has prompted herculean efforts to rapidly design and produce vaccines and other antiviral interventions. Nevertheless, the generalized availability of such therapeutics will be markedly out of phase with the first wave of this disease. Strategic drug repurposing combined with rapid testing of molecular targets could provide at least a pause in disease progression and aid mitigation. With respect to the current pandemic, COVID-19, in common with other enveloped viruses (e.g. HIV, Ebola, SARS, and MERS) encounter the endosomal/lysosomal host compartment as a critical step for infection and maturation. A surprisingly key interaction requires engagement of the Niemann-Pick type C1 (NPC1) pathway. This observation prompts the utilization of NPC1 inhibitors as antiviral agents. Fortunately, there are such molecules, in many cases available as generics that could be rapidly deployed in the upcoming months. Herein we expand upon this strategy and its scientific underpinning wherein given the biological conservation of SARS-CoV-1 and SARS-CoV-2, and the role of the NPC1-dependent late endosome/lysosome lipid pathway in coronavirus infections, we suggest that the known mechanistic information on NPC1 could be utilized within the context of COVID-19 and associated candidate therapeutics.

scholarly journals The Role of MicroRNAs in Hepatoblastoma Tumors

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 409 ◽  
Author(s):  
Ion Cristóbal ◽  
Marta Sanz-Álvarez ◽  
Melani Luque ◽  
Cristina Caramés ◽  
Federico Rojo ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Strategies ◽  
Substantial Contribution ◽  
Hepatic Malignancy ◽  
Recent Advances

Hepatoblastoma is the most common hepatic malignancy during childhood. However, little is still known about the molecular mechanisms that govern the development of this disease. This review is focused on the recent advances regarding the study of microRNAs in hepatoblastoma and their substantial contribution to improv our knowledge of the pathogenesis of this disease. We show here that miRNAs represent valuable tools to identify signaling pathways involved in hepatoblastoma progression as well as useful biomarkers and novel molecular targets to develop alternative therapeutic strategies in this disease.

scholarly journals Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity

2020 ◽  
Vol 61 (7) ◽  
pp. 972-982 ◽  
Author(s):  
Stephen L. Sturley ◽  
Tamayanthi Rajakumar ◽  
Natalie Hammond ◽  
Katsumi Higaki ◽  
Zsuzsa Márka ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Cell Receptor ◽  
Viral Infectivity ◽  
Rapid Testing ◽  
Lipid Trafficking ◽  
Angiotensin Converting Enzyme 2 ◽  
Functional Conservation ◽  
Host Cell Receptor ◽  
Type C ◽  
Niemann Pick

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.

scholarly journals Baculovirus utilizes cholesterol transporter Niemann–Pick C1 for host cell entry

2018 ◽  
Author(s):  
Zhihong Li ◽  
Junhong Wei ◽  
Youpeng Fan ◽  
Xionge Mei ◽  
Qiang He ◽  
...  
Keyword(s):  
Bombyx Mori ◽  
Molecular Mechanisms ◽  
Insect Cells ◽  
Foreign Gene ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Enveloped Viruses ◽  
Baculovirus Infection ◽  
Niemann Pick

ABSTRACTThe dual roles of baculovirus for the control of natural insect populations as an insecticide, and for foreign gene expression and delivery, have called for a comprehensive understanding of the molecular mechanisms governing viral infection. Here, we demonstrate that theBombyx moriNiemann-Pick C1 (BmNPC1) is essential for baculovirus infection in insect cells. Both pretreatment ofBombyx moriembryonic cells (BmE) with NPC1 antagonists (imipramine or U18666A) and down-regulation of NPC1 expression resulted in a significant reduction in baculovirus BmNPV (Bombyx morinuclear polyhedrosis virus) infectivity. Furthermore, we show that the major glycoprotein gp64 of BmNPV, responsible for both receptor binding and fusion, is able to interact predominantly with the BmNPC1 C domain, with an enhanced binding capacity at low pH conditions, indicating that NPC1 most likely plays a role during viral fusion in endosomal compartments. Our results, combined with previous studies identifying an essential role of hNPC1 in filovirus infection, suggest that the glycoprotein of several enveloped viruses possess a shared strategy of exploiting host NPC1 proteins during virus intracellular entry events.IMPORTANCEBmNPV is one of the most important members of theBaculoviridae; many viruses in this family have been frequently employed as viral vectors for foreign gene delivery or expression and as biopesticides, but their host receptors still remain unclear. Here, we describe that the intracellular cholesterol transporter BmNPC1 is indispensable for BmNPV infection in insect cells, and it interacts with the major viral glycoprotein gp64. Our study on the role of BmNPC1 in baculovirus infection has further expanded the list of the enveloped viruses that require host NPC1 proteins for entry, and will ultimately help us to uncover the molecular mechanism of the involvement of NPC1 proteins in the entry process of many enveloped viruses.

Genetic background of cholesterol absorption efficacy. The role of Niemann–Pick C1-like 1 receptor and its genetic variation in lipid metabolism

2010 ◽  
Vol 151 (34) ◽  
pp. 1376-1383 ◽  
Author(s):  
Mariann Harangi ◽  
István Balogh ◽  
János Harangi ◽  
György Paragh
Keyword(s):  
Genetic Variation ◽  
Lipid Metabolism ◽  
Genetic Background ◽  
Cholesterol Absorption ◽  
Niemann Pick

A Niemann–Pick C1-like-1 egy szterolfelismerő domént tartalmazó membránfehérje, amelyet nagy számban expresszálnak csúcsi felszínükön a bélhámsejtek. Az utóbbi évek vizsgálatai azt igazolták, hogy ez a fehérje szükséges a szabad koleszterin bejutásához a bélhámsejtekbe a bél lumenéből. Biokémiai vizsgálatok azt igazolták, hogy a Niemann–Pick C1-like-1-hez kötődik az ezetimib, amely egy hatékony koleszterinfelszívódást gátló szer. A bélből történő koleszterinfelszívódás ütemében és az ezetimibkezelés hatékonyságában tapasztalt egyéni eltérések hátterében felmerült néhány Niemann–Pick C1-like-1 génvariáció oki szerepe.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

Is Immune Response Relevant in Interstitial Lung Disease?

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.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

scholarly journals Targeting macrophages in cancer immunotherapy

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.

scholarly journals Role of husband’s attitude towards the usage of contraceptives for unmet need of family planning among married women of reproductive age in Pakistan

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Muhammad Farhan Asif ◽  
Zahid Pervaiz ◽  
Jawad Rahim Afridi ◽  
Ghulam Abid ◽  
Zohra S. Lassi
Keyword(s):  
Family Planning ◽  
Unmet Need ◽  
Wealth Quintile ◽  
Married Women ◽  
Reproductive Age ◽  
Women Of Reproductive Age ◽  
Family Planning Programs ◽  
Contraception Use ◽  
Wide Range

Abstract Background Family planning services deliver a wide range of benefits to the well-being of females and the community. It can curtail the risk of maternal and neonatal mortality through the reduction in abortions and pregnancies. The government of Pakistan has been struggling to convince people about the usefulness of family planning programs. However, different factors related to social norms, values, and culture are important to determine the success of these programs. One such factor is the patriarchal structure of Pakistani society where most of the household decisions are made by men. The objective of this research is to examine the role of the husband’s attitude towards the usage of contraceptives for the unmet need of family planning (UMNFP) among married women of reproductive age (MWRA) in Pakistan. Method The dataset of Pakistan Demographic and Health Survey 2017–18 is utilized to examine the role of the husband’s attitude towards the usage of contraceptives in UMNFP among MWRA in Pakistan. Results The UMNFP was considerably lower among MWRA between 40 years and above compared to women 15–19 years. The odds of UMNFP were higher among women and men who were educated up to the primary level compared to those with no education. Odds of UMNFP were higher among women from the poor wealth quintile compared to the poorest wealth quintile; similarly, it was significantly lower among women who were from the richer and the richest wealth quintile compared to the poorest wealth quintile. The odds of UMNFP were lower among women who were employed compared to those who were not employed. Lastly, the odds of UMNFP were higher among women whose husbands opposed to using contraceptives, who perceived that there was a religious prohibition for such use and when a decision on the contraception use was solely made by the husband. Conclusions Husband’s attitude towards the usage of contraceptives is an important predictor of UMNFP. Liaising with the community and religious leaders to persuade people particularly men about the usefulness of family planning programs and encouraging men to understand their women’s say in using contraceptives should be encouraged.

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

Life ◽  
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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