scholarly journals Astrovirus Replication Is Inhibited by Nitazoxanide In Vitro and In Vivo

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Virginia Hargest ◽  
Bridgett Sharp ◽  
Brandi Livingston ◽  
Valerie Cortez ◽  
Stacey Schultz-Cherry
Keyword(s):  
Therapeutic Strategy ◽  
The Elderly ◽  
Persistent Diarrhea ◽  
Fatal Disease ◽  
Viral Shedding ◽  
Human Astroviruses ◽  
Effective Therapeutic Strategy ◽  
Human Astrovirus

ABSTRACT Astroviruses (AstV) are a leading cause of diarrhea, especially in the very young, the elderly, and immunocompromised populations. Despite their significant impact on public health, no drug therapies for astrovirus have been identified. In this study, we fill this gap in knowledge and demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication in vitro with a 50% effective concentration (EC50) of approximately 1.47 μM. It can be administered up to 8 h postinfection and is effective against multiple human astrovirus serotypes, including clinical isolates. Most importantly, NTZ reduces viral shedding in vivo, exhibiting its potential as a future clinical therapeutic. IMPORTANCE Human astroviruses (HAstV) are thought to cause between 2 and 9% of acute, nonbacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants, where the virus has been associated with necrotizing enterocolitis and severe and persistent diarrhea, as well as rare instances of systemic and fatal disease. And yet, no antivirals have been identified to treat astrovirus infection. Our study provides the first evidence that nitazoxanide may be an effective therapeutic strategy against astrovirus disease.

scholarly journals Astrovirus Replication Is Inhibited by Nitazoxanide In Vitro and In Vivo

2019 ◽  
Author(s):  
Virginia Hargest ◽  
Bridgett Sharp ◽  
Brandi Livingston ◽  
Valerie Cortez ◽  
Stacey Schultz-Cherry
Keyword(s):  
Therapeutic Strategy ◽  
The Elderly ◽  
Effective Concentration ◽  
Persistent Diarrhea ◽  
Fatal Disease ◽  
Human Astroviruses ◽  
Effective Therapeutic Strategy ◽  
Human Astrovirus

AbstractAstroviruses (AstV) are a leading cause of diarrhea especially in the very young, the elderly, and immunocompromised populations. Despite their significant impact on public health, no drug therapies for astrovirus have been identified. In this study we fill this gap in knowledge and demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication in vitro with a 50% effective concentration (EC50) of approximately 1.47μM. It can be administered up to 8 hours post-infection and is effective against multiple human astrovirus serotypes including clinical isolates. Most importantly, NTZ reduces viral shed and clinical disease (diarrhea) in vivo, exhibiting its potential as a future clinical therapeutic.ImportanceHuman astroviruses (HAstV) are thought to cause between 2 and 9% of acute, non-bacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants where the virus has been associated with necrotizing enterocolitis, severe and persistent diarrhea, as well as systemic and often fatal disease. Yet no antivirals have been identified to treat astrovirus infection. Our study provides the first evidence that nitazoxanide may be an effective therapeutic strategy against astrovirus disease.

Excavating Anticonvulsant Compounds from Prescriptions of Traditional Chinese Medicine in the Treatment of Epilepsy

2018 ◽  
Vol 46 (04) ◽  
pp. 707-737 ◽  
Author(s):  
Zefeng Zhao ◽  
Xirui He ◽  
Cuixia Ma ◽  
Shaoping Wu ◽  
Ye Cuan ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Therapeutic Strategy ◽  
In Vitro Models ◽  
New Drugs ◽  
Treatment Of Epilepsy ◽  
Effective Therapeutic Strategy ◽  
Promising Source

Traditional Chinese medicine (TCM) has a long history and been widely used in prevention and treatment of epilepsy in China. This paper is intended to review the advances in the active anticonvulsant compounds isolated from herbs in the prescription of TCM in the treatment of epilepsy. These compounds were introduced with the details including classification, CAS number specific structure and druggability data. Meanwhile, much of the research in these compounds in the last two decades has shown that they exhibited favorable pharmacological properties in treatment of epilepsy both in in vivo and in vitro models. In addition, in this present review, the evaluation of the effects of the anticonvulsant classical TCM prescriptions is discussed. According to these rewarding pharmacological effects and chemical substances, the prescription of TCM herbs could be an effective therapeutic strategy for epilepsy patients, and also could be a promising source for the development of new drugs.

scholarly journals Type I Interferon Response Limits Astrovirus Replication and Protects against Increased Barrier PermeabilityIn VitroandIn Vivo

2015 ◽  
Vol 90 (4) ◽  
pp. 1988-1996 ◽  
Author(s):  
Shauna A. Marvin ◽  
C. Theodore Huerta ◽  
Bridgett Sharp ◽  
Pamela Freiden ◽  
Troy D. Cline ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Barrier Permeability ◽  
Type I Ifns ◽  
Human Astroviruses ◽  
Human Astrovirus ◽  
New Evidence

ABSTRACTLittle is known about intrinsic epithelial cell responses against astrovirus infection. Here we show that human astrovirus type 1 (HAstV-1) infection induces type I interferon (beta interferon [IFN-β]) production in differentiated Caco2 cells, which not only inhibits viral replication by blocking positive-strand viral RNA and capsid protein synthesis but also protects against HAstV-1-increased barrier permeability. Excitingly, we found similar resultsin vivousing a murine astrovirus (MuAstV) model, providing new evidence that virus-induced type I IFNs may protect against astrovirus replication and pathogenesisin vivo.IMPORTANCEHuman astroviruses are a major cause of pediatric diarrhea, yet little is known about the immune response. Here we show that type I interferon limits astrovirus infection and preserves barrier permeability bothin vitroandin vivo. Importantly, we characterized a new mouse model for studying astrovirus replication and pathogenesis.

scholarly journals Essential Oils: An Effective Therapeutic Strategy against SARS-CoV-2

2021 ◽  
Vol 12 (6) ◽  
pp. 719-724
Author(s):  
Santwana Palai ◽  
◽  
Shyam Sundar Kesh ◽  
Keyword(s):  
Essential Oils ◽  
Viral Entry ◽  
Therapeutic Strategy ◽  
Supportive Therapy ◽  
Medicinal And Aromatic Plants ◽  
Herbal Plants ◽  
Effective Therapeutic Strategy ◽  
Novel Coronavirus

Thousands of individuals have perished as a result of Covid-19 and it has turned into a global problem. The novel coronavirus 2019 (nCoV-2019), also known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spread rapidly following its discovery in Wuhan patients with acute pneumonia in China. No medication or vaccine are available to treat human coronavirus infection successfully. The alternative therapies and cures are not are effective or authorised to treat Corona virus. Treatments are primarily supportive because no particular pandemic cure has been licenced. New interventions will most likely take months to years to mature. Using antiviral medicinal herbs as an auxiliary or supportive therapy seems to be a viable alternative. The essential oils of medicinal plants have antiviral and immunomodulatory effects. Being rich in antioxidants, essential oils can be used to develop new antiviral remedies. Such beneficial essential oils are being evaluated and exploited for its potent therapeutic use against many viruses. These natural compounds bestow antiviral actions by disrupting the viral life cycle during viral entry, assembly, replication, discharge and virus-specific host targets. This study highlights the essential oils derived from medicinal and aromatic plants with in vitro and in vivo antiviral effects. Essential oils having known pharmacokinetic and pharmacodynamic properties can be repurposed as a strategy against deadly SARS-CoV-2 infection. These essential oils of herbal plants can be an effective therapeutic strategy against SARS-CoV-2 when used along with conventional antiviral medicines.

Combinatorial Inhibition of mTORC2 and Hsp90 Leads to a Distinctly Effective Therapeutic Strategy in Malignant Pheochromocytoma

2019 ◽  
Vol 19 (9) ◽  
pp. 698-706
Author(s):  
Xiaohua Zhang ◽  
Fengbin Gao ◽  
Shan Zhong
Keyword(s):  
Pc12 Cells ◽  
Therapeutic Strategy ◽  
Akt Signaling ◽  
Therapeutic Strategies ◽  
Malignant Pheochromocytoma ◽  
Inhibit Tumor Growth ◽  
Effective Therapeutic Strategy ◽  
Hsp90 Function

Background: Malignant pheochromocytoma (mPCC) is an uncommon tumor with poor prognosis, and no effective therapeutic strategy exists as yet. Discovering new and effective therapeutic strategies to improve prognosis is an urgent need. Objective: To investigate whether a combinatorial inhibition of both mTORC2 and Hsp90 in PC12 cells could lead to a distinct anti-tumor effect in vitro and in vivo that was greater than the inhibition of mTORC2 or Hsp90 alone. Methods: Targeting mTORC2 was assessed by knockdown of Rictor using shRNA, and 17-AAG was used to inhibit Hsp90 function. Results: Combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vitro that was greater than the inhibition of mTORC2 or Hsp90 alone. Inhibiting Hsp90 specifically could inhibit tumor growth of sh-Rictor cells in vivo, suggesting that the combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vivo. Western blotting has shown that both p-Akt Ser473 and p-Akt Thr450 showed significantly decreased expression after targeting mTORC2, while p-Akt Thr308 did not. However, all three different p-AKTs, including p-Akt Ser473, p-Akt Thr450 and p-Akt Thr308, showed a significantly decreased expression in combinatorial inhibition of both mTORC2 and Hsp90. Collectively, it revealed that combinatorial inhibition of mTORC2 and Hsp90 could destabilize the Akt signaling. Conclusion: Our results demonstrated that combinatorial inhibition of mTORC2 and Hsp90 could increase their anti-tumor effect and destabilize the Akt signaling in PC12 cells, suggesting a combinatorial inhibition of both mTORC2 and Hsp90 which might be an effective therapeutic strategy for mPCC.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

scholarly journals Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zetao Chen ◽  
Yihong Chen ◽  
Yan Li ◽  
Weidong Lian ◽  
Kehong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Smad Pathway ◽  
Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

scholarly journals MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR, RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN VITRO AND IN VIVO

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii414-iii414
Author(s):  
Muh-Lii Liang ◽  
Tsung-Han Hsieh ◽  
Tai-Tong Wong
Keyword(s):  
Dna Repair ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Rna Seq ◽  
Downstream Target ◽  
Rb Phosphorylation ◽  
Glial Lineage

Abstract BACKGROUND Glial-lineage tumors constitute a heterogeneous group of neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas, which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at improving neoadjuvant chemotherapy and deferring radiotherapy because radiation exposure may cause long-term side effects on the developing brain in young children. Despite aggressive treatment, more than half the high-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment. METHODS By using integrated bioinformatics and through experimental validation, we found that at least one gene among CCND1, CDK4, and CDK6 was overexpressed in pHGGs and ependymomas. RESULTS The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of abemaciclib was validated in vitro in pHGGs and ependymoma cells and in vivo by using subcutaneously implanted ependymoma cells from patient-derived xenograft (PDX) in mouse models. Abemaciclib demonstrated the suppression of RB phosphorylation, downstream target genes of E2F, G2M checkpoint, and DNA repair, resulting in tumor suppression. CONCLUSION Abemaciclib showed encouraging results in preclinical pediatric glial-lineage tumors models and represented a potential therapeutic strategy for treating challenging tumors in children.

scholarly journals Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme

2020 ◽  
Vol 318 (5) ◽  
pp. H1296-H1307 ◽  
Author(s):  
Carlos J. Munoz ◽  
Ivan S. Pires ◽  
Jin Hyen Baek ◽  
Paul W. Buehler ◽  
Andre F. Palmer ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Capillary Density ◽  
Microvascular Blood Flow ◽  
Systemic Hypertension ◽  
Proof Of Concept ◽  
Heme Transfer ◽  
Ligand Transfer ◽  
Novel Therapeutic

This study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.

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