Mitophagosomes induced during EV-D68 infection promote viral nonlytic release.

Enterovirus-D68 (EV-D68) is a plus-strand RNA virus that primarily causes infant respiratory infections. In rare pediatric cases, infection with EV-D68 has been associated with acute flaccid myelitis, a polio-like paralytic disease. We have previously demonstrated that EV-D68 induces nonselective autophagy for its benefit.

Transcription factor EB (TFEB) interaction with RagC is disrupted during enterovirus D68 infection.

Unlabelled: Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no protective vaccines or antivirals are available to combat this virus. Like other enteroviruses, EV-D68 uses components of the cellular autophagy pathway to rewire membranes for its replication.

Viruses and autophagy: bend, but don't break.

Autophagy is a constitutive cellular process of degradation required to maintain homeostasis and turn over spent organelles and aggregated proteins. For some viruses, the process can be antiviral, degrading viral proteins or virions themselves. For many other viruses, the induction of the autophagic process provides a benefit and promotes viral replication.

SIRT-1 is required for release of enveloped enteroviruses.

Enterovirus D68 (EV-D68) is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we show that the histone deacetylase, SIRT-1, is essential for autophagy and EV-D68 infection. Knockdown of SIRT-1 inhibits autophagy and reduces EV-D68 extracellular titers.

Enterovirus D68 capsid formation and stability requires acidic compartments.

The respiratory picornavirus enterovirus D68 is a causative agent of acute flaccid myelitis, a childhood paralysis disease identified in the last decade. Poliovirus, another picornavirus associated with paralytic disease, is a fecal-oral virus that survives acidic environments when passing from host to host. Here, we follow up on our previous work showing a requirement for acidic intracellular compartments for maturation cleavage of poliovirus particles.

Enterovirus D68 capsid formation and stability requires acidic compartments.

Enterovirus D68 (EV-D68), a picornavirus traditionally associated with respiratory infections, has recently been linked to a polio-like paralytic condition known as acute flaccid myelitis (AFM). EV-D68 is understudied, and much of the field's understanding of this virus is based on studies of poliovirus. For poliovirus, we previously showed that low pH promotes virus capsid maturation, but here we show that, for EV-D68, inhibition of compartment acidification during a specific window of infection causes a defect in capsid formation and maintenance.

SNAP23 is essential for germination of EV-D68 replication organelles.

Picornaviruses rearrange host cell membranes to facilitate their own replication. Here we investigate the Qbc SNARE, SNAP23, which is found at the plasma membrane and plays roles in exocytosis. We found that knockdown of SNAP23 expression inhibits virus replication but not release from cells.

Starvation after infection restricts enterovirus D68 replication.

Enterovirus D68 (EV-D68) is a respiratory pathogen associated with acute flaccid myelitis, a childhood paralysis disease. No approved vaccine or antiviral treatment exists against EV-D68. Infection with this virus induces the formation of autophagosomes to enhance its replication but blocks the downstream autophagosome- lysosome fusion steps.

Identification of the phytobioactive Polygonum cuspidatum as an antiviral source for restricting dengue virus entry.

Dengue virus (DENV) is a mosquito-borne pathogen that is becoming a serious global threat, owing to its rising incidence in inter-tropical regions that yield over 50 million annual infections. There are currently no approved antiviral agents for the management of dengue, and recent shortcomings in its immunization called for immediate action to develop effective drugs with prophylactic ability to better manage its infection. In an attempt to discover novel antiviral sources, we identified the medicinal herb Polygonum cuspidatum (PC) as a bioactive botanical material against DENV infectivity.

Compounds isolated from Hayata induce ossification through multiple pathways.

The process of bone metabolism includes catabolism of old or mature bone and anabolism of new bone, carried out by osteoclasts and osteoblasts respectively. Any imbalance in this process results in loss of bone mass or osteoporosis. Drugs available to combat osteoporosis have certain adverse effects and are unable to improve bone formation, hence identifying new agents to fulfil these therapeutic gaps is required.

Targeting Autophagy Augments BBR-Mediated Cell Death in Human Hepatoma Cells Harboring Hepatitis C Virus RNA.

Hepatocellular carcinoma (HCC), including hepatitis C virus (HCV)-induced HCC, is a deadly disease highly refractory to chemotherapy, thus requiring the continuous identification of novel treatment strategies. Berberine (BBR) has been previously reported to inhibit hepatoma cell growth, but the main type of cell death elicited by BBR, and whether the alkaloid can inhibit hepatoma cells carrying HCV genomes, is unclear. Herein, we show that BBR treatment induced a biphasic cell death irrespective of the presence of HCV subgenomic replicon RNA, first triggering apoptosis that then progressed to necrosis between 24 and 48 h post-treatment.

Virus-Like Particle Systems for Vaccine Development against Viruses in the Flaviviridae Family.

Viruses in the Flaviviridae family are important human and animal pathogens that impose serious threats to global public health. This family of viruses includes emerging and re-emerging viruses, most of which are transmitted by infected mosquito or tick bites. Currently, there is no protective vaccine or effective antiviral treatment against the majority of these viruses, and due to their growing spread, several strategies have been employed to manufacture prophylactic vaccines against these infectious agents including virus-like particle (VLP) subunit vaccines.

Antiviral Activities of Silymarin and Derivatives.

Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development.

Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy.

Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) plays a key role in regulating cellular mitophagy.

Berberine inhibits hepatitis C virus entry by targeting the viral E2 glycoprotein.

Background: Despite the advent of direct-acting antivirals (DAAs), HCV remains an important public health problem globally. There is at present no effective vaccine against the virus, and the DAAs in current use cannot prevent de novo infection, including in liver transplant setting wherein donor livers inevitably become re-infected. Developing inhibitors to HCV entry using nature-derived small molecules may help to expand/complement the current treatment options.

Identification of baicalin from Bofutsushosan and Daisaikoto as a potent inducer of glucose uptake and modulator of insulin signaling-associated pathways.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia that can lead to long-term complications including heart diseases, stroke, retinopathy, and renal failure. Treatment strategies include stimulating glucose uptake and controlling blood glucose level. Bofutsushosan (BOF) and Daisaikoto (DAI) are two herb-based kampo medicines that have been demonstrated to improve metabolism-associated disorders including obesity, hyperlipidemia, and nonalcoholic fatty liver.

Methanolic Extract of Inhibits the Early Viral Entry Steps of Hepatitis C Virus Infection.

Hepatitis C Virus (HCV) remains an important public health threat with approximately 170 million carriers worldwide who are at risk of developing hepatitis C-associated end-stage liver diseases. Despite improvement of HCV treatment using the novel direct-acting antivirals (DAAs) targeting viral replication, there is a lack of prophylactic measures for protection against HCV infection. Identifying novel antivirals such as those that target viral entry could help broaden the therapeutic arsenal against HCV.

Combination treatment of ergosterol followed by amphotericin B induces necrotic cell death in human hepatocellular carcinoma cells.

The incidence of liver cancer, the second leading cause of cancer-related deaths has increased over the past few decades. Although recent treatments such as sorafenib are promising in patients with advanced hepatocellular carcinoma (HCC), the response rates remain poor thereby warranting the identification of novel therapeutic agents against liver cancer. Herein, we investigated the anti-cancer effect of ergosterol (a secondary metabolite in medicinal fungus) pretreatment followed by amphotericin B (AmB) treatment on liver cancer cell lines.

Highly bioavailable silibinin nanoparticles inhibit HCV infection.

Objective: Silibinin is a flavonolignan that is well established for its robust antiviral activity against HCV infection and has undergone several clinical trials for the management of hepatitis C. Despite its potency, silibinin suffers from poor solubility and bioavailability, restricting its clinical use. To overcome this limitation, we developed highly bioavailable silibinin nanoparticles (SB-NPs) and evaluated their efficiency against HCV infection.

(4R,6S)-2-Dihydromenisdaurilide is a Butenolide that Efficiently Inhibits Hepatitis C Virus Entry.

Without a vaccine, hepatitis C virus (HCV) remains a significant threat, putting 170-300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma. Although the direct-acting antivirals targeting HCV replication have revolutionized the treatment of hepatitis C, several obstacles persist, including resistance development, potential side-effects, and the prohibitive cost that limits their availability. Furthermore, treatment of HCV re-infection in liver transplantation remains a significant challenge.

Activity-based and fraction-guided analysis of Phyllanthus urinaria identifies loliolide as a potent inhibitor of hepatitis C virus entry.

Without a vaccine, hepatitis C virus (HCV) remains a global medical and socio-economic burden, predisposing about 170 million carriers worldwide to end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Although the recently developed direct-acting antivirals (DAAs) have revolutionized hepatitis C treatment, most of them are unsuitable for monotherapy due to risks of resistance, thus necessitating combination with interferon (IFN)-alpha, ribavirin, or additional DAAs. More importantly, the high cost associated with the DAAs restricts their accessibility to most parts of the world.