Utilization of Aloe Compounds in Combatting Viral Diseases.

Plants contain underutilized resources of compounds that can be employed to combat viral diseases. Aloe vera (L.) Burm. f. (syn. Aloe barbadensis Mill.) has a long history of use in traditional medicine, and A. vera extracts have been reported to possess a huge breadth of pharmacological activities. Here, we discuss the potential of A. vera compounds as antivirals and immunomodulators for the treatment of viral diseases. In particular, we highlight the use of aloe emodin and acemannan as lead compounds that should be considered for further development in the management and prevention of viral diseases. Given the immunomodulatory capacity of A. vera compounds, especially those found in Aloe gel, we also put forward the idea that these compounds should be considered as adjuvants for viral vaccines. Lastly, we present some of the current limitations to the clinical applications of compounds from Aloe, especially from A. vera.

Effect of processed aloe vera gel on immunogenicity in inactivated quadrivalent influenza vaccine and upper respiratory tract infection in healthy adults: A randomized double-blind placebo-controlled trial.

BACKGROUND: Aloe vera is a functional food with various pharmacological functions, including an immune-modulating effect. Until now, A. vera has never been studied as an adjuvant in influenza vaccine, and its effects on upper respiratory tract infection (URI) are unknown. PURPOSE: The objective of our study was to investigate the effect of processed A. vera gel (PAG) on immunogenicity of quadrivalent inactivated influenza vaccine and URI in healthy adults. STUDY DESIGN: A randomized, double-blind, placebo-controlled clinical trial was performed. METHODS: This study was conducted in 100 healthy adults at a single center from September 2017 to May 2018. Subjects were randomly divided into a PAG group (n = 50) and a placebo group (n = 50). The enrolled subjects were instructed to ingest the study drug for 8 weeks. The participants received a single dose of quadrivalent inactivated influenza vaccine after taking the study drug for the first 4 weeks of the study. The primary endpoint was seroprotection rate against at least one viral strain at 4 weeks post-vaccination. Other outcomes were seroprotection rate at 24 weeks post-vaccination, seroconversion rate, geometric mean fold increase (GMFI) at 4 and 24 weeks post-vaccination, seroprotection rate ratio and geometric mean titer ratio (GMTR) at 4 weeks post-vaccination between PAG and placebo groups, and incidence, severity, and duration of URI. RESULTS: The European Committee for proprietary medicinal products (CPMP) evaluation criteria were met at least one in the PAG and placebo groups for all strains. However, there was no significant difference in the seroprotection rate at 4 weeks post-vaccination against all strains in both PAG and placebo groups. Among secondary endpoints, the GMFI at 4 weeks post-vaccination for the A/H3N2 was significantly higher in the PAG than in placebo group. The GMTR as adjuvant effect was 1.382 (95% CI, 1.014-1.1883). Kaplan-Meier curve analysis showed a reduction in incidence of URI (p = 0.035), and a generalized estimating equation model identified a decrease in repeated URI events (odds ratio 0.57; 95% CI, 0.39-0.83; p = 0.003) in the PAG group. CONCLUSIONS: Oral intake of PAG did not show a significant increase in seroprotection rate from an immunogenicity perspective. However, it reduced the number of URI episodes. A well-designed further study is needed on the effect of PAG's antibody response against A/H3N2 in the future.

Inhibitory effects of aprotinin on influenza A and B viruses in vitro and in vivo.

Influenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. In this study, we found aprotinin, a serine protease inhibitor, as an anti-influenza candidate through screening of compound libraries. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). However, because there were no reports of its inhibitory effects on the other types of influenza viruses, we investigated the inhibitory effects of aprotinin in vitro on a wide range of influenza viruses, including avian and oseltamivir-resistant influenza virus strains. Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. We have also confirmed its activity in mice infected with a lethal dose of influenza virus, showing a significant increase in survival rate. Our findings suggest that aprotinin has the capacity to inhibit a wide range of influenza virus subtypes and should be considered for development as a therapeutic agent against influenza.

Lipophilic statins inhibit Zika virus production in Vero cells.

Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family. ZIKV infection has been associated with neurological complications such as microcephaly in newborns and Guillain-Barré syndrome in adults; thus, therapeutic agents are urgently needed. Statins are clinically approved for lowering cholesterol levels to prevent cardiovascular disease but have shown potential as antiviral drugs. In this study, we explored the possibility of utilizing statins as anti-ZIKV drugs. We found that, generally, lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and simvastatin) could reduce ZIKV production in vitro and result in smaller foci of infection. Time-of-drug-addition assay revealed that early treatment with statins is more beneficial than late treatment; however, statins could not completely inhibit the entry stage of ZIKV infection. Furthermore, individual lipophilic statins differed in anti-ZIKV capacity, with fluvastatin being the most efficient at low concentrations. Taken together, this study shows that statins or their derivatives have the potential to be used as anti-ZIKV therapeutic agents.

Neurotrophic activity of DA-9801, a mixture extract of Dioscorea japonica Thunb. and Dioscorea nipponica Makino, in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea japonica Thunb. has been traditionally used to treat polyuria and diabetes in Korea. AIM OF THE STUDY: We previously report the effects of Dioscorea japonica Thunb. extract on glucose control, NGF induction, and neuroprotection in a rodent diabetic model. Since the most potent fraction, DA-9801, was identified from a mixture of Dioscorea japonica Thunb. (DJ) and Dioscorea nipponica Makino (DN) following bioactivity-guided fractionation, here, we investigated the potential mechanism of the extract activity against diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: A 1:3 mixture of DJ and DN was extracted with ethanol (DA-9801) and further fractionated into an ethylacetate-soluble fraction (DA-9801E). Effects of these extracts on neurite outgrowth were measured in PC-12 cells and DRG neurons. Effects on cell viability and TrkA phosphorylation were evaluated in PC-12 cells. NGF induction effect was determined in primary Schwann cells as well as IMS32 cells (immortalized Schwann cells). RESULTS: No cytotoxicity was observed in PC-12 cells at the concentration below 500 µg/ml of either DA-9801 or DA-9801E. DA-9801 and DA-9801E at 100 µg/ml and 10 µg/ml, respectively, showed a significant effect on neurite outgrowth in PC-12 cells and DRG neurons in the presence of or absence a low concentration of NGF (2 ng/ml). The Trk-A phosphorylation effect of DA9801 was confirmed in PC-12 cells. An NGF induction effect of these extracts was not detected in either IMS-32 cells, or primary Schwann cells. CONCLUSIONS: The NGF agonistic activity of DA-9801 and DA-9801E was demonstrated, which may contribute to their neuroprotective effect against DPN. Studies of the detailed mechanism of these extracts as well as identification of the active components are warranted for the development of an anti-DPN drug from DJ and DN.

A novel missense mutation in the mouse hairless gene causes irreversible hair loss: genetic and molecular analyses of Hr m1Enu.

A novel autosomal recessive mutant was produced using N-ethyl-N-nitrosourea mutagenesis. The characteristics of the mutant mice included progressive irreversible hair loss within a month of birth, wrinkled skin, and long curved nails. Linkage analysis revealed that the causative gene is linked to D14Mit193 on chromosome 14. Sequence analysis of the complete cDNA of the candidate gene, hairless (Hr), identified a homozygous G-to-T transition at nucleotide 3572, leading to the substitution of glycine by tryptophan, designated Gly960Trp. This missense mutation occurs in the vicinity of repression domain 3 of the hairless protein (HR). This allele was named Hr(m1Enu). The relative amounts of Hr mRNA and HR protein determined by real-time PCR and Western blot analyses, respectively, were slightly elevated in the mutant mice. Quantitative real-time PCR analysis revealed the increased expression of Kc1 and Vdr in the mutant mice, whereas the expression of Nrs1 and Krtap16-6 was decreased. These results suggest that the Gly960Trp substitution in HR protein in Hr(m1Enu) mice may alter the function of HR as a transcriptional corepressor.