Inter-kingdom regulation of human transcriptome by dietary microRNAs: Emerging bioactives from edible plants to treat human diseases?

MicroRNAs (miRNAs) are small non-coding RNAs between 18 and 23 nts in size which regulate the translation and stability of target mRNAs. MiRNAs from dietary plants are conventionally thought to be degraded during the gastrointestinal digestion process. A few recent reports suggest that dietary microRNAs may exhibit resistance to this process, enter systemic circulation and exert biological effects on animal physiology.The horizontal transfer of miRNAs into systemic circulation is not feasible for all dietary miRNAs due to lack of bioavailability. Hence, this is a highly debated proposition with conflicting data presented in literature. Dietary miRNAs may exhibit such cross-kingdom regulation if present in extracellular vesicles which increases their bioavailability. These vesicular structures from plants are known as edible nanoparticles (ENPs). ENPs have been isolated from several edible plants. These nano-sized vesicles are filled with bioactives, proteins, lipids and miRNAs, in a bioavailable form. ENP-derived miRNAs are gaining attention due to their relative stability and resistance to degradation. ENP-derived miRNAs may enter systemic circulation and target mRNAs in recipient cells. With the COVID-19 pandemic threat worldwide, it appears that ENP-derived miRNAs could also be exploited for targeted therapeutics against SARS-CoV-2.ENP-derived miRNAs are probably more bioavailable and are spontaneously absorbed in intestinal epithelium to suppress target transcripts in human/microbial/viral kingdoms. Such cross-kingdom regulation exhibited by dietary miRNAs, if properly investigated and validated, may aid in the development of non-toxic and cost-effective therapeutics to treat human diseases.

Inter-kingdom regulation of human transcriptome by dietary microRNAs: Emerging bioactives from edible plants to treat human diseases?

Abstract: Background MicroRNAs (miRNAs) are small non-coding RNAs between 18 and 23 nts in size which regulate the translation and stability of target mRNAs. MiRNAs from dietary plants are conventionally thought to be degraded during the gastrointestinal digestion process. A few recent reports suggest that dietary microRNAs may exhibit resistance to this process, enter systemic circulation and exert biological effects on animal physiology. Scope and approach The horizontal transfer of miRNAs into systemic circulation is not feasible for all dietary miRNAs due to lack of bioavailability. Hence, this is a highly debated proposition with conflicting data presented in literature. Dietary miRNAs may exhibit such cross-kingdom regulation if present in extracellular vesicles which increases their bioavailability. These vesicular structures from plants are known as edible nanoparticles (ENPs). ENPs have been isolated from several edible plants. These nano-sized vesicles are filled with bioactives, proteins, lipids and miRNAs, in a bioavailable form. ENP-derived miRNAs are gaining attention due to their relative stability and resistance to degradation. ENP-derived miRNAs may enter systemic circulation and target mRNAs in recipient cells. With the COVID-19 pandemic threat worldwide, it appears that ENP-derived miRNAs could also be exploited for targeted therapeutics against SARS-CoV-2. Key findings and conclusions ENP-derived miRNAs are probably more bioavailable and are spontaneously absorbed in intestinal epithelium to suppress target transcripts in human/microbial/viral kingdoms. Such cross-kingdom regulation exhibited by dietary miRNAs, if properly investigated and validated, may aid in the development of non-toxic and cost-effective therapeutics to treat human diseases.

Low pH-Based Method to Increase the Yield of Plant-Derived Nanoparticles from Fresh Ginger Rhizomes.

Plant-derived nanoparticles (PDNPs) are naturally occurring exosome-like nanovesicles derived from dietary plants containing key plant bioactives. Ginger-derived PDNPs have a therapeutic effect on alcohol-induced liver injury, inflammatory bowel disease, and colon cancer. PDNPs are conventionally purified by differential ultracentrifugation, a technique not amenable for scale up. We have recently developed a polyethylene glycol (PEG) 6000-based method for cost-effective purification of ginger PDNPs, with comparable efficiency to differential ultracentrifugation (Sci. Rep. 2020, 10 (1), 4456.). Herein, we report a 4-5-fold higher ginger PDNP recovery when PEG precipitation was carried out in low pH conditions (pH 4 and 5). Low pH-derived ginger PDNPs were smaller in size without an overt change in zeta potential. The spontaneous intracellular entry and protection against oxidative stress in A431 cells were similar between ginger PDNPs purified under low, neutral, and alkaline pH. Low-pH purified ginger PDNPs had higher levels of total polyphenolic content compared to PDNPs purified under neutral and alkaline pH. Recently, ginger PDNP-derived microRNAs have been shown to exhibit cross-kingdom regulation by targeting human, gut microbiome, and viral transcripts. Using qRT-PCR, we also verified the presence of miRNAs that were predicted to target SARS-CoV-2 in ginger PDNPs purified under low pH. Thus, we have developed a method to purify ginger PDNPs in high yields by using low-pH conditions without affecting the major bioactive contents of PDNPs.

Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2.

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India) conducted a serosurvey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS-CoV2 anti-nucleocapsid (anti-NC) antibodies, 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n = 607) and 6 (n = 175) months showed stable anti-NC antibodies but declining neutralization activity. Local seropositivity was higher in densely populated cities and was inversely correlated with a 30-day change in regional test positivity rates (TPRs). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of seropositivity were high-exposure work (odds ratio, 95% confidence interval, p value: 2.23, 1.92-2.59, <0.0001), use of public transport (1.79, 1.43-2.24, <0.0001), not smoking (1.52, 1.16-1.99, 0.0257), non-vegetarian diet (1.67, 1.41-1.99, <0.0001), and B blood group (1.36, 1.15-1.61, 0.001).

Edible plant-derived exosomal microRNAs: Exploiting a cross-kingdom regulatory mechanism for targeting SARS-CoV-2.

BACKGROUND: The current COVID-19 pandemic is caused by SARS-CoV-2 which belongs to coronaviridae family. Despite the global prevalence, there are currently no vaccines or drugs. Dietary plant derived exosome-like vesicles are known as edible nanoparticles (ENPs). ENPs are filled with microRNAs (miRNAs), in bioavailable form. Recently, cross-kingdom regulation of human transcripts by plant miRNAs have been demonstrated. However, ENP derived miRNAs targeting SARS-CoV-2 has not been described. STUDY DESIGN: Mature ENP-derived miRNA sequences were retrieved from small RNA sequencing datasets available in the literature. In silico target prediction was performed to identify miRNAs that could target SARS-CoV-2. ENPs were isolated from ginger and grapefruit plants and the expression of SARS-CoV-2 targeting miRNAs were confirmed by qRT-PCR. RESULTS: From a total of 260 ENP-derived miRNAs, we identified 22 miRNAs that could potentially target SARS-CoV-2 genome. 11 miRNAs showed absolute target specificity towards SARS-CoV-2 but not SARS-CoV. ENPs from soybean, ginger, hamimelon, grapefruit, tomato and pear possess multiple miRNAs targeting different regions within SARS-CoV-2. Interestingly, osa/cme miR-530b-5p specifically targeted the ribosomal slippage site between ORF1a and ORF1b. We validated the relative expression of six miRNAs (miR-5077, miR-6300, miR-156a, miR-169, miR-5059 and miR-166 m) in ginger and grapefruit ENPs by RT-PCR which showed differential enrichment of specific miRNAs in ginger and grapefruit ENPs. CONCLUSION: Since administration of ENPs leads to their accumulation into lung tissues in vivo, ENP derived miRNAs targeting SARS-CoV-2 genome has the potential to be developed as an alternative therapy.