Potential COVID-19 remedies from repurposed drugs and herbal small RNAs.

To date, SARS-CoV-2 has caused millions of deaths, but the choice of treatment is limited. We previously established a platform for identifying Food and Drug Administration (FDA)-approved repurposed drugs for avian influenza A virus infections that could be used for coronavirus disease 2019 (COVID-19) treatment. In this study, we analyzed blood samples from two cohorts of 63 COVID-19 patients, including 19 patients with severe disease. Among the 39 FDA-approved drugs we identified for COVID-19 therapy in both cohorts, 23 drugs were confirmed by literature mining data, including 14 drugs already under COVID-19 clinical trials and 9 drugs reported for COVID-19 treatments, suggesting the remaining 16 FDA-approved drugs may be candidates for COVID-19 therapy. Additionally, we previously reported that herbal small RNAs (sRNAs) could be effective components in traditional Chinese medicine (TCM) for treating COVID-19. Based on the abundance of sRNAs, we screened the 245 TCMs in the Bencao (herbal) sRNA Atlas that we had previously established, and we found that the top 12 TCMs for COVID-19 treatment was consistent across both cohorts. We validated the efficiency of the top 30 sRNAs from each of the top 3 TCMs for COVID-19 treatment in poly(I:C)-stimulated human non-small cell lung cancer cells (A549 cells). In conclusion, our study recommends potential COVID-19 remedies using FDA-approved repurposed drugs and herbal sRNAs from TCMs.

Herbal inhibitors of SARS-CoV-2 Mpro effectively ameliorate acute lung injury in mice.

Coronavirus disease 2019, a newly emerging serious infectious disease, has spread worldwide. To date, effective drugs against the disease are limited. Traditional Chinese medicine was commonly used in treating COVID-19 patients in China. Here we tried to identify herbal effective lipid compounds from the lipid library of 92 heat-clearing and detoxication Chinese herbs. Through virtual screening, enzymatic activity and inhibition assays, and surface plasmon resonance tests, we identified lipid compounds targeting the main protease (Mpro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and verified their functions. Here, we found that natural lipid compounds LPC (14:0/0:0) and LPC (16:0/0:0) could target SARS-CoV-2 Mpro , recover cell death induced by SARS-CoV-2, and ameliorate acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induced by bacterial lipopolysaccharides and virus poly (I:C) mimics in vivo and in vitro. Our results suggest that LPC (14:0/0:0) and LPC (16:0/0:0) might be potential pan remedy against ARDS.

Camel milk modulates ethanol-induced changes in the gut microbiome and transcriptome in a mouse model of acute alcoholic liver disease.

Morbidity and mortality as a result of liver disease are major problems around the world, especially from alcoholic liver disease (ALD), which is characterized by hepatic inflammation and intestinal microbial imbalance. In this study, we investigated the hepatoprotective effects of camel milk (CM) in a mouse model of acute ALD and the underlying mechanism at the gut microbiota and transcriptome level. Male Institute of Cancer Research mice (n = 24; Beijing Weitong Lihua Experimental Animal Technology Co. Ltd., China) were divided into 3 groups: normal diet (NC); normal diet, then ethanol (ET); and normal diet and camel milk (CM), then ethanol (ET+CM). Analysis of serum biochemical indexes and histology revealed a reduction in hepatic inflammation in the ET+CM group. Sequencing of 16S rRNA showed that CM modulated the microbial communities, with an increased proportion of Lactobacillus and reduced Bacteroides, Alistipes, and Rikenellaceae RC9 gut group. Comparative hepatic transcriptome analysis revealed 315 differentially expressed genes (DEG) in the ET+CM and ET groups (150 upregulated and 165 downregulated). Enrichment analysis revealed that CM downregulated the expression of inflammation-related (ILB and CXCL1) genes in the IL-17 and tumor necrosis factor (TNF-α) pathways. We conclude that CM modulates liver inflammation and alleviates the intestinal microbial disorder caused by acute alcohol injury, indicating the potential of dietary CM in protection against alcohol-induced liver injury.

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway.

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

Herbal small RNAs in patients with COVID-19 linked to reduced DEG expression.

In China, more than 80% of patients with coronavirus disease 2019 (COVID-19) received traditional Chinese medicine (TCM) as a treatment and their clinical efficacy have been reported. However, the underlying molecular mechanism remains unclear. Previous studies have identified herbal small RNAs (sRNAs) as novel functional components. In this study, a cohort of 22 patients with COVID-19 treated with Toujie Quwen (TQ) granules was analyzed. We observed thousands of herbal small RNAs that entered the blood cells of patients after the consumption of TQ granules. In response to this treatment, the reduced differentially expressed genes (DEGs) were highly correlated with the predicted target genes of the most prevalent herbal sRNAs detected in the blood. Moreover, the predicted target genes of the top 30 sRNAs from each of the 245 TCMs in the Bencao sRNA Atlas overlapped with 337 upregulated DEGs in patients with mild COVID-19, and 33 TCMs, with more than 50% overlapping genes were identified as effective TCMs. These predicted target genes of top 30 sRNAs from Juhong, Gualoupi and Foshou were confirmed experimentally. Our results not only elucidated a novel molecular mechanism of TCM potential clinical efficacy for COVID-19 patients, but also provided 33 effective COVID-19 TCMs for prescription optimization.

Oral administration of the herbal oligonucleotide XKC-sRNA-h3 prevents angiotensin II-induced hypertension in mice.

Hypertension has become a growing public health concern worldwide. In fact, hypertension is commonly associated with increased morbidity and mortality. Currently, oligonucleotide drugs have proven to be promising therapeutic agents for various diseases. In the present study, we aimed to demonstrate that a herbal small RNA (sRNA), XKC-sRNA-h3 (B55710460, F221. I000082.B11), exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme (ACE) in mice. When compared with captopril, oral administration of the sphingosine (d18:1)-XKC-sRNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice. Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension.

A comprehensive analysis of the Bencao (herbal) small RNA Atlas reveals novel RNA therapeutics for treating human diseases.

Cross-kingdom herbal miRNA was first reported in 2012. Using a modified herbal extraction protocol, we obtained 73,677,287 sequences by RNA-seq from 245 traditional Chinese Medicine (TCM), of which 20,758,257 were unique sequences. We constructed a Bencao (herbal) small RNA (sRNA) Atlas ( http://bencao.bmicc.cn ), annotated the sequences by sequence-based clustering, and created a nomenclature system for Bencao sRNAs. The profiles of 21,757 miRNAs in the Atlas were highly consistent with those of plant miRNAs in miRBase. Using software tools, our results demonstrated that all human genes might be regulated by sRNAs from the Bencao sRNA Atlas, part of the predicted human target genes were experimentally validated, suggesting that Bencao sRNAs might be one of the main bioactive components of herbal medicines. We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions. Moreover, the decoctosome, a lipo-nano particle consisting of 0.5%-2.5% of the decoction, demonstrated potent medical effects. We propose a Bencao (herbal) Index, including small-molecule compounds (SM), protein peptides (P), nucleic acid (N), non-nucleic and non-proteinogenic large-molecule compounds (LM) and elements from Mendeleev's periodic table (E), to quantitatively measure the medical effects of botanic medicine. The Bencao sRNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine, and may provide potential remedies for the theory and practice of one medicine.

A botanical medicine dragon's blood exhibited clinical antithrombosis efficacy similar to low molecular weight heparin.

Deep vein thrombosis (DVT) is a common complication following traumatic fracture with a 0.5%-1% annual incidence. Low molecular weight heparin (LMWH) is the most commonly used anticoagulation drug for DVT prevention, but treatment with LMWH is invasive. Our aim is to compare the antithrombotic effect of dragon's blood, an oral botanical anticoagulant medicine approved by the Chinese FDA, with LMWH in patients undergoing hip fracture surgery and to explore the molecular mechanisms of anticoagulation treatment. Our study recruited patients and divided them into LMWH and dragon's blood treatment group. Coagulation index tests, Doppler ultrasound and mRNA sequencing were performed before and after anticoagulation therapy. There was no significant difference in postoperative DVT incidence between the two groups (23.1% versus 15.4%, P=0.694). D-dimer (D-D) and fibrinogen degradation product (FDP) showed significant reductions in both groups after anticoagulation treatments. We identified SLC4A1, PROS1, PRKAR2B and seven other genes as being differentially expressed during anticoagulation therapy in both groups. Genes correlated with coagulation indexes were also identified. Dragon's blood and LMWH showed similar effects on DVT and produced similar gene expression changes in patients undergoing hip fracture surgery, indicating that dragon's blood is a more convenient antithrombosis medicine (oral) than LMWH (hypodermic injection).

Comparative analysis of fecal microbial communities in cattle and Bactrian camels.

Bactrian camels may have a unique gastrointestinal (GI) microbiome because of their distinctive digestive systems, unique eating habits and extreme living conditions. However, understanding of the microbial communities in the Bactrian camel GI tract is still limited. In this study, microbial communities were investigated by comparative analyses of 16S rRNA hypervariable region V4 sequences of fecal bacteria sampled from 94 animals in four population groups: Inner Mongolian cattle (IMG-Cattle), Inner Mongolian domestic Bactrian camels (IMG-DBC), Mongolian domestic Bactrian camels (MG-DBC), and Mongolian wild Bactrian camels (MG-WBC). A total of 2,097,985 high-quality reads were obtained and yielded 471,767,607 bases of sequence. Firmicutes was the predominant phylum in the population groups IMG-Cattle, IMG-DBC and MG-WBC, followed (except in the Inner Mongolian cattle) by Verrucomicrobia. Bacteroidetes were abundant in the IMG-DBC and MG-WBC populations. Hierarchical clustered heatmap analysis revealed that the microbial community composition within the three Bactrian camel groups was relatively similar, and somewhat distinct from that in the cattle. A similar result was determined by principal component analysis, in which the camels grouped together. We also found several species-specific differences in microbial communities at the genus level: for example, Desulfovibrio was abundant in the IMG-DBC and MG-WBC groups; Pseudomonas was abundant in the IMG-Cattle group; and Fibrobacter, Coprobacillus, and Paludibacter were scarce in the MG-WBC group. Such differences may be related to different eating habits and living conditions of the cattle and the various camel populations.