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Referring back to the “therapeutics” section this subject required a Substack of its own, so here we are…
Examples include baicalein and cancer; quercetin and cancer prevention; berberine and coronary heart disease; artemisinin and atherosclerosis; icariin and osteoarthritis; silymarin and colon cancer; metformin and breast cancer; resveratrol and the inhibition of cancer cell proliferation.
As is often the case we can thank Chinese researchers for conducting almost all of this research, western research is notably absent.
Due to the number of therapeutics available to us and the number of lncRNAs interacted with I will focus on a few of the more important ones, especially in relation to carcinogenesis.
At the time of writing it's never been more important to focus on this in particular, the latest data from @EthicalSkeptic indicates a 10 sigma number of cancer cases. 10 sigma deviation is not just a black swan but more like a flock of black swans and an upwards trend is clearly developing. Let us hope this starts to abate soon:
Along with using search engines I conducted a keyword search of PubMed to provide reference material.
It's quite revealing that whilst some of our favourites have been researched in great detail the same can't be said for the officially authorised drugs administered en masse. Trust us!
Future literature reviews will include a section on research into interactions with lncRNAs, where available. As a heads-up, icariin returns 5 results on PubMed alone.
Baicalein/Baicalin
Baicalin is a flavone glycoside extracted from from herbs in the genus Scutellaria (skullcaps), a flavonoid and is the glucuronide of baicalein.
Baicalin as a treatment for hypertensive disorder complicating pregnancy
From 2021 and Zhao et al conducted an in vitro investigation into the effects of baicalin on human umbilical vein endothelial cells (HUVECs) which had been stimulated with Angiotension II (Ang II) to mimic trophoblastic and vascular endothelial injuries induced by hypertension1.
Hypertensive disorder complicating pregnancy (HDP) is a relatively common and potentially dangerous disorder for both the infant and the mother2:
Hypertensive disorder complicating pregnancy (HDP) is the main cause of adverse maternal and infant outcomes, with an incidence of 5%–12%, and usually occurring after the 20th week of pregnancy (1). The main typical manifestations of HDP are hypertension, edema and proteinuria, but most pregnant women with mild HDP lack obvious clinical manifestations. Severe HDP can cause coma, convulsion, organ failure and other symptoms, and even lead to complications such as placental abruption, intrauterine fetal death and cerebrovascular events (2, 3). The pathogenesis and etiology of HDP have not been completely clear, and it is generally believed to be related to maternal, placental, fetal and other pathogenic factors (4). According to the severity of the disease, HDP can be divided into gestational hypertension, preeclampsia, eclampsia, pregnancy complicated with chronic hypertension and chronic hypertension complicated with preeclampsia. In HDP, gestational hypertension and preeclampsia are more likely to occur, which may induce maternal and infant death.
Trophoblast: “The trophoblast (from Greek trephein: to feed; and blastos: germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans.[1] They provide nutrients to the embryo and develop into a large part of the placenta.[2][3] They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After gastrulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm.[citation needed] After the first differentiation, the cells in the human embryo lose their totipotency and are no longer totipotent stem cells because they cannot form a trophoblast. They are now pluripotent stem cells.3”
In the study they added 20 μM of Ang II to the cell culture plate containing HTR-8/SVneo and HUVECs and then incubated it for 48 hours to simulate the pathology.
HTR-8/SVneo is an immortalized cell line commonly used to model extravillous trophoblasts(EVTs), which are a form of differentiated trophoblast cells of the placenta4.
Baicalin was added at the same time in concentrations of 1, 5 and 25 μM.
HDCP causes extensive damage to vascular endothelial cells and reduces the proliferative and invasive abilities of trophoblast cells. Pathology is mediated in several ways:
Reduced invasion of trophoblasts, with shallow or restricted infiltration, leads to abnormal blood vessel recasting, ischemia at the maternal-foetal interface and hypoxia.
The ischemic and hypoxic microenvironment also leads to an excessive inflammatory immune response, which further damages the endothelial cells.
MiR-205-5p levels correlate positively with the severity of preeclampsia (PE), and is abnormally expressed in the peripheral blood and placental tissues. It is differentially expressed in trophoblasts exposed to hypoxia and can restrain vascular endothelial cell proliferation and angiogenesis by downregulating the targeted gene vascular endothelial growth factor A (VEGFA).
LncRNA NEAT1 is an oncogene and can promote colorectal cancer (CRC) by modulating miR-205-5p and VEGFA. It can inhibit viruses such as HIV by inducing the formation of nuclear paraspeckles and also mitigate oxidative stress-induced vascular endothelial cell injury, and so it can reduce the likelihood of HDCP by targeting this microRNA.
Previous studies have found that baicalin can markedly suppress miR-205.
So what did the research show?
Their research found that Ang II greatly reduced the cell viability of trophoblastic and vascular endothelial cells, apart from the plates with mid to high doses of baicalin, indicating that baicalin could repair cellular damage:
Figure 1: Baicalin enhanced the viability of Ang II-stimulated trophoblastic cells and vascular endothelial cells. (a) The viability of HTR-8/SVneo cells was measured by performing CCK-8 assay. (b) The viability of human umbilical vein endothelial cells (HUVECs) was measured by performing CCK-8 assay. ***p < 0.001 versus Control group; #p < 0.05, ##p < 0.01 versus Model group https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
Flow cytometry then revealed that baicalin reduced the apoptosis of Ang II-stimulated trophoblastic and vascular endothelial cells in a dose dependant manner:
Figure 2: Baicalin reduced the apoptosis of Ang II-stimulated trophoblastic cells. (a) Annexin V-FITC/PI assay was performed to determine the apoptosis of HTR-8/SVneo cells. (b) Quantitative analysis of the apoptosis rate of HTR-8/SVneo cells by flow cytometry analysis. (c) TUNEL staining was applied to assess the apoptosis of HTR-8/SVneo cells. ***p < 0.001 versus Control group; #p < 0.05, ###p < 0.001 versus Model group. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
Figure 3: Baicalin reduced the apoptosis of Ang II-stimulated vascular endothelial cells. (a) Annexin V-FITC/PI assay was performed to determine the apoptosis of human umbilical vein endothelial cells (HUVECs). (b) Quantitative analysis of the apoptosis rate of HUVECs by flow cytometry analysis. (c) TUNEL staining was applied to assess the apoptosis of HUVECs. ***p < 0.001 versus Control group; ###p < 0.001 versus Model group. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
The invasive ability of Ang II-stimulated trophoblastic cells was induced in a dose-dependant manner, associated with the reversal of ANG II induced decreased expression of the invasion-related matrix metalloproteases MMP2 & MMP9:
Figure 4: Baicalin raised the invasive ability of Ang II-stimulated trophoblastic cells. (a) The invasive ability of HTR-8/SVneo cells and the number of invading cells were measured by transwell assay. (b) Quantitative analysis of the invasion of HTR-8/SVneo cells by transwell assay. (c) Representative bands of Act-MMP2 and Act-MMP9 by western blot analysis. (d) Quantitative analysis of Act-MMP2 and Act-MMP9 levels by western blot analysis. ***p < 0.001 versus Control group; #p < 0.05, ##p < 0.01, ###p < 0.001 versus Model group. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
In vitro angiogenesis of vascular endothelial cells was induced:
Figure 5: Baicalin induced a stronger in vitro angiogenesis of vascular endothelial cells. (a) Tube formation assay of human umbilical vein endothelial cells (HUVECs). (b) Representative bands of vascular endothelial growth factor (VEGF) and HIF-1α by western blot analysis. (c) Quantitative analysis of VEGF and HIF-1α levels by western blot analysis. ***p < 0.001 versus Control group; ##p < 0.01, ###p < 0.001 versus Model group. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
Levels of Ang II mediated, apoptosis-inducing ROS were restrained by baicalin:
Figure 6: Baicalin restrained the rise of cellular reactive oxygen species (ROS) level induced by Ang II. (a) ROS levels in HTR-8/SVneo cells were quantified by DCFH-DA staining. (b) ROS levels in human umbilical vein endothelial cells (HUVECs) were quantified by DCFH-DA staining. ***p < 0.001 versus Control group; ##p < 0.01, ###p < 0.001 versus Model group. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/jog.14789?saml_referrer
And finally, baicalin upregulated NEAT1, which acted as a miR-205 sponge to impede the combination of miR-205-5p and MMP9 or VEGF. This may be a useful therapeutic for those treated with mRNA synthetic viral protein gene therapies as one study found that vaccine breakthrough infections were associated with NEAT1 downregulation5 amongst other factors6.
The above pathophysiological changes are an almost perfect recipe for aggressive carcinogenesis for the same reasons that they help the growing foetus by reversing the action of tumor suppressive miR-205.
So does this mean that baicalin can be highly oncogenic too? Not at all as it is context sensitive. A study by Dou et al (2018) found that baicalin inhibits colon cancer (which is promoted by miR-205 suppression7) by inducing tumor cell apoptosis via MAPK ERK and p38 signalling, and tumor cell senescence due to telomere shortening via the inhibition of telomerase reverse transcriptase8. Thus other tumor suppressive signalling pathways are selectively activated.
HDPC is a major cause of maternal and fetal mortality in the developing world and is also a vital issue for public health.1Although there are many studies on the pathogenesis, etiology, prediction, and treatment, there is currently no particular drug of choice to precisely deal with HDPC.
By this the authors mean that there are drugs available but the side effects may be “intolerable”9:
In contrast, flavonoids from baicalin have not demonstrated teratogenic or abortive effects, so they are generally considered safe10.
…As presented in this current study, we demonstrated that baicalin upregulated lncRNA NEAT1 and downregulated miR-205-5p, reversing the modulation of Ang II stimulation on lncRNA NEAT1 and miR-205-5p levels in trophoblastic cells and vascular endothelial cells. More importantly, baicalin elevated lncRNA NEAT1 to competitively sponge with miR-205-5p, thereby arresting the combination of miR-205-5p and MMP9 or VEGF.
To conclude, it was validated that baicalin improved the viability and repressed the apoptosis of trophoblasts and vascular endothelial cells, enhanced the invasive ability of trophoblasts and facilitated angiogenesis of vascular endothelial cells. As a possible mechanism, baicalin might alleviate trophoblastic and vascular endothelial injuries through promoting lncRNA NEAT1 to impede the combination of miR-205-5p and MMP9 or VEGF.
In fact, the risk of side effects from allopathic hypotensive’s or other complications is so great that induced labour is often the preferred option, but this isn't a risk free option either:
…In most cases of pre-eclampsia, having your baby at about the 37th to 38th week of pregnancy is recommended. This may mean that labour needs to be started artificially (known as induced labour) or you may need to have a caesarean section11.
Regarding baicalin, more research and further clinical trials are certainly warranted to study pharmacokinetic effects, dosing and use as a prophylactic vs being administered in an emergency.
The authors declared that they have no competing interests.
According to a study by Fang et al (2023) Western medicine is already late to the party, baicalin has been used for thousands of years in traditional Chinese medicine (TCM) to protect the foetus and avoid miscarriage12:
The root of Scutellaria baicalensis Georgi, also called Huangqin, is frequently used in traditional Chinese medicine. In ancient China, S. baicalensis root was used to clear heat, protect the fetus, and avoid a miscarriage for thousands of years. In modern times, pregnancy-related diseases can seriously affect maternal and fetal health, but few systematic studies have explored the mechanisms and potential targets of S. baicalensis root in the treatment of pregnancy-related diseases.
2. Traditional uses of S. baicalensis root during pregnancy in ancient China
TCM has long been used to help women have successful pregnancies in China [13]. The root of S. baicalensis was given the name Huangqin [1], [2]. Huangqin plays a role in hemostasis, clearing heat, protecting the fetus and preventing spontaneous abortion, to sustain a pregnancy [14]. Table 1 summarizes ancient Chinese records on Huangqin’s traditional uses in human pregnancy.
With growing evidence that the main components of S. baicalensis root are associated with improved outcomes in pregnancy-related diseases, the extract of S. baicalensis root should be considered as a source for therapeutic compounds, and the nanoparticle delivery system can be used to deliver these compounds to the placenta, optimizing treatments. Thus, this combination of TCM and advanced technologies could successfully establish an innovative clinical treatment for pregnancy-related diseases.
Baicalin and cancer
From 2022, Farooqi et al wrote a mini-review on the regulation of cell signalling pathways and lncRNAs by baicalin in different cancers13.
Ezrin (also known as cytovillin or villin-2) is a protein encoded by the EZR gene and is involved with cancer metastasis. Overexpression has been reported in breast cancer, lung cancer, osteosarcoma, leukaemia, cutaneous melanoma and colorectal sarcoma14.
lnc-SH3GL1-3 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via the EGFR/ERK/AP-1 pathway15.
It has low cancer specificity. With renal and liver cancer high expression indicates an unfavourable prognosis (pink plot), whereas with cervical and endometrial cancer high expression is favourable16:
With the liver, SH3GL1 promotes tumorigenesis by activating the β-Catenin signaling pathway17. This pathway is highly conserved through evolution and regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal18.
PAX8-AS1-N, or paired box gene 8 antisense RNA 1 is an lncRNA which is overexpressed in the thyroid gland and under-expression is associated with hypothyroidism19.
In myeloid leukaemia, silencing of PAX8-AS1-N decreases cell viability, enhances apoptosis and suppresses resistance to the chemotherapeutic Doxorubicin via the miR-378g/ERBB2 axis20.
In contrast, PAX8-AS1-N was down-regulated in breast cancer and reduced expression of PAX8-AS1-N indicated poor survival of breast cancer patients via binding to miR-17-5p and the upregulation of miR-17-5p targets such as PTEN, CDKN1A, and ZBTB421.
With osteoporosis (OP), silencing of PAX8-AS1-N suppresses progression of the disease by inactivating autophagy of osteoblasts via the miR-1252-5p/GNB1 axis22.
PTEN or Phosphatase And Tensin Homolog is a protein coding gene and a tumor suppressor that shows efficacy against a range of cancers. Loss of PTEN expression or defective mutations of the gene are associated with various cancers including prostate cancer (in up to 70% of cases), glioblastoma, endometrial, lung and breast cancer23.
Low expression of miR-424-3p correlates strongly with a poor prognosis for many cancers, especially prostate cancer and is associated with strongly aggressive phenotypes24.
BDLNR or baicalein downregulated lncRNA is required for baicalein-induced cell proliferation inhibition, cell death orientation, migration inhibition, and for in vivo tumor growth inhibition of cancers including cervical cancer25.
YBX1 Gene for Y-Box Binding Protein 1 is involved in various processes, such as translational repression, RNA stabilization, mRNA splicing, DNA repair and transcription regulation26.
The PI3K/AKT pathway is an intracellular signal transduction pathway that promotes metabolism, proliferation, cell survival, growth and angiogenesis in response to extracellular signals, and is overactive in many cancers27.
8. Regulation of Non-Coding RNAs
Discovery of non-coding RNAs (ncRNAs) has caused a paradigm shift in our understanding regarding the regulation of protein networks and cell signaling pathways in different cancers. Experimental verifications and validations related to microRNAs, long non-coding RNAs, and circular RNAs have led to exciting advancements in various facets of molecular oncology [92,93,94,95,96,97,98,99,100,101].
Ezrin is a target gene of miR-183 (Figure 4). There was an evident increase in the expression of miR-183 and simultaneous suppression of ezrin in baicalein-treated Saos-2 and MG-63 cells. Importantly, ezrin overexpression and miR-183 inhibition abolished baicalein-mediated inhibitory effects on migration and invasion of Saos-2 and MG-63 cells [102].
Figure 4. (A) Ezrin is a target gene of tumor suppressor miR-183. miR-183 inhibited tumorigenesis but ezrin promoted tumorigenesis. (B) miR-17-5p and miR-424-3p are oncogenic miRNAs. These miRNAs targeted PTEN. Tumor suppressor lncRNA blocked miR-17-5p-mediated targeting of PTEN and inhibited carcinogenesis. (C) BDLNR physically associated with YBX1 and promoted its binding to PIK3CA promoter and facilitated cancer progression.
Both baicalein treatments and overexpression of miR-3663-3p led to the downregulation of SH3GL1 and inactivation of ERK1/2, EGFR, and NF-κB/p65 transduction cascades. Tumors derived from miR-3663-3p-overexpressing Bel-7404 and SK-Hep-1 cells were smaller in size. Furthermore, levels of p-NF-κB/p65, p-ERK, and p-EGFR were reported to be profoundly reduced in the tumor tissues. Importantly, intraperitoneal injections of baicalein induced tumor retrogression in mice subcutaneously xenografted with Bel-7404 or SK-Hep-1 cells [103].
PAX8-AS1-N antagonized miR-17-5p-mediated targeting of PTEN, ZBTB4 (Zinc finger and BTB domain containing 4) and CDKN1A (Figure 4). PAX8-AS1-N knockdown promoted growth of breast cancer xenografts andbaicalein-mediated growth inhibition was attenuated significantly by PAX8-AS1-N knockdown [104].
Baicalein downregulated miR-424-3p, upregulated PTEN and reduced the levels of PI3K and p-AKT in H460 and A549 cells. PTEN is a tumor suppressor and inactivates PI3K/AKT-driven signaling. PTEN has been reported to be directly targeted by miR-424-3p. It was shown that miR-424-3p overexpression or PTEN silencing partially weakened baicalein-mediated repressive effects on H460 and A549 cells [105].
BDLNR (baicalein downregulated long non-coding RNA) physically associated with YBX1 and promoted its binding to the PIK3CA promoter and activated PIK3CA expression and the PI3K/AKT pathway (Figure 4). Baicalein-mediated tumor suppression was significantly impaired in mice inoculated with BDLNR-overexpressing HeLa ells [106].
Keeping in view the fact that miRNAs and lncRNAs drive malignant phenotypes from multiple perspectives, in this section, we focus on baicalein-mediated effects on critical signaling cascades modulated by miRNAs and lncRNAs in cancers to demonstrate an up-to-date understanding of this area of research.
This is why it is important to thoroughly understand how out therapeutics work (or not!), including going down the rabbit hole of lncRNA interactions and feedback loops.
The alternative is to rush a product to market with no regulatory oversight and a “don’t look, don’t ask, don’t report” mentality🙈🙉🙊:
It is exciting to note that cutting-edge research has provided rich and information-dense pictures of protein signaling cascades which play fundamental roles in cancer onset, progression, drug resistance, and loss of apoptosis. Hyperactive/underactive pathways, presence or absence of important feedback mechanisms, and ectopic expression of proteins play central roles in cancer progression. Nevertheless, even this level of understanding may not be sufficient to realistically analyze the therapeutic targets within the context of the cellular networks. Accordingly, it is essential to drill down deep into the intricacies of signaling deregulations to identify signaling molecules and pathways which fuel the survival of cancer cells.
Excitingly, the interplay between inhibition and activation is a universal theme of signal transduction cascades and is mirrored at every level and scale of hierarchically organized protein networks. Therefore, feedback and feedforward loops are the linchpin mechanisms which allow precise and critical control over entire pathways and enable the cells to portray highly complicated modes of response.
An important key question now looms for the field of cancer drug discovery: which proteins can be considered as the most plausible drug targets within a pathway so that result-oriented therapeutic strategies can be rationally designed for proof-of-concept studies regarding the cancer chemopreventive role of baicalein with maximum efficacy and minimum side effects to the patient?
As an aside, like an off-duty police officer who recognises a criminal in the street I was reading an article about a novel cancer therapy drug when I saw oncogenic lncRNA YBX1 being referred to.
Researchers from the University of East Anglia are hoping to bring to clinical trials a drug called CADD522 which should inhibit a primary bone cancer of children by blocking YBX1-interacting small RNAs (as above, snap!) and RUNX gene expression, which is currently treated by low efficacy/high toxicity chemotherapy and amputation - not a good prognosis, with a 5 year survival rate of only 42%28.
As for baicalein, more research into its oncogenic pathways targeting is warranted to fully map these with a view to optimising its use as an anti-cancer drug still further.
These include the TGF (transforming growth factor), SMAD protein (Mothers against decapentaplegic), SHH (Sonic hedgehog protein)/GLI (zinc finger protein), TRAIL (apoptosis inducing ligand), PDGFR (platelet derived growth factor) & VEGFR (vascular endothelial growth factor) induced signalling pathways and other affected, unknown lncRNAs.
No conflict of interest was declared.
Quercetin
Quercetin is a bright yellow coloured flavonol from the flavonoid group of polyphenols and has been researched in some detail. It is a multi-action therapeutic, with anti-viral, anti-bacterial, anti-cancer, anti-oxidant, anti-inflammatory, anti-diabetic, cardio protective, liver protective, anti-arthritic and Alzheimer’s disease inhibitory properties amongst others29.
One of the most abundant dietary flavonoids, it can be extracted from a range of foods. Capers contain the highest concentration but most of us probably ingest the majority of our quercetin from onions, yellow peppers and perhaps kale30.
In fact, onions are a great dietary source, but you still need to eat a lot of them! Bioavailability of extracts is generally low in comparison to when eaten in foods such as these, with systemic availability around 5 times higher31, but it can be enhanced by taking with bromelain32, vitamin C33 or as the synthesised dihydrate form, which whilst not ideal still has higher availability then regular quercetin34.
Plasma quercetin concentration–time curves in metabolically healthy men and women after a single oral dose of quercetin from capsules filled with quercetin dihydrate (circles) or onion skin extract powder (squares) (n = 12). Values represent mean ± SEM. Plasma concentrations differ significantly over time between the two treatment groups (P < 0.0001 for the effect of time, and P < 0.0001 for the time × treatment interaction using repeated-measures ANOVA). The last two data points are connected by a dashed line as elimination processes during this time cannot be reliably determined. https://link.springer.com/article/10.1007/s00394-015-1084-x
From 2022, Wang et al published a literature review of research into the targeting of lncRNAs by quercetin in cancer prevention and therapy35:
It has well documented that quercetin exerts anticancer actions by inhibiting cell proliferation, inducing apoptosis, and retarding the invasion and metastasis of cancer cells. However, the exact mechanism of quercetin-mediated cancer chemoprevention is still not fully understood. With the advances in high-throughput sequencing technologies, the intricate oncogenic signaling networks have been gradually characterized. Increasing evidence on the close association between noncoding RNA (ncRNAs) and cancer etiopathogenesis emphasizes the potential of ncRNAs as promising molecular targets for cancer treatment. Available experimental studies indicate that quercetin can dominate multiple cancer-associated ncRNAs, hence repressing carcinogenesis and cancer development. Thus, modulation of ncRNAs serves as a key mechanism responsible for the anticancer effects of quercetin.
Biological functions:
Existing evidence has proven that the antioxidant activity of quercetin is predominantly manifested through its impact on glutathione (GSH), antioxidant enzymatic activity, reactive oxygen species (ROS), and various signaling cascades (e.g., NF-κB, AMPK, and PI3K/Akt) [32]. GSH can defend against oxidative stress by acting as a hydrogen donor in the neutralization of hydrogen peroxide [33]. In vivo experimental results showed that high intake of quercetin significantly enhanced GSH production in the liver [34]. Quercetin also stimulated the expression of the antioxidant enzymes glutathione peroxidase 1 (GPX1), catalase (CAT), and superoxide dismutase 1 (SOD1) in the liver by activating the nuclear factor E2-related factor 2 (Nrf2) pathway. Oppositely, quercetin exhibited a powerful suppressive effect against key enzymes with oxidative activities, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) [35]. Thus, quercetin functions to strengthen the antioxidant defense system.
Quercetin has strong antioxidant and free radical scavenging capacities by removing ROS and inhibiting lipid peroxidation [36]. It is known that iron is a life-supporting micronutrient that is dispensable in the human diet and plays a crucial role in various fundamental metabolic processes. However, excessive iron accumulation can cause cell and tissue damage, since highly reactive iron catalyzes ROS generation. Quercetin effectively reduces iron deposition to inhibit lipid peroxidation and eliminates iron-catalyzed ROS production [37]. Based on the above evidence, quercetin exerts iron-chelating and ROS-scavenging activities.
…It has been well documented that quercetin exhibitspowerful anti-inflammatory effects and attenuates the inflammation process. The immunosuppressive capacities of quercetin are mediated by its effects on the levels of inflammatory cytokines, the generation of inflammation-producing enzymes (cyclooxygenase (COX) and lipoxygenase (LOX)), the maintenance of the stability of mast cells, and functional properties of immune cells (e.g., peripheral blood mononuclear cells and T cells) [2]. Quercetin showsbroad-spectrum antimicrobial properties. It was reported that quercetin had a significant inhibitory effect on the growth of pathogenic microbes such as Aspergillus flavus, Candida albicans, Escherichia coli, Listeria, Proteus, Pseudomonas aeruginosa, Salmonella enteritidis, Shigella, and Staphylococcus aureus [41–43]. The antimicrobial mechanisms of quercetin involve the destruction of bacterial cell wall/membrane, alternation of cell permeability, regulation of protein synthesis and abundance, inhibition of enzymatic activities, and nucleic acid biosynthesis.
Cancer cell proliferation is inhibited by targeting various miRNAs.
Induction of cellular apoptotic pathways, including by upregulating tumor suppressor p53.
Inhibition of cancer cell migration and invasion.
Enhanced chemosensitivity of cancer cells to therapeutics such as cisplatin.
Interactions with circRNAs and lncRNAs.
Circular RNA (or circRNA) is a type of single-stranded RNA which, unlike linear RNA, forms a covalently closed continuous loop. In circular RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together. This feature confers numerous properties to circular RNA, many of which have only recently been identified.
Many types of circular RNA arise from otherwise protein-coding genes. Some circular RNA has been shown to code for proteins.[1][2] Some types of circular RNA have also recently shown potential as gene regulators. The biological function of most circular RNA is unclear.
Because circular RNA does not have 5' or 3' ends, it is resistant to exonuclease-mediated degradation and is presumably more stable than most linear RNA in cells.[3] Circular RNA has been linked to some diseases such as cancer.[4]36
This is a representative figure showing mature mRNA splicing and corresponding canonical biogenesis of circRNAs which might include B.1) direct back splicing. B.2) Intron pairing driven circularization, B.3) debranching resistant intron lariat and B.4) lariat-driven circularization (exon skipping). https://en.wikipedia.org/wiki/Circular_RNA#/media/File:Circular_RNA_Biogenesis.jpg
Quercetin and its derivatives modulate a wide range of cancer related noncoding and long noncoding RNAs:
CCAT1 or Colon Cancer Associated Transcript 1 is a lncRNA that promotes tumor formation and is upregulated in colon cancer and other cancer cell types37.
MALAT1 or Metastasis Associated Lung Adenocarcinoma Transcript 1 is perhaps the best known and most significant lncRNA that it interacts with. "It may act as a transcriptional regulator for numerous genes, including some genes involved in cancer metastasis and cell migration, and it is involved in cell cycle regulation. Its upregulation in multiple cancerous tissues has been associated with the proliferation and metastasis of tumor cells"38.
LncRNAs ENST00000313807 and ENST00000449307 are co-expressed with miRNA LRG1, which play important roles in anti-colorectal cancer mechanisms of quercetin, through competitively binding with miR-509639.
Protein coding MYO10 or Myosin X functions as an actin-based molecular motor and plays a role in the integration of F-actin and microtubule cytoskeletons during cellular meiosis (cell division)40.
And protein coding ARPP19 or CAMP Regulated Phosphoprotein 19 is a phosphatase inhibitorthatplays a role in regulating mitosis (where replicated chromosomes are separated into two new nuclei)41. “…ablation of this protein in mouse embryonic fibroblasts promotes the premature dephosphorylation of mitotic substrates resulting in the disruption of the correct temporal order of cellular events during mitotic progression”42.
Targeting multiple cancer pathways makes it less likely that mutated cells will be able to escape its inhibitory effects, unlike certain allopathic chemotherapeutics that are designed to target just one or so pathways and are often associated with undesirable off-target side effects, thus need to be used in combination:
Henceforth, multitargeted therapy or combination therapy is more superior to single-agent therapy in most cancer treatments. Additionally, combination chemotherapy agents with different mechanisms of action and also nonoverlapping toxicities can be chosen to decrease the resistance and toxicities43.
Anticancer effects of quercetin and its derivatives by regulation of ncRNAs. ncRNAs participate in key processes during cancer development and progression by modulating their target genes or affecting the activity of cancer-related signaling cascades. Thus, quercetin plays an important role in controlling carcinogenesis, cancer cell proliferation, apoptosis, chemosensitivity, migration, and invasion via alteration of the expression and function of cancer-relevant ncRNAs. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9155922/figure/fig2/
Next we shall go through these in detail, walking through this key section of the review:
7.6. Anticancer Actions of Quercetin Mediated by lncRNAs and circRNAs
Phytochemicals, including curcumin, quercetin, and resveratrol, have emerged as important regulators of lncRNAs in different types of cancers[6]. Hyperoside is a flavonol glycoside compound and exhibits anticancer activities against various cancers [118].
Hyperoside is the 3-O-galactoside of quercetin44. A glycoside it is mainly present in plants of the Hypericum and Crataegus genera, as well as a variety of fruits and vegetables, including onions45.
Protein coding FOXO1 or Forkhead Box O1 is thought to play a part in myogenic growth and differentiation. It is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress or starvation, where it can induce autophagic cell death and apoptosis46. In the light of this and their effects on angiogenesis and cancer metabolism FOXOs are generally considered to be tumor suppressors:47
Foxo1 played a key role in cancer cell apoptosis. The expression level of Foxo1 was decreased, while that of lncRNA colon cancer associated transcript 1 (CCAT1) was elevated in non-small-cell lung cancer (NSCLC) cells. Hyperoside was able to enhance Foxo1 expression by downregulating CCAT1 in NSCLC cells. Further investigation showed that hyperoside repressed the proliferation and promoted the apoptosis of NSCLC cells via the CCAT1-mediated Foxo1 signaling.
Significant downregulation of oncogenic MALAT1. I checked out the referenced in vitro study [21] of treated prostate cancer cells and they used a concentration of 10mM in DMSO, which is very high in comparison to measured peak human plasma concentrations of .43uM (431 nmol/L)48.
Mean (bold line) and individual (fine line) plasma concentration-time curves of quercetin after oral intake of 50 (A), 100 (B), or 150 mg (C) quercetin to a subgroup of 15 volunteers (n = 5 per dosage group). The last 2 data points are connected by a dashed line, because elimination processes during this time cannot be reliably determined. https://www.sciencedirect.com/science/article/pii/S0022316622099205?via%3Dihub
However, its more complicated than that as long term area under the curve with repeat dosing, IV administration, co-administration, concentration/accumulation in tumor tissues or presence of metabolites of quercetin also need consideration. Low plasma may mean its been absorbed and your MALAT1 is being knocked down regardless.
INTRAVENOUS QUERCETIN: Intravenous Quercetin has studied potential for increased bioavailability [1,2,4] as well as potent potential anti-tumor activity [4-5]. Intravenous data in human subjects shows it to be tolerated and safe [1-3]. Data available suggest multiple mechanisms of action in Tyrosine Kinase inhibition [4] as well as tumor growth suppression [5]. Two years of clinical use has revealed no adverse events when used under standard dose and administration guidelines [3].49
This is why in vivo and clinical trials are needed urgently:
The expression level of MALAT1 was remarkably diminished in quercetin-treated prostate cancer cells [21]. MALAT1 played an oncogenic role in cancer progression. Mechanistically, MALAT1 promoted the EMT process in prostate cancer cells by upregulating N-cadherin and downregulating E-cadherin. Moreover, MALAT1 activated the PI3K/Akt signaling cascade by increasing the expression level of phosphorylated Akt. Quercetin inhibited cell proliferation, invasion, and migration but facilitated apoptosis in prostate cancer cells via blocking the EMT process and the PI3K/Akt signaling cascade by targeting MALAT1. Oppositely, MALAT1 overexpression conferred chemoresistance to prostate cancer cells against the cytotoxicity of quercetin. Thus, MALAT1 could antagonize the tumor-suppressive effects of quercetin. These results suggested that MALAT1 could be a pivotal target in quercetin treatment of prostate cancer, providing a novel molecular basis for the clinical use of quercetin in treating prostate cancer.
Protein coding gene LRG1 for Leucine Rich Alpha-2-Glycoprotein 1 is involved with protein to protein interaction, signal transduction (eg JAK-STAT signalling pathways or biochemical cascades), cell adhesion, granulocyte differentiation, and neovascularisation of damaged cells or in cancer tissues via transforming growth factor beta (TGFb) signalling to endothelial cells50:
Quercetin inhibited the proliferation and induced the apoptosis of colon cancer cells by regulating the expression of several lncRNAs (Figure 2) [113]. Quercetin had the ability to downregulate leucine-rich α-2-glycoprotein-1 (LRG1), which might explain its role as an anticancer compound.The lncRNAs ENST00000313807 and ENST00000449307 were able to increase LRG1 expression through competitive interaction with miR-5096. It was likely that quercetin induced colon cancer cell apoptosis by inhibiting LRG1 expression via downregulating ENST00000313807 and ENST00000449307. In addition, the circRNA (8: 93786223|93822563) was predicted to regulate LRG1 expression by competitively combining with miR-5096 [113]. The role and mechanisms of action of the circRNA/miRNA/LRG1 axis in quercetin-mediated tumor inhibition deserve further investigation.
Quercetin can suppress the proliferation of cervical cancer cells via interactions with a wide range of oncogenes, an androgen receptor, miRNAs, ncRNAs and lncRNAs including MALAT1 and 71 circRNAs:
Quercetin suppressed the proliferation of cervical cancer cells [119]. The combined analyses of the Gene Expression Omnibus (GEO) database and RNA-sequencing results indicated that quercetin altered the expression of several genes, including Jun protooncogene (JUN), androgen receptor (AR), and EGFR. Further exploration of the upstream interacting ncRNAs of these genes identified one lncRNA (MALAT1) and seventy-one circRNAs (e.g., hsa_circ_001859, hsa_circ_0089761, MYO10, and ARPP19). The lncRNA/circRNA-miRNA-mRNA regulatory networks might take part in the antagonistic effects of quercetin against cervical cancer. These results might help provide valuable diagnostic biomarkers and therapeutic targets for cervical cancer. However, it is of great necessity to determine the genuine roles and clinical significance of the identified ncRNAs in cervical cancer.
Finally, albeit the potential of quercetin to treat cancer, its poor bioavailability and the requirement for high doses have a negative impact on its clinical efficacy. As nano-based formulations can enhance the bioavailability and particular targeting of natural compounds, their use may attenuate the dosage and improve the therapeutic effectiveness of quercetin [120]. Collectively, bioactive quercetin is widely available and has various health benefits with limited side effects. Quercetin holds great potential to become an effective agent for cancer prevention and treatment or an adjuvant agent in combination with conventional anticancer therapies. Quercetin is capable of targeting various ncRNAs that need to be further deciphered to adequately understand how this bioactive compound could be useful in cancer intervention.
The authors declared no competing financial interests.
Quercetin and clinical trials
Data is mixed from the few trials that have been conducted, and long term prevention has not been assessed. More research and delivery systems need to be developed:
Galasso et al (2013) administered either 500 mg/d of quercetin, 100 mg/d of genistein or placebo to 18 men with elevated prostate-specific antigen (PSA), a marker for prostate cancer, over 3 months51:
INTRODUCTION AND OBJECTIVES
Polyphenols are known to have beneficial effects in the chemoprevention of prostate cancer. Several in vitro and in vivo studies demonstrated the anticancerogenic action of the flavonoids quercetin and genistein. However, human interventions still have to prove that these substances have chemopreventive efficacies. Therefore, this study aims to investigate the effect of genistein and quercetin supplementation on the concentration and dynamics of prostate-specific antigen (PSA) in men with rising PSA-levels.
METHODS
The first interim analysis of the ongoing QUERGEN trial included a total of 18 men with elevated PSA concentrations. The subjects were randomized to receive either 500 mg/d of quercetin (Q), 100 mg/d of genistein (G) or placebo (P) for 3 months. Serum PSA as primary endpoint and bioavailability of quercetin and genistein through HPLC analyses were assessed prior to intervention and after the supplementation period.
RESULTS
The blood quercetin concentration increased significantly in the quercetin intervention group (pre: 0.5±0.07 μmol/l, post: 1.2±0.05 μmol/l, p=0.0313). Genistein supplementation also tended to increase genistein levels (pre: 1.1±0.05 μmol/, post: 1.3 ±0.06 μmol/l, ns). Total and free PSA did not change significantly in none of the groups (Q: pre tPSA 8.9±2.9 ng/ml, post 10.5±3.8 ng/ml, ns; pre fPSA: 0.8±0.2 ng/ml, post: 1.0±0.3 ng/ml; ns; G: pre tPSA: 9.5±2.3 ng/ml, post: 9.6±2.2 ng/ml; ns; pre fPSA 0.7±0.1 ng/ml, post: 0.8±0.3 ng/ml, ns; P: pre tPSA: 6.3±0.8 ng/ml, post: 7.4±0.8 ng/ml, ns; pre fPSA 0.9±0.2 ng/ml, post: 0.8±0.1 ng/ml, ns). However, there was a trend to an inverse association between the PSA dynamics and the intake of genistein. After intervention PSA doubling time was higher in the genistein intervention group compared with quercetin and placebo receiving subjects (G: 16.2±7.8 months, Q: 7.0±2.8 months, P: 7.5±1.8 months, ns). Furthermore, the log2-transformated PSA slope was 0.08 ng/ml in the genistein group and thus lower compared to the other groups (P: 0.25 and Q: 0.20 ng/ml, ns).
CONCLUSIONS
In this interim analysis, the results suggest that dietary intervention with genistein may have an impact on PSA slope in men with deviant PSA constellation suspicious for prostate cancer. In contrast, the intake of quercetin did not impact on PSA dynamics. Within the QUERGEN trial more patients with longer intervention periods are currently recruited to verify these initial results.
In contrast quercetin administered by IV to ovarian cancer patients demonstrated antitumor activity.
Tyrosine kinases are enzymes that are found at high levels in some types of cancer, and inhibition can stop cancer cells from growing. They are a part of many cell functions including cell signalling, growth and division 52.
We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.
More on clinical trials and other data from an article by Hein (2020) on Medscape54:
But do these preclinical results translate to anticancer effects in humans?
Unfortunately, clinical trials addressing this question are lacking. Several observational studies evaluating the link between dietary flavonoid intake and cancer have been published, with many showing an inverse association. The best evidence looking specifically at quercetin intake comes from a 2013 pooled analysis of cohort and case-control studies by Woo and Kim. These researchers found that a higher intake of quercetin was associated with 20% lower odds of cancer, with an even greater risk reduction in smokers. However, individual studies addressing various forms of cancer show mixed results. For instance, an inverse association between quercetin intake and both pancreatic cancer and gastric cancer has been reported, whereas studies on bladder cancer and ovarian cancer risk failed to identify such a link. Observational research on quercetin's effect on lung cancer risk has been particularly conflicting, with separate studies showing no association, a trend toward inverse association, and a 35% lower odds of lung cancer with increased quercetin intake.
We must recognize that such studies cannot address causation, only association, making it difficult to say whether quercetin intake alone was responsible for the reduced cancer risk. Although most of the studies were adjusted to account for potential confounders, including intake of other flavonoids, use of other supplements, physical activity, education, and socioeconomic status, it's impossible to fully account for the known and unknown variables that might influence the results. To gather data for these studies, researchers must also rely on food diaries or the long-term memory of study participants' dietary habits, raising obvious concerns about reliability and recall bias.
Because these studies solely analyzed the dietary intake of quercetin, they tell us nothing about its possible effects when taken in supplement form. And although no safety concerns exist with quercetin from dietary sources, the long-term safety of supplemental quercetin is not well established in humans. Even if quercetin does have anticancer potential, its poor oral bioavailability may make these effects moot, although delivery systems to enhance absorption of quercetin are being investigated.
When discussing the proposed anticancer effects of quercetin, we must also be vigilant in calling out other preclinical research highlighting the possibility for quercetin-related drug interactions. Quercetin has been shown to interfere with several cytochrome P450 (CYP) isoenzymes and drug transporters, including inhibition of CYP2C9, CYP2D6, CYP3A4, organic anion transporting polypeptides, and P-glycoprotein. This suggests that quercetin may alter systemic exposure to a majority of prescription and nonprescription drugs on the market, including anticancer drugs.
Even if the jury is still out on quercetin's anticancer effects, and relevant concerns exist about its bioavailability, safety, and potential drug interactions, the evidence that suggests a lower risk for cancer with dietary intake could potentially be beneficial. While patients may wish to adopt healthier diets with foods known to contain high concentrations of quercetin and other flavonoids, it's too early for healthcare providers to specifically recommend quercetin, particularly in supplement form, for the prevention or treatment of cancer.
If this leads us to conclude anything its to incorporate flavonoids into your diet or via high dose supplements with vitamin C or bromelain for synergistic effects.
And get cooking your German onion cake (as recommended by one of Dr Jo’s followers. It looks delicious!) or even those kale smoothies, yeah🤢.
A PubMed search generated only 1 result. This was by Li and Zhan (2020). They used qRT-PCR to analyse 16 before and after lncRNA expression patterns of ovarian cancer cell lines treated with ivermectin, and then assessed survival prognostics of high and low risk groups using the Kaplan-Meier method55.
LncRNA expressions affected by ivermectin:
Most of these are oncogenic, some are tumor suppressors.
HCG15 or HLA Complex Group 15 is associated with cerebral palsy and is a hypoxia-responsive lncRNA that facilitates hepatocellular carcinoma cell proliferation and invasion by enhancing ZNF641 transcription56.
KIF9-AS1 or KIF9 Antisense RNA 1 is associated with thioredoxin, leucocytes and platelets. It can also promote cell apoptosis by targeting the microRNA-148a-3p/suppressor of cytokine signaling axis in inflammatory bowel disease57.
PDCD4-AS1 or PDCD4 Antisense RNA 1 is a tumor suppressor thatalleviates triple negative breast cancer by increasing expression of IQGAP2 via miR-10b-5p58. This was significantly upregulated by ivermectin in both cell lines.
ZNF674-AS1 or ZNF674 Antisense RNA 1 (Head To Head) is associated with hepatocellular carcinoma.
ZNRF3-AS1 or ZNRF3 Antisense RNA 1 is associated with heel bone mineral density, erythrocyte counts, pancreatic carcinoma and HDL cholesterol.
SOS1-IT1 or SOS1 Intronic Transcript 1 promotes endometrial cancer progression by regulating a hypoxia signaling pathway59.
LINC00565 or Long Intergenic Non-Protein Coding RNA565 promotes the progression of colorectal cancer by upregulating EZH260.
SNHG3 or Small Nucleolar RNA Host Gene 3 expressionis associated with familial Alzheimer Disease, colorectal cancer and poor ovarian cancer prognosis.
PLCH1-AS1 or PLCH1 Antisense RNA 1 is associated with insomnia, educational attainment and long or short sightedness (hypermetropia or myopia).
Overexpression of WWTR1-AS1 or WWTR1 Antisense RNA 1 is associated with tumor aggressiveness and unfavourable survival in head-neck squamous cell carcinoma61.
LINC00517 or Long Intergenic Non-Protein Coding RNA 517 is associated with lung squamous cell carcinoma and lung adenocarcinoma62.
AL109767.1 gave no search results other than this paper (!), but AL109767.7 may be associated with B-cell malignancies63.
STARD13-IT1 or STARD13 Intronic Transcript 1 suppresses cell proliferation and metastasis in colorectal cancer64.
LBX2-AS1 or LBX2 Antisense RNA 1 is associated with renal cell carcinoma, nonpapillary and rectum adenoma.
LEMD1-AS1 or LEMD1 Antisense RNA 1 suppressesovarian cancer progression through regulating miR-183-5p/TP53 axis65.
And HOXC-AS3 or HOXC Cluster Antisense RNA 3 mediates tumorigenesis of gastric cancer by binding to YBX1 (its that oncogenic gene again!) 66.
Results: SILAC-based quantitative proteomics found the protein expression levels of EIF4A3 and 116 EIF4A3-binding mRNAs were inhibited by ivermectin in OC cells. Among the analyzed 16 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3), only 7 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, and LINC00565) were obtained for further lasso regression when combined with the results of drug testing and overall survival analysis. Lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565). The high-risk and low-risk groups based on the prognostic model were significantly related to overall survival and clinicopathologic characteristics (survival status, lymphatic invasion, cancer status, and clinical stage) in OC patients and remained independent risk factors according to multivariate COX analysis (p < 0.05).
Conclusion: Those findings provided the potential targeted lncRNA-EIF4A3-mRNA pathways of ivermectin in OC, and constructed the effective prognostic model, which benefits discovery of novel mechanism of ivermectin to suppress ovarian cancer cells, and the ivermectin-related molecule-panel changes benefit for its personalized drug therapy and prognostic assessment towards its predictive, preventive, and personalized medicine (PPPM) in OCs.
Keywords: EIF4A3; Ivermectin; Ovarian cancer; Personalized drug therapy; Predictive preventive personalized medicine (PPPM); Prognostic assessment; Prognostic model; TCGA; lncRNAs.
It is the first time to provide lncRNA signature in OC cell lines before and after ivermectin treatment with different drug concentration and provide the correlation of risk score and clinical traits according to prognosis model. Cancer is a complex disease controlled by multiple genes and many signaling pathways, so a key molecule-panel is necessary for personalized drug therapy practice [21]. Constructing ivermectin-mediated multi-lncRNA prognosis model could be reliable and effective for OC prognostic assessment towards PPPM clinical practice. These findings demonstrate a novel link between ivermectin and the lncRNA-EIF4A3-mRNA axes in OCs, indicating that the use of ivermectin may be a new therapeutic approach for OCs.
LncRNA played important roles in OC [29]. This study provided a sixteen-lnRNA signature in OCs, including HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3, which showed a changed profile when OCs were treated with ivermectin. Some of them have been proved significantly in cancers. For example, SNHG3 expressions were associated with poor prognosis and enhanced malignant progression of OC. SNHG3 was significantly increased in OC tissues compared to adjacent normal tissues. Higher SNHG3 expressions were positively associated with lymph node metastasis, OC stage, and poor prognosis [40]. RNA pull-down mass spectrometry analysis found that YBX1 interacted with HOXC-AS3, and RNA-seq analysis found a marked overlap between genes that were differentially expressed after YBX1 knockdown and those genes that were transcriptionally regulated by HOXC-AS3, which suggested a novel lncRNA HOXC-AS3 mediate tumorigenesis of cancer by binding to YBX1 [41]. ZNF674-AS1 expressions in the hepatocellular carcinoma cell lines HCCLM3, HepG2, SK-Hep1, MHCC97H, Hep3B, and HuH7 were significantly downregulated compared to that in the normal liver cell line QSG-7701, whose results were consistent with the test of hepatocellular carcinoma tissues, and ZNF674-AS1 expressions were significantly correlated with clinical stage, metastasis, and histopathologic grading [42]. It is necessary to further study the detailed molecular mechanisms underlying ivermectin-mediated suppression of tumor growth. However, the regulatory relationships between ivermectin and lncRNAs have not been reported until now.
Large-scale clinical data are also needed to validate ivermectin-related lncRNA-panel biomarker for OC survival prediction after the treatment with ivermectin. Moreover, although ivermectin is extensively used for anti-parasites, currently, its antitumor effects are all derived from the experimental studies in the cell and animal models. It has not been used in cancer patients for clinical trials. Thus, extensive studies will still be needed for the realistic implementation of ivermectin in individual or in combination with other drugs into clinical practice in prediction, prevention, and personalized drug therapy of OCs.
…This study found that ivermectin inhibited OC migration, and that ivermectin-mediated lncRNA-EIF4A3-mRNA axes were the potential mechanism in OCs. The optimized three-lncRNA signature model (ZNRF3-AS1, SOS1-IT1, and LINC00565) provided a good assessment system to significantly associate survival risk with the expression profile of these three lncRNAs. These findings are the precious resource and have practical significance for drug redirecting of ivermectin in OC treatment for personalized drug therapy and prognostic assessment towards its PPPM practice.
…The lncRNA-EIF4A3-mRNA axes play important roles in the therapeutic process of ivermectin treatment of OC. EIF4A3 is a central molecule in the ivermectin drug signaling pathway to realize the personalized drug therapy of ivermectin in OC. Moreover, it is well known that the development of an anticancer new drug is a time-consuming long-term research process and needs lots of money, and the huge increase in national healthcare costs is becoming a concern worldwide. In such a social context, the repositioning of the existed drugs for their new uses for other diseases has recently gained extensive attentions.
No competing interests were declared.
Lactoferrin and cancer
Lactoferrin, or lactotransferrin, is a globular glycoprotein that is found in various fluids including saliva, tears, nasal secretions and especially in milk, as the nomenclature implies. Human colostrum has the highest concentration, followed by human milk and then cow milk at around 150 mg/L. It is one of the components of the immune system and has antifungal, antibacterial and anticancer properties67 and can modulate human peripheral blood monocyte derived macrophage responses to infection or inflammatory factors68.
At the mucosa surfaces of the respiratory, urogenital and intestinal tracts, Lf contributes to the primary innate immune defense system and has antimicrobial activity against a variety of pathogens [4]. Thus, Lf has been considered the body’s first line of defense as well as an acute phase protein of innate immunity.
Lf exists in the whole gastrointestinal tract and is considered as a natural compound that can inhibit the growth of pathogenic bacteria [5]. Lf, like lysozyme or defensin, is the first line of defense against bacterial infections. They kill invading bacteria by depleting essential cofactors like free iron, degrading bacterial cell wall components or using other mechanisms that have not been fully elucidated [6]. Furthermore, Lf participates in the regulation of inflammatory response, and plays a key role in maintaining gut homeostasis [7].69
The bovine form is recommended and researched for anti-cancer efficacy70 and is much cheaper than the human form71.
Human LF and bovine LF possess high sequence homology and have very similar antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, and immunomodulatory activities (19–21). Consequently, it is common to give the bovine form rather than say a recombinant human form as a supplement. Bovine LF is also deemed a “generally recognized as safe” substance by the Food and Drug Administration (FDA, USA), and is commercially available in large quantities (19).
Lactoferrin as a Nutraceutical
There is little doubt that oral LF can be of health benefit to the host, and while it is not considered to be absolutely necessary for mammalian life (so it is not a vitamin), it is reasonable to class it as a nutraceutical along with a variety of other molecules such as those mentioned in various papers (180, 181). As a nutraceutical, the bioavailability of LF would clearly be an important consideration in its use for the prevention or treatment of COVID-19. Enteric coating of LF capsules has been proposed as a measure to maximize the uptake of LF by the receptors located in the brush-border of the small intestine (182). Enteric coating allows LF release some distance from LF-degrading pepsin activities in the stomach, allowing it to remain intact, in the form capable of binding small intestinal LF receptors for uptake and eventual transfer into the systemic circulation (182). In a rodent study, the “absorption” of enteric-formulated LF was approximately 10-fold higher than that of regular LF introduced into the stomach of experimental animals (128). In view of these investigations, the authors of this paper regard enteric-coated LF as superior to regular LF supplements with respect to bioavailability and potential application for the prevention or therapy for coronaviruses such as the SARS-Cov-2 involved in COVID-19.
A PubMed search returned 5 results and only one of these was relevant to cancer and it is paywalled but I can post the abstract…
Lactoferricin is an amphipathic, cationic peptide with anti-microbial and anti-cancer properties. It can be generated by the pepsin-mediated digestion of lactoferrin, i.e. the conversion can take place in your stomach. Human Lactoferricin differs from Bovine Lactoferricin in that the human form has 25 residues, the bovine form 49 residues. They have ~70% sequence similarity. The human form forms a coiled structure whilst Bovine Lactoferricin forms a β-pleated sheet.
Published in 2022 by Pan et al, they performed a bioinformatics analysis of a lactoferricin peptide called TLP18 using PPA-Pred2, a binding affinity predictor for protein-protein complexes73.
TLP18 is a truncated peptide of lactoferricin with 18 amino acids of the N-terminus of the parent peptide, which shows higher activity in controlling cervical cancer cell growth by regulating the NF-κB interacting lncRNA (NKILA)/NF-κB feedback loop.
NKILA or NF-KappaB Interacting LncRNA is associated with tongue squamous cell carcinoma and nasopharyngeal carcinoma, amongst others74.
Abstract
Background: Lactoferricin peptide (LP) has been reported to control cancer cell proliferation. NF-κB interacting lncRNA (NKILA) is a tumor suppressor in several cancers.
Objective: We aimed to explore the potential function of the truncated LP (TLP) in the prevention of cervical cancer cell proliferation.
Methods: Bioinformatics analysis via PPA-Pred2 showed that 18-aa N-terminus of truncated lactoferricin peptide (TLP18, FKCRRWQWRMKKLGAPSI) shows higher affinity with nuclear factor kappaB (NF-κB) than LP. The effects of LP and TLP18 on cervical cancer cells SiHa and HeLa and the related mechanisms were explored by investigating NF-κB and lncRNA-NKILA.
Results: TLP18 shows an inhibitory rate up to 0.4-fold higher than LP on the growth of cervical cancer cells (P<0.05). NKILA siRNA promoted cell growth whether LP or TLP18 treatment (P<0.05). TLP18 treatment increases the level of lncRNA-NKILA and reduces the level of NF-κB up to 0.2-fold and 0.6-fold higher than LP (P<0.05), respectively. NKILA siRNA increased the levels of NF-κB, cleaved caspase-3, and BAX (P<0.05). TLP18 increased apoptotic cell rate up to 0.2-fold higher than LP, while NKILA siRNA inhibited cell apoptosis cell growth even LP or TLP18 treatment.
Conclusion: Truncated Lactoferricin peptide controls cervical cancer cell proliferation via lncRNA- NKILA/NF-κB feedback loop.
So, whilst lacking the experimental details and discussion, we know that lactoferrin can be digested to form lactoferricin and a truncated form that can act to increase expression of a tumour suppressing siRNA called NKILA.
Take your pick, but siRNA is short for “small interfering”, ”short interfering” or “silencing” RNA.
SiRNAs are a type of lncRNA which interfere with the expression of specific genes with complementary nucleotide sequences by degrading the mRNA after transcription, preventing translation of nuclear factor kappaB (NF-κB) in the case of NKILA.
NF-kB is a protein complex, classically formed from a heterodimer of p50 and RelA that controls transcription of DNA, cytokine production and cell survival. Dysregulation is associated with cancer, inflammatory and autoimmune diseases, septic shock, viral infections and impaired development of immunity. Active NF-kB turns on the genes which keep a cell proliferating, inhibiting apoptosis and promoting metastasis and escape from responses by the immune system. It is enhanced in 41% of cases of nasopharyngeal carcinoma, colorectal cancer, prostate cancer and pancreatic tumors75. This also provides guidance as to which cancers are more likely to be responsive to treatments including lactoferrin or lactoferricin.
Mechanism of NF-κB action. P (circled) denotes phosphorylation and then degradation of the inhibitory protein IkBα, mediated by the enzyme IkB kinase. Coactivators and RNA polymerase then assist with mRNA transcription of the complex in the nucleus, before export and protein translation.https://en.wikipedia.org/wiki/NF-%CE%BAB#/media/File:NFKB_mechanism_of_action.png
Ke et al (2018) investigated how NKILA inhibits NF-κB signaling and suppresses tumor metastasis in cancer patients. They used qPCR to obtain expression profiles of NKILA and detected it in 137 paired ESCC cancer tissues (esophageal squamous cell carcinoma) and noncancerous tissues, using GAPDH as a normalisation control.
GAPDH (glyceraldehyde 3-phosphate dehydrogenase) is frequently used as an endogenous control for qPCR analysis as its expression is consistent at different time points and with various experimental conditions76.
NKILA, lactoferrin and effects on leukocytes
NKILA can also promote M2 macrophage polarisation through the NF-κB signalling pathway77. The M2 phenotype is considered to be associated with tissue remodelling and repair, and can secrete anti-inflammatory factors such as IL-10 and TGF- β78.
And from 2018, Huang et al performed an in vitro investigation into how NKILA can also promote tumour immune invasion by sensitizing T-cells to activation-induced cell death, due to overexpression79. Tumour suppressor p53 can also cause a poor cancer prognosis if it has been expressed to excess80.
I am not aware of any cases of lactoferrin suppressing anti-tumour T-cells and promoting cancer, possibly because your starting point is usually to have a deficit of tumor suppressors in the first place. I am yet to see any research showing that it actually promotes cancer, even when administered at high doses, although it may show some toxicity to natural killer cells and lactoferrin doesn’t just suppress cancer through the NF-kB suppression pathway.
At low doses it increases the cytotoxicity of NK cells to cancer cell lines, but to what degree depends on the cell phenotype being treated.
Lactoferrin is an iron-binding glycoprotein implicated in particular in the control of immune functions and cell proliferation. We have investigated its involvement, at inflammatory concentrations, in cancer progression. We report that lactoferrin has a significant effect on natural killer (NK) cell cytotoxicity against haematopoietic and breast epithelial cell lines. Lactoferrin increases cytolysis at a low concentration (10 μg/ml) while at a high concentration (100 μg/ml) it modulates cytolysis depending on the target cell phenotype. By pre-treatment of either NK cells or target cells with lactoferrin, we have demonstrated that the lactoferrin effect is due both to a modulation of NK cell cytotoxicity and the target cell sensitivity to lysis. Lactoferrin binds to 91% of the naturally heterogeneous CD56dim/bright NK cell population and increases the NK cell cytotoxic activity at low concentrations. High concentrations of lactoferrin seem to be toxic for the CD56bright NK cells and decrease NK cell cytotoxicity. Lactoferrin also exerts an effect on target cells depending on the cell phenotype. It does not modify the susceptibility to lysis of haematopoietic cells such as Jurkat and K-562 cells, but does significantly increase that of the breast and colon epithelial cells. We have also demonstrated that lactoferrin inhibits epithelial cell proliferation by blocking the cell cycle progression.
To test NK cell cytotoxicity in the presence of lactoferrin, lactoferrin was added to the medium and maintained throughout the chromium release assay. Divergent results were obtained depending on cellular type and lactoferrin concentration. Whatever the effector/target ratio chosen, the addition of lactoferrin (10 μg/ml) resulted in a slight but significant increase of up to 15% in the lytic ability of the NK cells with regard to the haematopoietic Jurkat and K-562 cell lines (Fig. 1A). In contrast, a high concentration of lactoferrin (100 μg/ml) decreased by about 16 to 20% the lysis of these haematopoietic cells (Fig. 1B).
Effect of lactoferrin on haematopoietic cell cytolysis by NK cells. Lactoferrin is added simultaneously to the effector and target cells at the beginning of NK cytotoxic assay. At a low concentration (10 μg/ml), lactoferrin (□) enhances spontaneous cytotoxicity on the haematopoietic cell lines (A), while at high concentration (100 μg/ml), it decreases cytolysis of the haematopoietic cells (B) as compared to the control (■). Cytolysis is measured at the three arbitrarily chosen effector/target ratios of 20, 40, and 80, respectively. Results are expressed as the mean±SEM of three experiments using three different donors. https://www.sciencedirect.com/science/article/pii/S0167488998000135?via%3Dihub
Effect of lactoferrin on breast epithelial cell cytolysis by NK cells. Lactoferrin is added to the effector and the target cells at the beginning of NK cytotoxic assay. At a low concentration (10 μg/ml) (A) or high concentration (100 μg/ml) (B), lactoferrin (□) increases the cytolysis of both human breast and colon epithelial cells as compared to the control (■). Cytolysis is measured at the three arbitrarily chosen effector/target ratios, of 20, 40, and 80, respectively. The mean±SEM of experiments with three different donors are shown. https://www.sciencedirect.com/science/article/pii/S0167488998000135?via%3Dihub
Effect of lactoferrin on target cell sensitivity to lysis. Target cells are pre-incubated with lactoferrin (concentration ranging from 0 to 100 μg/ml) for 12 h in medium supplemented with 10% FCS. Target cell sensitization to lysis by lactoferrin was investigated on Jurkat (A), K-562 (B), HBL-100 (C) and HT29-18-C1 (D) cells. Error bars indicate±SEM. p<0.05, Student's t-test. https://www.sciencedirect.com/science/article/pii/S0167488998000135?via%3Dihub
Effect of lactoferrin on 3H-thymidine incorporation in HBL-100 (A) and HT29-18-C1 (B) epithelial cancer cell lines. Cancer cell proliferation is associated with increased thymidine uptake. Sub-confluent cells are cultured with lactoferrin (concentration ranging from 0 to 100 μg/ml) in 12-well plates for 24 h. After incubation with methyl 3H-thymidine for 4 h, the cells are lysed and incorporated methyl 3H-thymidine is counted. Each point is the mean±SEM of three experiments. https://www.sciencedirect.com/science/article/pii/S0167488998000135?via%3Dihub
Tumour induced inflammation could, paradoxically, cause degranulation of neutrophils and release of lactoferrin which can then further enhance the anti-tumour cytotoxicity of the NK cells, in a virtuous feedback cycle:
…Furthermore, we have demonstrated that the increase in NK cell cytotoxicity induced by lactoferrin is only observed at low concentrations of lactoferrin; at high concentrations, lactoferrin decreased NK cell activity. The physiologic level of lactoferrin in plasma does not exceed 2 μg/ml in healthy subjects [25]. Therefore, the slight increase in lactoferrin concentration caused by degranulation of neutrophils [2]during inflammation induced by tumour development could enhance NK cell functions in vivo. In contrast, the high concentrations of lactoferrin (50–100 μg/ml) used in vitro, can exert a toxic effect on NK cells and decrease their cytotoxic activity. In fact, all NK cells have the ability to mediate spontaneous cytotoxicity. The CD56bright cells, which exert the highest cytotoxic activity in the total CD56 NK cell population, bind more lactoferrin than the CD56dim cells. These CD56bright NK cells are sensitive to high concentrations of lactoferrin. Thus, at a high concentration of lactoferrin, only the CD56dim cells maintained spontaneous cytotoxic activity, explaining the decrease in but not the disappearance of the cytotoxicity.
An encouraging note to end with:
The antineoplastic activity of lactoferrin seems also to be due to the direct action on target cells. We have demonstrated a variability in the target cell response to pre-treatment by lactoferrin. The difference in sensitivity of the haematopoietic and the epithelial cells can be correlated to the target cell phenotype. Indeed, lactoferrin presents a variety of activities in vitro including control of proliferation and differentiation. Lactoferrin mRNA, mainly detected in normal breast epithelial tissues and in benign proliferative lesions, is down-regulated in some forms of cancer, such as human breast and colon epithelial cancers 26, 27, suggesting that lactoferrin is implicated in the tumour epithelial cell progression. In fact, Hurley et al. [7]reported that lactoferrin inhibits mammary cell growth. Furthermore, this effect was also observed on the HT-29 cells. Indeed, when transferrin was replaced by lactoferrin, HT-29 cells were unable to proliferate for a long time[28]. In our work, we have confirmed these previous observations and demonstrated that lactoferrin rapidly inhibits the proliferation of the transformed and tumour epithelial cell lines by a block in the cell cycle progression at the G1 to S transition.
Conclusion
Not only do we have in vitro, in vivo research and some clinical data to demonstrate the wide ranging therapeutic properties of baicalin, quercetin, ivermectin and lactoferrin but we also have some very revealing research and analysis into their specific modes of action right down to the level of genetics, - interactions not just with miRNAs but with lncRNAs too. This can be used to signpost areas for further research so that dosing, synergism and bioavailability can be optimised still further.
Advantages over the current trilogy of radiotherapy, allopathic chemotherapy and surgery include less off-target side effects due to toxicity, low cost, ready availability and a range of cancer pathways between targeted, including more efficient activation of the immune system already in place so that evasion by mutated tumour cells is less likely to lead to recurrences or metastasis.
A bonus of using therapeutics such as ivermectin or quercetin is that co-treatment of infections occurs alongside the cancer treatment. Reduction in the systemic load of parasites, bacteria, viruses or fungi and an improved gut biome can enhance their efficacy further still. Immune function can be enhanced to some extent by redirecting it to focus more on the cancer instead of the pathogen, with less pro-tumour pro-inflammatory cytokines circulating too.
Future therapeutic reviews will also feature research into interactions with lncRNAs, or I will add them as amendments and one-off Substacks once they have gone to preprint or through peer review.
This site is strictly an information website about potential therapeutic agents and a review of the current state of research. It does not advertise anything, provide medical advice, diagnosis or treatment. This site is not promoting any of these as potential treatments or offers any claims for efficacy. Its content is aimed at researchers, registered medical practitioners, nurses or pharmacists. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. Always consult a qualified health provider before introducing or stopping any medications as any possible drug interactions or effects will need to be considered.
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Zhao L, Xiong M, Liu Y. Baicalin enhances the proliferation and invasion of trophoblasts and suppresses vascular endothelial damage by modulating long non-coding RNA NEAT1/miRNA-205-5p in hypertensive disorder complicating pregnancy. J Obstet Gynaecol Res. 2021 Sep;47(9):3060-3070. doi: 10.1111/jog.14789. Epub 2021 Jun 7. PMID: 34101306.
Chen W, Guo Y, Yao X, Zhao D. Correlation of Blood Lipid and Serum Inflammatory Factor Levels With Hypertensive Disorder Complicating Pregnancy. Front Surg. 2022 Jun 17;9:917458. doi: 10.3389/fsurg.2022.917458. PMID: 35784937; PMCID: PMC9249135.
Chattopadhyay P, Mishra P, Mehta P, Soni J, Gupta R, Tarai B, Budhiraja S, Pandey R. Transcriptomic study reveals lncRNA-mediated downregulation of innate immune and inflammatory response in the SARS-CoV-2 vaccination breakthrough infections. Front Immunol. 2022 Nov 18;13:1035111. doi: 10.3389/fimmu.2022.1035111. PMID: 36466827; PMCID: PMC9716354.
Fan Y, Wang K. miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4. Mol Med Rep. 2020 Aug;22(2):633-642. doi: 10.3892/mmr.2020.11150. Epub 2020 May 18. PMID: 32467998; PMCID: PMC7339668.
Dou J, Wang Z, Ma L, Peng B, Mao K, Li C, Su M, Zhou C, Peng G. Baicalein and baicalin inhibit colon cancer using two distinct fashions of apoptosis and senescence. Oncotarget. 2018 Jan 8;9(28):20089-20102. doi: 10.18632/oncotarget.24015. PMID: 29732005; PMCID: PMC5929448.
Brown CM, Garovic VD. Drug treatment of hypertension in pregnancy. Drugs. 2014 Mar;74(3):283-96. doi: 10.1007/s40265-014-0187-7. PMID: 24554373; PMCID: PMC4558097.
Szulc M, Kujawski R, Mikołajczak PŁ, Bogacz A, Wolek M, Górska A, Czora-Poczwardowska K, Ożarowski M, Gryszczyńska A, Baraniak J, Kania-Dobrowolska M, Adamczak A, Iwańczyk-Skalska E, Jagodziński PP, Czerny B, Kamiński A, Uzar I, Seremak-Mrozikiewicz A. Combined Effects of Methyldopa and Baicalein or Scutellaria baicalensis Roots Extract on Blood Pressure, Heart Rate, and Expression of Inflammatory and Vascular Disease-Related Factors in Spontaneously Hypertensive Pregnant Rats.Pharmaceuticals. 2022; 15(11):1342. https://doi.org/10.3390/ph15111342
Hago AM, Gamallat Y, Mahmoud SA, Huang Y, Zhang J, Mahmoud YK, Wang J, Wei Y, Wang L, Zhou S, Awsh MA, Yabasin IB, Tang J. Ezrin expression is altered in mice lymphatic metastatic hepatocellular carcinoma and subcellular fractions upon Annexin 7 modulation in-vitro. Biomed Pharmacother. 2017 Jan;85:209-217. doi: 10.1016/j.biopha.2016.10.071. Epub 2016 Nov 30. PMID: 27914826.
Guan H, Zhao P, Dai Z, Liu X, Wang X. SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway. Tumour Biol. 2016 Sep;37(9):12153-12160. doi: 10.1007/s13277-016-5092-0. Epub 2016 May 24. PMID: 27220321.
Cong Zhang, Ning Li, chen Zhong et al. SH3GL1 Promotes Liver Tumorigenesis by Activating β-Catenin Signaling, 13 September 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-783516/v1]
Elsayed, O.M., Abdelazim, S.A., Darwish, H.A. et al.Association of LncRNA-PAX8-AS1 and LAIR-2 polymorphisms along with their expression with clinical and subclinical hypothyroidism.Sci Rep13, 6 (2023). https://doi.org/10.1038/s41598-022-26346-0
Yu X, Cao Y, Tang L, Yang Y, Chen F, Xia J. Baicalein inhibits breast cancer growth via activating a novel isoform of the long noncoding RNA PAX8-AS1-N. J Cell Biochem. 2018 Aug;119(8):6842-6856. doi: 10.1002/jcb.26881. Epub 2018 Apr 25. PMID: 29693272.
Huang, C., Li, R., Yang, C. et al.PAX8-AS1 knockdown facilitates cell growth and inactivates autophagy in osteoblasts via the miR-1252-5p/GNB1 axis in osteoporosis.Exp Mol Med53, 894–906 (2021). https://doi.org/10.1038/s12276-021-00621-y
Richardsen, E., Andersen, S., Al-Saad, S. et al.Low Expression of miR-424-3p is Highly Correlated with Clinical Failure in Prostate Cancer.Sci Rep9, 10662 (2019). https://doi.org/10.1038/s41598-019-47234-0
Sun W, Shen NM, Fu SL. Involvement of lncRNA-mediated signaling pathway in the development of cervical cancer. Eur Rev Med Pharmacol Sci. 2019 May;23(9):3672-3687. doi: 10.26355/eurrev_201905_17791. PMID: 31114992.
Salehi B, Machin L, Monzote L, Sharifi-Rad J, Ezzat SM, Salem MA, Merghany RM, El Mahdy NM, Kılıç CS, Sytar O, Sharifi-Rad M, Sharopov F, Martins N, Martorell M, Cho WC. Therapeutic Potential of Quercetin: New Insights and Perspectives for Human Health. ACS Omega. 2020 May 14;5(20):11849-11872. doi: 10.1021/acsomega.0c01818. PMID: 32478277; PMCID: PMC7254783.
Önal H, Arslan B, Üçüncü Ergun N, Topuz Ş, Yilmaz Semerci S, Kurnaz ME, Molu YM, Bozkurt MA, Süner N, Kocataş A. Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial. Turk J Biol. 2021 Aug 30;45(4):518-529. doi: 10.3906/biy-2104-16. PMID: 34803451; PMCID: PMC8573830.
Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol. 2020 Jun 19;11:1451. doi: 10.3389/fimmu.2020.01451. PMID: 32636851; PMCID: PMC7318306.
Shi Y, Williamson G. Comparison of the urinary excretion of quercetin glycosides from red onion and aglycone from dietary supplements in healthy subjects: a randomized, single-blinded, cross-over study. Food Funct. 2015 May;6(5):1443-8. doi: 10.1039/c5fo00155b. PMID: 25832541.
Wang M, Chen X, Yu F, Zhang L, Zhang Y, Chang W. The Targeting of Noncoding RNAs by Quercetin in Cancer Prevention and Therapy. Oxid Med Cell Longev. 2022 May 24;2022:4330681. doi: 10.1155/2022/4330681. PMID: 35656022; PMCID: PMC9155922.
Zhang Z, Li B, Xu P, Yang B. Integrated Whole Transcriptome Profiling and Bioinformatics Analysis for Revealing Regulatory Pathways Associated With Quercetin-Induced Apoptosis in HCT-116 Cells. Front Pharmacol. 2019 Jul 17;10:798. doi: 10.3389/fphar.2019.00798. PMID: 31379573; PMCID: PMC6651514.
Labbé, J.C., Vigneron, S., Méchali, F. et al.The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals an Arpp19/PP2A-B55 feedback loop.Nat Commun12, 3565 (2021). https://doi.org/10.1038/s41467-021-23657-0
Amjad MT, Chidharla A, Kasi A. Cancer Chemotherapy. [Updated 2022 Mar 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564367/
Farhan M, Silva M, Xingan X, Huang Y, Zheng W. Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis. Cells. 2020 Jun 30;9(7):1586. doi: 10.3390/cells9071586. PMID: 32629884; PMCID: PMC7407656.
Galasso, A., Aufderklamm, S., Damms-Machado, A., Miller, F., Stenzl, A., Bischoff, S., & Gakis, G. (2013). 800 CHEMOPREVENTIVE PROPERTIES OF THE FLAVONOIDS GENISTEIN AND QUERCETIN IN MEN WITH RISING PSA: FIRST RESULTS OF A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL (QUERGEN TRIAL).Journal of Urology, 189(4S). https://doi.org/10.1016/j.juro.2013.02.364
Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, Kerr DJ. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996 Apr;2(4):659-68. PMID: 9816216.
Li N, Zhan X. Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes. EPMA J. 2020 May 28;11(2):289-309. doi: 10.1007/s13167-020-00209-y. PMID: 32549918; PMCID: PMC7272521.
Yan H, He N, He S. HCG15 is a hypoxia-responsive lncRNA and facilitates hepatocellular carcinoma cell proliferation and invasion by enhancing ZNF641 transcription. Biochem Biophys Res Commun. 2022 Jun 11;608:170-176. doi: 10.1016/j.bbrc.2022.03.143. Epub 2022 Mar 28. PMID: 35427894.
Yao J, Gao R, Luo M, Li D, Guo L, Yu Z, Xiong F, Wei C, Wu B, Xu Z, Zhang D, Wang J, Wang L. Long noncoding RNA KIF9-AS1 promotes cell apoptosis by targeting the microRNA-148a-3p/suppressor of cytokine signaling axis in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2021 Dec 1;33(1S Suppl 1):e922-e932. doi: 10.1097/MEG.0000000000002309. PMID: 34750325; PMCID: PMC8734634.
Wang D, Wang Z, Zhang L, Sun S. LncRNA PDCD4-AS1 alleviates triple negative breast cancer by increasing expression of IQGAP2 via miR-10b-5p. Transl Oncol. 2021 Jan;14(1):100958. doi: 10.1016/j.tranon.2020.100958. Epub 2020 Nov 25. PMID: 33248413; PMCID: PMC7704410.
Liu H, Wan J, Feng Q, Li J, Liu J, Cui S. Long non-coding RNA SOS1-IT1 promotes endometrial cancer progression by regulating hypoxia signaling pathway. J Cell Commun Signal. 2022 Jun;16(2):253-270. doi: 10.1007/s12079-021-00651-1. Epub 2021 Oct 12. PMID: 34637090; PMCID: PMC8891412.
Shao X, Zhao T, Xi L, Zhang Y, He J, Zeng J, Deng L. LINC00565 promotes the progression of colorectal cancer by upregulating EZH2. Oncol Lett. 2021 Jan;21(1):53. doi: 10.3892/ol.2020.12314. Epub 2020 Nov 18. PMID: 33281964; PMCID: PMC7709565.
Li J, Li Z, Wu Y, Diao P, Zhang W, Wang Y, Yang J, Cheng J. Overexpression of lncRNA WWTR1-AS1 associates with tumor aggressiveness and unfavorable survival in head-neck squamous cell carcinoma. J Cell Biochem. 2019 Oct;120(10):18266-18277. doi: 10.1002/jcb.29132. Epub 2019 Jun 6. PMID: 31172583.
Liu B, Chen Y, Yang J. LncRNAs are altered in lung squamous cell carcinoma and lung adenocarcinoma. Oncotarget. 2017 Apr 11;8(15):24275-24291. doi: 10.18632/oncotarget.13651. PMID: 27903974; PMCID: PMC5421846.
Zhang E, He X, Zhang C, Su J, Lu X, Si X, Chen J, Yin D, Han L, De W. A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1. Genome Biol. 2018 Oct 4;19(1):154. doi: 10.1186/s13059-018-1523-0. PMID: 30286788; PMCID: PMC6172843.
Liang L, Wang Z-J, Ye G, Tang X-Y, Zhang Y-Y, Kong J-X, Du H-H. Distribution of Lactoferrin Is Related with Dynamics of Neutrophils in Bacterial Infected Mice Intestine.Molecules. 2020; 25(7):1496. https://doi.org/10.3390/molecules25071496
Pan Y, Jiang Y, Cui Y, Zhu J, Yu Y. Truncated Lactoferricin Peptide Controls Cervical Cancer Cell Proliferation via lncRNA-NKILA/NF-κB Feedback Loop. Protein Pept Lett. 2022;29(3):268-280. doi: 10.2174/0929866528666211206144110. PMID: 34872471.
Kell DB, Heyden EL, Pretorius E. The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Front Immunol. 2020 May 28;11:1221. doi: 10.3389/fimmu.2020.01221. PMID: 32574271; PMCID: PMC7271924.
Cui, S., Lv, X., Sun, G., Wu, W., Xu, H., Li, Y., Liu, Y., Li, J., Du, G., Wang, M., & Liu, L. (2022). Recent advances and prospects in purification and heterologous expression of lactoferrin.Food Bioengineering, 1, 58– 67. https://doi.org/10.1002/fbe2.12003
Zainuddin A, Chua KH, Abdul Rahim N, Makpol S. Effect of experimental treatment on GAPDH mRNA expression as a housekeeping gene in human diploid fibroblasts. BMC Mol Biol. 2010 Aug 14;11:59. doi: 10.1186/1471-2199-11-59. PMID: 20707929; PMCID: PMC2930638.
Jiang P, Li X. Regulatory Mechanism of lncRNAs in M1/M2 Macrophages Polarization in the Diseases of Different Etiology. Front Immunol. 2022 Jan 25;13:835932. doi: 10.3389/fimmu.2022.835932. PMID: 35145526; PMCID: PMC8822266.
Bi Y, Chen J, Hu F, Liu J, Li M, Zhao L. M2 Macrophages as a Potential Target for Antiatherosclerosis Treatment. Neural Plast. 2019 Feb 21;2019:6724903. doi: 10.1155/2019/6724903. PMID: 30923552; PMCID: PMC6409015.
Huang D, Chen J, Yang L, Ouyang Q, Li J, Lao L, Zhao J, Liu J, Lu Y, Xing Y, Chen F, Su F, Yao H, Liu Q, Su S, Song E. NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death. Nat Immunol. 2018 Oct;19(10):1112-1125. doi: 10.1038/s41590-018-0207-y. Epub 2018 Sep 17. PMID: 30224822.
Davidoff AM, Herndon JE 2nd, Glover NS, Kerns BJ, Pence JC, Iglehart JD, Marks JR. Relation between p53 overexpression and established prognostic factors in breast cancer. Surgery. 1991 Aug;110(2):259-64. PMID: 1858036.
Damiens E, Mazurier J, el Yazidi I, Masson M, Duthille I, Spik G, Boilly-Marer Y. Effects of human lactoferrin on NK cell cytotoxicity against haematopoietic and epithelial tumour cells. Biochim Biophys Acta. 1998 Apr 24;1402(3):277-87. doi: 10.1016/s0167-4889(98)00013-5. PMID: 9606986.
Love it; hills are so good for you overall, and cycling is another fave!
Precision Hydration in the UK has some interesting info...especially for heavy sweat-ers.
I can always use more compost than my 2 bins create; and also have a big leaf mulch pile. Here in New England, the "Coast of Maine" company makes an interesting Lobster Compost. Orchid and carnivorous growing media sounds intriguing!
With ~ 2 acres for our own use; our soil is tested in small batches and I use no heavy equipment; so I am always busy in our rocky soil. And I use local soil that I amend organically and with green manure cover crops; always cultivate organic practices even stricter standards than MOGFA Certified Organic (e.g., no Bt); but not tested or claimed Certified-it's just for us.
I call our little place of green organisms a "Plant Zoo" because I like growing a variety of Heirloom and Local habitat plants, and like to explore companion planting.
Love that background of horticulture and organic composts!
I did a hugelkutur bed I created with forest soil & mycorrhizae for the ginseng and goldenseal. Artemesia annua, Melissa officianalis, Echinacea purpurea, Oregano a few spp. multiplied like mad here...looking for Sarracenia and Epimedium...and silica-rich horsetails, etc to counter Aluminum from chemtrails...another subject for your Substack that I am interested in-soil science remediation! I am harvesting dandelion and stinging nettles now. And dividing Houttouynia chordata, Schisandra chinensis vines, etc...
Much food for thought; too bad we're not closer! I could send some Baikal or connect to let you know some of my seed sources if you wish.
I am a little over an hour to the start of the Boston Marathon; so interested in Sports Physiology too- if you are a runner, like me, I have boycotted Abbott World Marathon Majors because you can't participate if not jabbed with their mandatory Bioweapon. Shame on the BAA; and the rest of these events I had planned on running.
Love it; hills are so good for you overall, and cycling is another fave!
Precision Hydration in the UK has some interesting info...especially for heavy sweat-ers.
I can always use more compost than my 2 bins create; and also have a big leaf mulch pile. Here in New England, the "Coast of Maine" company makes an interesting Lobster Compost. Orchid and carnivorous growing media sounds intriguing!
With ~ 2 acres for our own use; our soil is tested in small batches and I use no heavy equipment; so I am always busy in our rocky soil. And I use local soil that I amend organically and with green manure cover crops; always cultivate organic practices even stricter standards than MOGFA Certified Organic (e.g., no Bt); but not tested or claimed Certified-it's just for us.
I call our little place of green organisms a "Plant Zoo" because I like growing a variety of Heirloom and Local habitat plants, and like to explore companion planting.
Nice chat-Back to work I go!
Love that background of horticulture and organic composts!
I did a hugelkutur bed I created with forest soil & mycorrhizae for the ginseng and goldenseal. Artemesia annua, Melissa officianalis, Echinacea purpurea, Oregano a few spp. multiplied like mad here...looking for Sarracenia and Epimedium...and silica-rich horsetails, etc to counter Aluminum from chemtrails...another subject for your Substack that I am interested in-soil science remediation! I am harvesting dandelion and stinging nettles now. And dividing Houttouynia chordata, Schisandra chinensis vines, etc...
Much food for thought; too bad we're not closer! I could send some Baikal or connect to let you know some of my seed sources if you wish.
I am a little over an hour to the start of the Boston Marathon; so interested in Sports Physiology too- if you are a runner, like me, I have boycotted Abbott World Marathon Majors because you can't participate if not jabbed with their mandatory Bioweapon. Shame on the BAA; and the rest of these events I had planned on running.