Therapeutic properties of Berberine

A literature review

May 20, 2022

Updates:

22nd May ‘22 : Berberine and multiple sclerosis.

23rd May ‘22: Amyloidosis and a possible correlation with cardiovascular incidents and excess deaths. Berberine as a potential therapeutic.

25th May ‘22: Comments by John Paul.

5th January ‘23: Hyperlinked contents page added (browser support varies).

Ferulic acid food sources.

Quercetin to improve bioavailability when used as an anti-cancer therapeutic.

Any extracts used in the following article are for non commercial research and educational purposes only and may be subject to copyright from their respective owners.

Abstract

This Substack is a scientific literature review of much of the current research into the therapeutic benefits of berberine.

It explores the rational for finding effective antivirals against COVID-19 as a matter of some urgency.

Berberine as a compound is described along with common plant based sources of the drug.

Significant antiviral activity has been demonstrated against alphaviruses, cytomegalovirus, herpes simplex, COVID-19, SARS, RSV, hepatitis-C and influenza, including at higher viral loads in the later course of infection where it may be too late to use other treatments effectively.

Anticancer activity by interaction with several pathways has been evidenced. The most interesting of these is by upregulation of the key tumor suppressor p53. Efficacy against myeloma, non-Hodgkin lymphoma and as a potential antitumor agent for Primary effusion lymphoma (PEL) is also indicated.

A significant reduction of inflammatory cytokines in COVID-19 patients and other in vitro studies is discussed, along with a reduction of pulmonary fibrosis in COVID-19 patients.

Evidence for the efficacy of berberine in type 2 diabetes is presented, and related positive results when used to manage obesity.

Suppression of mast cell mediated allergic responses has been demonstrated in animal trials and in vitro.

Limited but significant evidence of reduction of hypertension was found from trials involving rats and randomised control trials of humans, along with favourable blood sugar markers, but more research is needed.

Berberine is beneficial for MS sufferers too by suppressing autoimmune responses according to a humanised mouse and other studies, and attenuation of the sphingosine kinase 1 (Sphk1) signalling pathway may also be beneficial for inhibiting tumorigenesis.

Berberine or a derivative can inhibit amyloidosis by disrupting at least 2 pathways: reducing neutrophil elastase levels and by disrupting cytochrome induced ROS generation. Amyloidosis and a possible correlation with cardiovascular incidents and excess deaths is explored.

A synergistic association with Ferulic acid and with the chemotherapeutic agent cisplatin is discussed, and finally bioavailability, warnings and dosing guidance is provided.

Background

Due to antigenic shift, original antigenic sin and various other immunosuppressive factors (as reviewed in my other Substacks), vaccinologist G. Vanden Bossche recommends that antivirals be rolled out widely in preference to a program of boosters of very limited efficacy (eg 8-12 weeks) and terrible safety profiles:

Unless a large-scale antiviral program is immediately implemented in highly vaccinated countries, the increasing immune pressure exerted on Omicron’s pathogenicity will drive natural selection and propagation of new SC-2 variants (Newcos) that – in comparison to Omicron - will gain a tremendous competitive advantage on different fronts (full resistance to potentially neutralizing and potentially trans infection-inhibiting Abs induced by the vaccines and resulting in enhanced infectiousness, sustained transmissibility and high virulence) and in all segments of the population that find their innate immune effector capacity suppressed as a result of vaccination. C-19 vaccination not only suppresses the functionality of innate polyreactive Ab responses, which besides their protection from CoV also protect from other enveloped glycosylated viruses, but now also promotes viral infectiousness since the potentially neutralizing vaccinal Abs have become subject to viral resistance23. Since enhancing vaccinal Abs are now causing strong immune pressure on viral virulence in highly vaccinated populations, enhanced infectiousness (ADEI) is paving the way for new escape mutants that will promote ADED. Vaccination against Omicron will parallel the effect of natural exposure to Omicron in that both will predominantly lead to a recall of enhancing anti-NTD Abs. Vaccinees who are at the highest risk of contracting severe disease are those who got vaccinated prior to natural exposure. Once vaccinated, their innate immune cells may no longer be ‘trainable’ because of the prolonged suppressive effect of enhancing vaccinal Abs directed at the conserved antigenic site on S-NTD. In the vaccinees, these Abs will likely be boosted on regular occasions because of their increased susceptibility to the circulating variant. But even additional booster injections with the current C-19 vaccines are only going to further raise the anti-NTD Ab titers and are, therefore, equally prone to promoting selection and expansion of ADED-enabling Newcos in highly vaccinated populations. This sobering but truly scientific perspective is not even mentioning the many concerns raised in regard of the potential health consequences caused by long-lived suppression of immune recognition of selflike glycans that are expressed on host cells infected with other viruses (e.g., Influenza) or host cells that are pathologically altered by a non-infectious disease (e.g., cancer cells).1

I have collated a regularly updated reference of therapeutics for “long covid”& post transfection sequalae and was going to add Berberine as an alternative to Ivermectin as it has similar efficacy, but quickly discovered that a full literature review would exceed the word count limits of that Substack2, and as Ivermectin is de facto a prohibited drug in many countries/states, being regularly intercepted and seized by customs officials 3 all cost effective, safe, effective and accessible alternatives must be reviewed as matter of urgency. The potential demand could/indeed should be enormous given the public health implications of the current path we are on.

Comments by John Paul on therapeutics. L452 is a mutation in Delta, BA.2.12.1, BA.2.13, BA.4 and BA.5 that increases glycosylation of the virus to hide from the immune system & resist neutralising antibodies, assists binding to ACE2 and virulence4.

IVM is almost useless against any variant with the mutation L452. HCQ is good to stop inflammation but that is it, good tools to have.

Some other mutations also help to spread better, like Omicron mutations that does exactly this in the vaccinated (I covered this one recently). In fact, the more it uses ACE2, relatively better, because of the part below. So far the worst part of the virus is not entering your cells, but when it cases different type of cell deaths on your immune cells, setting off inflammation for weeks/months. Among other things I covered, like the opsonizing, etc. I have free access to IVM, and HCQ, I have used both on tons of people, and have (substantial) better results with the other things I tell people to take. From all the drugs both of these are heavily politicized and have strong emotional investment from both sides. Berberine/Metformin are the best prophylactic/early treatments one can have, allied with NAC/Glutathione and Niacin/Nicotoninamide Mononucleotide. With these, you recover so much faster if the infection is mild.

…there is not way you can treat this Frankenstein spike with just one drug/supplement. You said it yourself, 20 different pathways. For more... interesting results search for berberine/metformin and amyloid/prion.5

This is exemplified by rapid viral evolution under selective pressure from “leaky” vaccines, with new variant of concern BA.5 rapidly heading for dominance in heavily vaccinated countries at the time of writing.6 Other variants will quickly follow.7

What is Berberine?

Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as Berberis, such as Berberis vulgaris (barberry), Berberis aristata (tree turmeric), Mahonia aquifolium (Oregon grape), Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense (Amur cork tree),[2] Coptis chinensis (Chinese goldthread), Tinospora cordifolia, Argemone mexicana (prickly poppy), and Eschscholzia californica (Californian poppy). Berberine is usually found in the roots, rhizomes, stems, and bark.[3]
Due to its yellow color, Berberis species were used to dye wool, leather, and wood.[4] Under ultraviolet light, berberine shows a strong yellow fluorescence,[5] making it useful in histology for staining heparin in mast cells.[6] As a natural dye, berberine has a color index of 75160.8

The most common pharmacological source is from a herb called Goldenseal, Hydrastis canadensis, which is native to southeastern Canada and the eastern United States. Its in the buttercup family Ranunculaceae. Berberine concentration usually varies between 0.5% and 4.5%, being extracted from the rhizomes where the concentration is highest. The herb itself contains other isoquinoline alkaloids and is available as a therapeutic in its own right.9

What comes up repeatedly in the literature, as you shall see, is that although berberine works very well when taken on its own, it exerts a synergistic effect when taken with other therapeutics. This includes prescription drugs being used for chemotherapy and so on.

The roots of Barberry, Berberis vulgaris are another popular source, with concentrations of berberine chloride of 10.29% in one study.10

It can also be extracted from bark of the Amur Corktree, Phellodendron amurense:

Antiviral activity - alphaviruses

Alphaviruses are vector-borne, enveloped, positive-strand RNA viruses of the Togaviridae family. Chikungunya virus (CHIKV) causes an acute febrile illness, characterized chiefly by myalgia, nausea, headache, and maculopapular rash, which can progress to chronic arthralgia in a large fraction of the patients and persist for several months or even years, causing considerable suffering and economic loss (Burt et al., 2012). Hitherto restricted to tropical areas of Africa, the Indian sub-continent and South-East Asia, CHIKV recently invaded the western hemisphere, causing more than 1 million suspected infections in the Caribbean, as well as in Central, South and North America.

In one study, baby hamster kidney cells were infected in vitro with CHIKV and a robotic screening system was used to assess 3000 bioactive compounds for antiviral activity. Berberine (EC50 = 1.8uM), abamectin (EC50 = 1.5uM) and ivermectin (EC50 = 0.6uM) all inhibited replication in a dose-dependant manner and had broad antiviral activity against other alphaviruses, including Semliki Forest virus and Sindbis.

Ivermectin and Abamectin were also active against a well known flavivirus known as yellow fever virus. Both Ivermectin and Abamectin are fermentation products of a soil borne bacterium, Streptomyces avermitilis. Efficacy was assessed by monitoring the luciferase signature.

7 of the most active compounds, without toxicity, included abamectin, ivermectin, berberine, amphotericin b, cerivastatin, bromocriptine (p < 0.001 for all) and fenretinide (p < 0.01)

Ivermectin and abamectin completely abolished luciferase signal while the inhibition induced by amphotericin b, berberine, bromocriptine, cerivastatin and fenretinide varied between 40 and 85% compared to the non-treated sample.

Abamectin and ivermectin had the most powerful antiviral effects, berberine also showed clear signs of inhibition.

3.4. Effects of the hit compounds on CHIKV RNA synthesis, protein expression, and virus titer
Next, the anti-CHIKV activity of the compounds was evaluated using approaches independent of luciferase readout. The effect of the hit compounds at 3 μM concentration on CHIKV RNA and protein expression was studied in virus-infected BHK-21 cells. Abamectin and ivermectin were very powerful inhibitors of both positive-strand and negative-strand RNA production (Fig. 2A). Berberine and bromocriptine showed some inhibition while the other compounds (cerivastatin and fenretinide) did not have a clear effect on RNA levels. To study the effect of the hit compounds on CHIKV protein expression, viral nsP1 and E2 protein expression was analyzed in the presence of the hit compounds at 16 h postinfection (Fig. 2B) and viral nsP1 and nsP3 expression were analyzed at a higher MOI of 10 at 6 h postinfection (Fig. 2C). Abamectin and ivermectin showed strong reduction in CHIKV protein expression in infected cells, even at the higher MOI. Viral protein expression was also clearly reduced by berberine but not by bromocriptine or by the other compounds.

The effect of the compounds at 3 μM on the production of infectious CHIKV was studied in BHK-21 cells by determining virus titers with conventional plaque titration (Fig. 2D). Berberine was a highly efficient CHIKV inhibitor reducing virus production by 5 logs and abamectin and ivermectin by almost 4 logs compared to non-treated samples. Bromocriptine, cerivastatin and fenretinide did not have any effect on virus production under these experimental conditions. This experiment also confirmed that amphotericin b did not inhibit CHIKV production (data not shown). Altogether, our findings indicate that abamectin, berberine and ivermectin are strong inhibitors against CHIKV. These compounds did not exhibit any virucidal activity when mixed with SFV and CHIKV virus stocks

Interestingly, in this study, berberine was much more effective than abamectin and ivermectin when first administered to the cell lines later in the viral course (arrows).

If this is also seen in coronavirus infected humans then berberine may well be more effective at bringing down a high viral load than ivermectin, which is best taken as early as possible ie when first symptomatic.

SFV = Semliki Forest virus, CHIKV = Chikungunya virus, ABM = Abamectin, BBC = Berberin, IVM = Ivermectin. Higher bars = greater viral reduction, log scale:

This was an in vitro study of alphaviruses, not coronaviruses so it has its limitations, but the authors conclusions from this 2015 study are encouraging:

Berberine is an isoquinoline derivative obtained from medicinal plants of different species and is used as a traditional medicine and dietary supplement. Berberine is not in clinical use for humans but it has been reported to have several pharmacological properties e.g., antimicrobial, antidiabetic and anti-cancer effects (Tillhon et al., 2012). It has also been shown to be effective against hyperlipidemia (Kong et al., 2004) and to possess anti-inflammatory activity (Yao et al., 2015). This suggests that berberine might be affecting one or several host factors important for CHIKV replication. Berberine was earlier found to be effective against human cytomegalovirus (Hayashi et al., 2007), herpes simplex virus (HSV) (Chin et al., 2010) as well as influenza virus (Wu et al., 2011). Recent studies depicting berberine's antiviral activity against HSV (Song et al., 2014) and respiratory-syncytial virus (Shin et al., 2015) implicate the modulation of several cellular signaling pathways by the compound. It would be interesting to investigate which of the many pathways affected by berberine are critical for alphavirus replication. In our study, berberine was found to reduce levels of viral RNA synthesis (Fig. 2A) as well as downregulate CHIKV protein expression (Fig. 2B, C) but have a smaller effect than abamectin and ivermectin. Therefore, it was surprising that berberine was more effective in reducing the number of infectious particles produced (Fig. 2D), suggesting that berberine might be additionally targeting the latter phase of the CHIKV infection cycle. A similar observation was made in the time-of-addition experiments (Fig. 3) with both SFV and CHIKV where berberine continued to be effective when added later in the infection cycle. We currently pursue the isolation of resistant mutants, which could suggest the antiviral targets for the compounds and thereby help in understanding their mechanism of action. In future studies, we plan to evaluate the efficacy of these inhibitors in a mouse model. 11

Abamectin is currently marketed as an animal husbandry wormer drench (please don’t drink it), whereas its better known relation is available in tablet form for safe human consumption.

Antiviral activity - drug resistant strains of Cytomegalovirus (CMV)

CMV is a type of β-herpesvirus and is commonplace. In healthy adults infection can lead to fatigue, fever, sore throat and muscle aches although most will be asymptomatic. But it is a serious risk to infected new born babies and may be fatal to those with suppressed immunity.12 It can also be recombinant with adenoviruses, removing latency and promoting replication in both.13

In a 2019 study by Luganini et al, it was discovered that low micromolar concentrations of berberine were confirmed to suppress the replication of different HCMV strains, including those which were resistant to approved DNA polymerase inhibitors. It did this by interfering with the transactivating activity of viral IE2 protein and “represents a promising candidate for new antiviral strategies”.

Existing anti-HCMV therapies suffer from drawbacks including long term toxicity, poor bio-availability and selection of resistant viral strains.

Berberine was shown to exert broad-spectrum anti-HCMV activity:

BERBERINE SHOWED A DOSE-DEPENDENT INHIBITION OF CMV

Berberine can also modulate multiple host cell signalling pathways, including NF-kB and mitogen activated protein kinases (MAPK), including ERK1/2 and p38, which both HCMV’s and coronaviruses exploit.14

In conclusion, the results of this study suggest BBR as another attractive candidate for a new class of anti-HCMV drugs that exert their effects via novel pathways that target IE2 functions, and warrant further investigations to evaluate whether BBR may be effective in animal models of CMV infection. Indeed, BBR is active also against MCMV replication and prevents the transactivation of a prototypic MCMV E gene mediated by the IE3 protein, the murine homolog of HCMV IE2. Given this high similarity between HCMV IE2 and MCMV IE3, the investigation of the therapeutic potential of BBR in the murine model of CMV infection is worth pursuing.15

Again, this was an in vitro assessment that didn’t include coronavirus infections of humans, and they do recommend a follow up with animal studies. No conflicts of interest were registered.

Antiviral activity - COVID-19 and SARS

In a 2021 study by Wang et al they cite previous studies showed that berberine has shown various biological activities that may help against COVID-19, and that it is an ingredient as recommended by the China National Health Commission for COVID-19, a promising orally administered therapeutic candidate to be combined with other therapies.

They report that modes of action include antiviral, anti-allergy and inflammation, hepatoprotection (ie liver) as well as by reducing oxidative stress. Antiviral activities include anti-influenza, anti-hepatitis C, anti-cytomegalovirus and anti-alphavirus, as discussed above.

Many inflammatory markers were suppressed, whilst viral infection and replication was significantly inhibited.

The researchers developed a more biologically active form of berberine nanomedicine called NIT-X which was 98-100% effective at reducing histamine, inducing gamma interferon from CD8+ T cells, reducing immunoglobulin E and anaphylaxis in peanut allergic mice after 4 weeks administration at 2 mg / mouse / day. Again, this was by interference with the MAPK & ERK inflammatory signalling pathways and downregulation of pro‐inflammatory transcription factors NFκB and AP‐1 .

It has demonstrated cytokine moderating effects, both directly and indirectly, and has several different cell cycle regulating gene targets, with low toxicity. This has implications for both regulating viral replication, cell apoptosis and pro-tumor effects.16

For the study they used:

…computational modelling…target mining, gene ontology enrichment, pathway analyses, protein‐protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic‐berberine nanomedicine, named NIT‐X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN‐γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS‐CoV‐2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL‐1α, IL‐8, IL‐6, and CCL‐2 in SARS‐CoV‐2 infected Calu3 cells were significantly suppressed by NIT‐X. By supporting protective immunity while inhibiting pro‐inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID‐19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID‐19 and SARS.

In addition, the inhibition of replication of SARS‐CoV‐2 by berberine/NIT‐X has been validated in vitro. The suppression of ACE2, TMPRSS2, IL‐1α, IL‐8, IL‐6, and CCL‐2 by berberine/NIT‐X were further validated. The results of these analyses will contribute to a molecular‐level understanding of how berberine functions in the prevention and treatment of COVID‐19 and SARS, providing both the rationale and tools needed to further validate its efficacy. Given the discovery of the high oral bioavailable ability of berberine nanomedicine (NIT‐X), 26 the current study may lead to a development of berberine/NIT‐X as an orally active therapeutic against COVID‐19 and SARS.

NLRP3 activation is well recognized as a trigger for CoV inflammatory cascade and tissue damage. 117 , 118 , 119 Berberine has been reported to alleviate influenza virus‐induced inflammatory lesions by restricting NLRP3 inflammasome activation through decreasing ROS generation. 49 NLRP3 may, therefore, be a high priority target of berberine against CoVs in the regulation of “NOD‐like receptor signaling pathway (P11).” “Apoptosis (P5)” further emphasizes the regulation of apoptosis by berberine, which is an innate immune response to viral infection. The cytokine‐related pathways include “IL‐17 signaling pathway (P12)” and “TNF signaling pathway (P13),” which play a crucial role in modulating immune pathophysiology of viral infection. 120 , 121 It is reported that the severity of COVID‐19 and SARS positively correlates with levels of Th17 cell‐related pro‐inflammatory cytokines including IL‐17, IL‐6, IL‐1, TNF, and IFN‐γ. 122 And berberine has been found to regulate differentiation and amelioration of Th1 and Th2 cell to impact the corresponding cytokines, 123 indicating IL‐17 and TNF might be the main cytokines regulated by berberine to control the course of infection. In addition, the “AGE‐RAGE signaling pathway in diabetic complications (P7)” is related to inflammatory regulation. AGE‐RAGE signaling elicits activation of multiple intracellular signaling pathways involving NADPH oxidase, protein kinase C, and MAPKs, then, resulting in NF‐κB activation. 124 Much evidence 125 shows that pulmonary tissues express a remarkably high basal level of RAGE, which is a key molecule in the onset and sustainment of the inflammatory response in many disease pathologies. Berberine has been discovered to regulate AGEs‐RAGE signaling pathway in mesangial cells exerting renoprotective effects during diabetic nephropathy, 50 which might indicate its possible role in regulation of AGEs‐RAGE signaling during SARS‐CoV and SARS‐CoV‐2 infection. 126 In addition, “Pathway in cancer (P1)” and “Pancreatic cancer (P15)” stand for complex pathways involving various activities including inflammatory process, metabolic regulation, cell proliferation, and cell apoptosis, part of which may be regulated by berberine to resist against the virus.

Berberine has been shown to significantly suppress TNF‐α and IL‐6 expression induced by HIV protease inhibitors even at low concentrations. 147 The production of IL‐1α/β and TNF‐α have been reported to be suppressed by berberine via the inhibition of IκB degradation in human lung cells. 44 , 148 Berberine can regulate the production or effects of inflammatory cytokines directly or indirectly, 149 , 150 which make it a promising agent in the prevention and treatment of COVID‐19 and SARS. Moreover, the regulation of cell proliferation by berberine has been mentioned previously. The targets related with cell proliferation and cell cycle include CDK4, TP53, CCND1, CDKN1A, and MYC and it is known that berberine can up‐regulate varicocele‐induced CDK4 and CCND1 expression reduction in rat testicles. 151 Berberine may also balance cell proliferation and apoptosis during viral infection via signaling regulation. In conclusion, these genes are all promising targets on which berberine may act to regulate immune responses, inflammatory processes, and cell activities against COVID‐19 and SARS infection

They do call for more studies to provide direct evidence that berberine is an antagonist to ACE2, TMPRSS2 protein and other virus receptor targets but their conclusions from this research are promising.

They do refer to gastrointestinal side‐effects from high doses of the conventional form of berberine, and other studies have shown high risk of renal failure & death from Remdesivir17, with low antiviral efficacy and poor outcomes18, but a synergistic effect if taken with berberine:

Berberine/NIT‐X may exhibit a number of possible clinical prospective applications as follows: (1) Given that berberine improves the Th1 immune response at the early stage of infection, then, inhibits inflammatory responses triggered by viruses at the late stage, it is possible that berberine can be both a preventive and treatment option for individuals at a higher risk of viral infection such as immune‐compromised patients. (2) Our computational modeling showed that berberine targets a cancer pathway, an AGE‐RAGE signaling pathway in diabetic complications, and a number of other viral infection‐related immune response pathways. Therefore, berberine/NIT‐X may have be potentially useful for patients with preexisting condition such as cancer, diabetes, and patients with other viral infection including influenza, EBV, CMV, HBV, etc. (3) Clinically, a high dosage of berberine may cause gastrointestinal side‐effects. berberine/NIT‐X boosts oral bioavailability and reduces the dosage of oral administration by 6 times, and thereby may evade the side‐effects caused by high dosage. (4) Berberine might regulate host immune responses, inhibit host viral receptors, and block virus proteins to prevent and treat SARS and COVID‐19. Therefore, the co‐treatment with immune supplements such as ascorbic acid, antiviral drugs such as remdesivir, or antibodies from convalescent plasma might be interesting avenues to enhance the effects of berberine. Recently, strong synergistic in vitro antiviral activities between remdesivir and berberine have been reported, 182 which further supports our hypothesis.19

There were several conflicts of interests registered by Xiu-Min Li but not by the other authors.

In another 2021 study, Rodriguez-Rodriguez et al20 screened a panel of FDA-approved compounds that have been shown to possess antiviral or antimicrobial activity for their ability to inhibit SARS-CoV-2. They found that most of these were ineffective, but an antiparasitic pyrimidine biosynthesis inhibitor (also prescribed to HIV patients) called atovaquone was able to reduce SARS-CoV-2 replication in Vero E6 and human lung cells, and berberine had similar efficacy.

Screen of FDA-approved compounds against SARS-CoV-2 on Vero E6 cells

3.5. Berberine Chloride Inhibits SARS-CoV-2 Replication and Infectivity
In addition to FDA-approved compounds we were also interested in testing compounds used in holistic medicine for anti-SARS-CoV-2 activity. Berberine chloride (BBC) is an orally bioavailable plant-derived molecule that has been shown to have antiviral activity [28,42,43] and can enhance the antibacterial activity of some antibiotics [44,45]. Given the role of BBC in blocking alphavirus infection [28,46], we hypothesized that this molecule may work against SARS-CoV-2 as well. To begin, we infected Vero E6 cells with SARS-CoV-2 and 6 hours post infection added increasing concentrations of BBC or DMSO. We then quantified viral particles in the supernatant at 24 hpi (Figure 5A,B). As a control, we used CHIKV, an alphavirus that has been shown to be sensitive to BBC (Figure 5C) [28,46]. We found that BBC was able to reduce SARS-CoV-2 replication in Vero E6 cells in a dose-dependent manner similar to that of CHIKV. To expand these findings to a human and physiologically relevant cell line, we performed the same infections in Calu3 cells (Figure 5D,E). Interestingly, we found SARS-CoV-2 infection to be inhibited only at the highest concentration tested. These data suggest that in terms of SARS-CoV-2 infection, BBC may have a different effective concentration in Calu3 cells.

Vero E6 cells = Kidney epithelial cells from the African Green Monkey.21

Calu3 cells = A human lung cancer cell line commonly used in cancer research and drug development.22

Dimethyl sulfoxide (DMSO) is “a colorless liquid that gained notoriety for its ability to penetrate the skin and other biological membranes”, used as an alternative treatment and a negative control23.

Figure 5. Berberine chloride inhibits SARS-CoV-2 replication in vitro. (A) Cytotoxicity of BBC in Vero E6 cells measured by MTT assay. N = 2 with internal triplicates. Vero E6 cells were infected with SARS-CoV-2 (MOI = 0.1) (B) or CHIKV (MOI = 1) (C) BBC or DMSO was added at 6 hpi and supernatants were harvested at 24 hpi. Viral titers were quantified by plaque assay. Data represent the mean and range of two independent experiments with internal duplicates. Students t-test. (D) Cytotoxicity of BBC in Calu3 cells measured by MTT assay. N = 2 with internal duplicates. (E) Calu3 cells were infected with SARS-CoV-2 (MOI = 0.1) and BBC was added at 6 hpi. Supernatants were harvested at 36 hpi. Viral titers were quantified by plaque assay. Data represent the mean and SEM. N = 3 with internal duplicates. Students t-test. ND = not detected (below limit of detection):

This study identifies the anti-SARS-CoV-2 activities of atovaquone and BBC in vitro. In addition, and equally important, we showed that multiple compounds do not inhibit SARS-CoV-2 in vitro. Together, these points give us insight into some of the host pathways SARS-CoV-2 uses for replication and highlights pathways that we can target for antiviral development. Therefore, it is essential to conduct compound screens for antiviral activity against multiple emerging RNA viruses before the next pandemic.

Conflicts of interest were indeed registered, which may have skewed the tone of this paper, as per the previous paragraph:

Conflicts of Interest
K.C. has received research support from Pfizer, Takeda, Pacific Biosciences, and Abbvie; consulted for or received an honorarium from Puretech Health, Genentech, and Abbvie; and holds U.S. patent 10,722,600 and provisional patents 62/935,035 and 63/157,225.

Berberine and anti-cancer activity

The previous study showed that the P1 and P15 pancreatic cancer pathways were targeted. A 2019 paper by Zhang et al further expands on this by investigating the specific underlying anti-tumor mechanisms.24

Berberine exerts its anti-tumor effects through multiple pathways, including upregulating the tumor suppressor p53, inducing senescence, apoptosis, cell cycle arrest including by upregulating micro RNA’s such as miR-23a.

Caspases are involved with apoptosis, matrix metalloproteases (MMP’s), alongside VEGF, assist with cancer cell metastasis & tumor angiogenesis25.

“Bcl-2 ( B-cell lymphoma 2 ), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death ( apoptosis ), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis”26

Tumor necrosis factor alpha (TNFa) has dual roles, both in promoting innate and adaptive immune responses as well as being an important factor in cancer progression and metastasis.27

TP53 plays an important role in the induction of tumor cell apoptosis. In another study, the effects of berberine on the arachidonic acid (AA) metabolic pathway in HCC were examined. Berberine altered the viability and apoptosis of HCC cells in a dose-dependent fashion by inducing the translocation of apoptosis-inducing factors between the mitochondria and nucleus. Berberine also suppressed the levels of cytosolic phospholipase A2 (cPLA) and COX-2, which increased the ratio of AA to PEG-2 (Feng et al., 2012). Collectively, these findings suggest that tumor protein p53 (TP53) is closely associated with the anti-tumor effects induced by berberine (Figure 1 and Table 1).

This is interesting as we know that viral or transfected spike protein in the nucleus downregulates p53 and BRCA28, so berberine as an antagonist to this process may be of particular therapeutic value, along with the positive, inhibitory effects on the other pro-cancer pathways.

A 2014 paper by Qing et al details how berberine induces apoptosis in myeloma tumor cells by several pathways, including by hypomethylating (ie demethylating/reactivating) a promotor of p5329.

Efficacy against non-Hodgkin lymphoma and as a potential antitumor agent for Primary effusion lymphoma (PEL) is also indicated via suppression of the NF-κB pathway30.

Berberine and reduction of inflammatory cytokines

In a 2021 research letter to the British Journal of Surgery31, Zhang et al report on 39 patients admitted to 3 Chinese hospitals between January and April 2020 with severe COVID-19.

18 patients were allocated to the berberine group and 17 to the control group.

Bloods were tested including for including serum interleukin (IL-6), serum tumour necrosis factor (TNFα), C-reactive protein (CRP), procalcitonin and white blood cell (WBC) count, and were measured on days 1, 3, 7 and 14 after admission:

Except for the Acute Physiology and Chronic Health Evaluation (APACHE) II score, other basic clinical characteristics of age, sex, exposure history, co-morbidity, symptoms and the Sequential Organ Failure Assessment (SOFA) score were similar in the two groups. No significant difference was observed between the two groups in the trend of IL-6, TNF-α, CRP, procalcitonin and WBC levels within 14 days (Fig. 1). In subgroup analyses of patients with diarrhoea, berberine significantly improved the changes in IL-6, TNF-α and CRP levels (P < 0.050). Diarrhoea was defined as the passage of loose stools more than three times daily. Only one patient developed a mild rash, which disappeared shortly after the withdrawal of berberine.

Blood concentrations of inflammatory mediators in patients with severe COVID-19 in the two treatment groups and the subgroups with diarrhoea

They found that COVID-19 mediated IL-6 levels correlated with intestinal inflammation, tissue damage and diarrhoea. They speculate that berberine may reduce blood inflammatory cytokine levels, protecting and maintaining gastrointestinal function, but lacked specific study data on intestinal mucosal barriers & microenvironment.

Based on other literature, they judged the optimal berberine dose to reduce inflammation caused by COVID-19 to be 900mg daily. They also report other studies showing anti-influenza effects in vitro, inhibition of lung injury and reduction in oxygen free radicals (ROS) in mice suffering from pneumonia associated with influenza. No conflicts of interest were registered.

Berberine and reduction of pulmonary fibrosis in COVID-19 patients

Cao et al (May ‘22) predicted the role of berberine protein targets32 by analysing the Pharmmapper database and the 3D structure in the Pubchem database. Common gene targets were then analyzed by GO and KEGG by DAVID database33. They found that Berberine had 250 gene targets, COVID-19 pneumonia pulmonary fibrosis had 191 gene targets, and 23 of these were common to both:

Molecular docking showed that berberine was associated with CCl2, IL-6, STAT3 and TNF-α. GO and KEGG analysis reveals that berberine mainly plays a vital role by the signaling pathways of influenza, inflammation and immune response.
Conclusion Berberine acts on TNF-α, STAT3, IL-6, CCL2 and other targets to inhibit inflammation and the activation of fibrocytes to achieve the purpose of treating COVID-19 pneumonia pulmonary fibrosis.

Fig. 1. Common targets and common targets-active ingredient networks. Targets of the intersection of berberine and COVID-19 pneumonia pulmonary fibrosis.

…Firstly, berberine through TNF-α inhibited inflammatory reaction and reduce the activation of fibroblasts. Secondly, berberine inhibited the synergistic effect between IL-6 and STAT3, and reduced the inflammatory response. Lastly, berberine inhibited the chemotaxis of CCL2 to fibroblasts and reduces inflammation.
Pulmonary fibrosis is a serious complication of end-stage COVID-19 characterized by fibroblast proliferation and accumulation of large amounts of extracellular matrix, accompanied by inflammatory damage and tissue destruction. Pulmonary fibrosis can severely affect human respiratory function. The clinical manifestations are dry cough and progressive dyspnea. As the disease and lung injury worsen, the patients’ respiratory function will continue to deteriorate. However, there is still a lack of effective drugs for the treatment of pulmonary fibrosis.
Traditional Chinese medicine has significant impact on COVID-19 treatment and recovery prognosis (Chen et al., 2022). Berberine is a quaternary ammonium alkaloid isolated from the traditional Chinese medicine Coptis Rhizoma. Clinical studies have shown that berberine has anti-inflammatory and enhanced leukocyte phagocytosis effects. Although Chitra has shown that berberine attenuates pulmonary fibrotic injury by inhibiting Smad and non-Smad signaling cascades (Chitra et al., 2015), the mechanism by which berberine treats pulmonary fibrosis remains unclear (Li et al., 2019). This study can get rid of experimental techniques limits to realize the research on the mechanism of berberine in pulmonary fibrosis from a macroscopic to a microscopic perspective. Since the effect of berberine on pulmonary fibrosis depends on the network of signaling pathways, this study can more comprehensively study the relationship between different signaling factors, and provide multiple research directions for follow-up research. Chowdhury (2021) used tools of molecular docking to find that berberine can inhibit the function of the 3CLpro protein, thereby controlling viral replication. Compared with the traditional Computer Simulation Analysis, this study achieves from gene expression to protein regulation to molecular interaction. Experimental results verifies that berberine can act on relevant core targets in regulating pulmonary fibrosis.

As fibrosis in other organs, particularly the heart, may be a complication of myocarditis common gene targets make it very likely that berberine should be effective at reducing long term cardiovascular damage there too.

The researchers note that further research is hoped for, and expressed no declarations of competing interest.

Efficacy of Berberine in Patients with Type 2 Diabetes

Quite an old paper from 2008 with a small sample size, but Yin, Xing and Ye34 took 36 adults newly diagnosed with type 2 diabetes, and they were randomly assigned either berberine or metformin (0.5 g t.i.d.) for 3 months.

A1c is a blood sugar test,

The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (HbA1c; from 9.5% ± 0.5% to 7.5% ± 0.4%, P<0.01), fasting blood glucose (FBG; from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L, P<0.01), postprandial blood glucose (PBG; from 19.8 ± 1.7 to 11.1 ± 0.9 mmol/L, P<0.01) and plasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03 mmol/L, P<0.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering FBG and PBG from one week to the end of the trial. HbA1c decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced by 28.1% and 44.7% (P<0.001), respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly as well. During the trial, 20 (34.5%) patients suffered from transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.

Berberine, its effect on the management of obesity and related metabolic consequences

Ilyas et al (2020)35 conducted a systematic review. They found that berberine affects gut microbiota by reducing diversity of microbes starting at a dose of 100mg/kg/day. In animal models they found that it explicates an action on glucose through the inhibition of α-glycosidase at a dose of 200 mg/kg/day.

They also found that berberine is effective against differentiation of adipocytes (fat cells) through a decrease in LXRs (oxysterol receptors), PPARs (peroxisome proliferator-activated receptors involved in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms.36) and SREBPs (sterol regulatory element-binding proteins) at 150 mg/kg/day. Lipid levels in rats were were decreased at doses ranging from 40 to 380 mg/kg/day.

Hepatic gluconeogenesis was also inhibited through the PEPCK (Phospheoenolpyruvate carboxykinase), G6Pase (Glucose-6-phosphate ) and AMPK (AMP-activated protein kinase) pathways. “Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis”37

All the above preclinical data are confirmed in human studies where Berberine can modulate the diversity of gut microbes at the dose of 500 mg/day. In addition, Berberine is found to have a beneficial impact on gene regulation for the absorption of cholesterol at a daily dose of 300 mg in humans, an amelioration on glucose accumulation at 1.0 g daily dose was also observed. For all these reasons, this review gives an important good account of the impact of Berberine in obesity treatment and prevention.

Berberine and suppression of mast cell mediated allergic responses

Fu et al (2019)38 investigated the anti-allergic effects of berberine in cellular and animal models:

In this study, the results of the in vitro model of immunoglobulin (Ig) E-mediated mast cell degranulation showed that berberine significantly inhibited the release of β-hexosaminidase (β-HEX), histamine, IL-4 and TNF-α in rat basophilic leukemia cells (RBL-2H3 cells). Pretreatment with berberine prevented morphological changes in IgE-stimulated RBL-2H3 cells such as the recovery of an elongated shape. Pretreatment with berberine also suppressed the phosphorylation of antigen-induced Lyn, Syk, and Gab2, thus suppressing the downstream MAPK pathways. In the in vivo model of allergic responses, administration of berberine inhibited passive cutaneous anaphylaxis (PCA) in mice. The above results indicate berberine could suppress mast cell activation and allergic responses.

Beta hex is involved with lipid storage and are markers of mast cell degranulation (ie allergic response). Lower is better:

The FcɛRI-mediated signaling pathway is induced by antigen binding to IgE antibodies in mast cells. “The phosphorylation of Lyn and Syk, key proteins of the signaling pathway, were markedly attenuated by berberine. Berberine or Bay 61-3606 also downregulated Gab2”. Lower is better:

MAPK signalling is a key feature involved with the production of proinflammatory cytokines and berberine significantly suppressed these and TNFa as a consequence. Lower is better:

Passive cutaneous anaphylaxis (PCA) is an animal model for inflammatory reactions in Type I allergy39. Berberine and chlorpheniramine significantly suppressed PCA, lower is better:

Berberine for the treatment of hypertension

A 2017 study by Ma et al of diabetic rats40 reported that:

Results of the study suggest that chronic administration of 100 mg/kg/day berberine not only lowered blood glucose but also reduced blood pressure and improved vasodilation in diabetic rats. Furthermore, berberine markedly increased the function and expression of BKCa β1-subunit in cerebral vascular smooth muscle cells (VSMCs) isolated from diabetic rats or when exposed to hyperglycemia condition. The present study provided initial evidences that berberine reduced blood pressure and improved vasodilation in diabetic rats by activation of BKCa channel in VSMCs, which suggested that berberine might provide a combinational therapy for controlling hyperglycemia and blood pressure in diabetes. Furthermore, our work indicated that activation of BKCa channel might be the underlying mechanism responsible for the vascular protection of berberine in diabetes.

And in 2020 Suadoni and Atherton conducted a systematic review41 of five randomised controlled trials and two non-randomised controlled trials with 614 participants and had some interesting findings:

Compared to metformin, berberine provided a statistically significant moderate reduction effect on systolic blood pressure (-11.87 [-16.64, -7.10] mmHg). A proprietary nutraceutical containing berberine as one of its ingredients was in one study significantly effective at reducing blood pressure compared to placebo (-11.80 [-18.73, -4.87] mmHg systolic, and -11.10 [-15.17, -7.43] mmHg diastolic), and also effective in another study compared to dietary advice (-3.40 [-5.48, -1.32] mmHg for systolic 24 h ambulatory blood pressure), although effects could not be reliably attributed to berberine alone. The herbal extract Chunghyul-dan, which contains berberine, showed a significant beneficial moderate effect compared to no treatment on systolic 24 h ambulatory blood pressure (-7.34 [-13.14, -1.54] mmHg) in one study, but in another study employing higher dose and longer treatment duration, no effects were detected.

They concluded that the current evidence is not strong enough to be attributed to berberine alone and that higher quality studies should be conducted:

6.2. Implications for research
This review includes only seven trial. Most trials’ group size was small, duration was short, and related papers lacked details around trial design. Papers often omitted results on primary outcomes, or reported results without following widely accepted reporting standards.
A significant gap in the evidence is the lack of data around clinical endpoints, such as cardiovascular events. Adding these would increase the weight of the evidence, avoiding reliance on surrogate outcomes.
Given the methodological limitations demonstrated by the trials, there are some considerations for future trials. First, they should be adequately powered to allow for greater precision and estimate of long-term relatively rare events. Second, long-term follow-up should be considered to estimate clinically significant endpoints. And, finally, design and reporting of trials should follow the standards of the CONSORT statement.
Acknowledgements
This work was carried out as part of a MSc Advanced Practice (Nursing) at Edinburgh Napier University, which was funded by Burdett Trust for Nursing, grant no. 448.

Berberine and multiple sclerosis: moderation of demyelination

Berberine is beneficial for MS sufferers too by suppressing autoimmune responses according to a humanised mouse (ie murine) and other studies:

Luo et al (2017)42:

Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration.

MMP-9 is a matrix metalloproteinase. A proteinase can break down proteins into their constituent peptides or single amino acids, destroying extracellular matrix as part of normal physiological processes like wound healing. But MMP-9 has also been associated with several chronic inflammatory autoimmune diseases, including rheumatoid arthritis, Sjögren's syndrome, idiopathic uveitis, and systemic lupus erythematosus43. Ma et al (2010)44:

Background: Berberine, an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-inflammatory and neuroprotective effects. However, there are no reports about the effects and mechanisms of berberine in experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS).
Methodology/principal findings: Female C57 BL/6 mice immunized with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide were treated with berberine at the day of disease onset and medication was administered daily until mice were sacrificed. Blood-brain barrier (BBB) permeability and the alteration of matrix metalloproteinase-2 (MMP-2, 72 kDa) and matrix metalloproteinase-9 (MMP-9, 92 kDa) in the brain and cerebrospinal fluid (CSF) of EAE mice were detected by quantitative measurement for Evan's blue (EB) content, Western blot and gelatin zymography respectively. The results showed that berberine attenuated clinical and pathological parameters of EAE, reduced the permeability of BBB, inhibited the activity and expression of MMP-9 but not MMP-2 in the CSF and brain of EAE mice.
Conclusions/significance: These findings suggest that berberine is effective to attenuate the clinical severity of EAE in C57 BL/6 mice by reducing the permeability of BBB, decreasing the expression and activity of MMP-9, and decreasing the inflammatory infiltration. We think that berberine might be a potential therapeutic agent for MS.

Attenuation of the sphingosine kinase 1 (Sphk1) signalling pathway by berberine may also be beneficial for inhibiting tumorigenesis. Bao et al (2017)45:

Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.

Berberine and inhibition of amyloid toxicity

On May 17th ‘22 a paper was published by Sofie Nyström and Per Hammarström in the Journal of the American Chemical Society46 in which they had conducted an in vitro investigation into spike protein induced amyloidosis:

SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 spike protein (S-protein). Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates during incubation at 37 °C. Three 20-amino acid long synthetic spike peptides (sequence 192–211, 601–620, 1166–1185) fulfilled three amyloid fibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, and ultrastructural fibrillar morphology. Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 h of S-protein coincubation with the protease neutrophil elastase (NE) in vitro. NE efficiently cleaved S-protein, rendering exposure of amyloidogenic segments and accumulation of the amyloidogenic peptide 194–203, part of the most amyloidogenic synthetic spike peptide. NE is overexpressed at inflamed sites of viral infection. Our data propose a molecular mechanism for potential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.

In conclusion, we herein proposed a simple molecular mechanism for how SARS-CoV-2 S-protein endoproteolyzed by NE can form amyloidogenic S-peptides, such as segment 194–203, and lead to exposure of multiple amyloidogenic segments in proteolytically nicked S-protein.
It is possible that other amyloidogenic peptides and S-protein nicked by other proteases could be involved if this process occurs in vivo. We found that all common coronaviruses infecting humans contain amyloidogenic sequences (Figure S8A). Nonetheless, the magnitude of diverse COVID-19 symptoms was not previously reported. The segment 194–213 is unique for SARS-CoV-2 (Figure S8B) which, in combination with acute inflammation and neutrophil recruitment known to be more prevalent in COVID-19 compared to other viral infections, could explain the putative COVID-19 associated amyloid formation. It should be mentioned that amyloidosis is rather common in the elderly population and its associations with viral infections is a matter of discussion. Recent studies demonstrate that COVID-19 recovered patients have an increased risk of type II diabetes, an amyloid associated disease. While our study is limited to in vitro findings of pure preparations of peptides and proteins, the results propose taking S-protein amyloidogenesis into account when studying COVID-19 and long COVID-19 symptoms.

A working hypothesis by Walter Chesnut et al is that spike protein mediated amyloidosis contributes to much of the pathology from infection or transfection, and explains why embalmers are reporting finding many unusually large clots in the deceased.47

But do these fibrils arise spontaneously? It is well known that many illnesses, such as Alzheimer's, are preceded by a process where the body cuts up large proteins into smaller pieces, which can in turn produce the harmful amyloid. In their study, the researchers show that an enzyme from immune system's white blood cells can cut up coronavirus' spike protein. When the spike protein is cut up, it produces the exact piece of protein which, according to the researchers' analysis, is most likely to produce amyloid. This enzyme is released in large quantities from one type of white blood cells, neutrophils, which are released early on during infections such as COVID-19. When the researchers mixed pure spike protein with this enzyme, called neutrophil elastase, unusual fibrils were produced.
"We have never seen such perfect, but scary, fibrils as these ones from the amyloid-producing SARS-CoV-2 spike protein and pieces thereof. The fibrils starting from the full-sized spike protein branched out like limbs on a body. Amyloids don't usually branch out like that. We believe that it is due to the characteristics of the spike protein," says Per Hammarström, professor at the Department of Physics, Chemistry and Biology (IFM) at Linköping University.
Previous research, including a study by South African researchers, has indicated that the spike protein may be involved in the production of small blood clots. The blood contains the fibrin protein, which helps the blood to coagulate when a vessel is damaged, so that the hole seals again and stops bleeding. When the injury has begun to heal, the coagulate is supposed to be broken up by plasmin, which is also found in blood. The researchers at LiU mixed amyloid-producing protein pieces from the spike protein together with these bodily substances in test tubes, and saw that the fibrin coagulate which was then produced could not be broken down in the usual way by plasmin. This newly discovered mechanism may lie behind the production of similar micro blood clots that have been observed in both serious and long-term COVID-19. Disturbed blood coagulation is also seen in many amyloid-related illnesses.
"We can see that the spike protein, when affected by our own immune system, can produce amyloid structures, and that this can potentially affect our blood coagulation. We believe that this discovery is significant for many fields of research, and we hope that other researchers will examine the questions that it raises," says Sofie Nyström, who is an associate professor at IFM and the other author on the study.48

Drakos et al (2021) on coronary microvascular disease in COVID-19 patients49:

Recently, Rovas et al. performed intravital microscopy to quantify vascular density and glycocalyx dimensions in sublingual microvessels of hospitalized adult patients with moderate-to-severe or critical COVID-1917. Interestingly, COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries. In addition, several serum markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19 patients. Hence, the authors concluded that COVID-19 is accompanied by endothelial activation, glycocalyx damage, and severe capillary impairment and that COVID-19 might have a distinctive vascular phenotype. Obviously, the exact pathomechanism leading to reduced global MPR in post-COVID-19 patients in the present study is unclear. However, based on studies like that of Rovas et al. and previous studies addressing coronary physiology in case of viral myocarditis17–20, we speculate that (a) endothelial dysfunction with impaired vasomotility and reduced vasodilatory capacity of coronary resistance vessels, (b) rarefaction of coronary arterioles and capillaries in the myocardium and (c) microvascular obstruction due to the preceding prothrombotic milieu may play a major role for the occurrence of CMD in post-COVID-19 patients.

There are two key amyloidosis pathways that animal studies have shown may be suppressed by berberine. The first key one involves normalisation of the previously referred to neutrophil elastase (NE) levels - Tang et al (2017)50.

One must caution that animal studies may not translate to human studies, a sufficient dose of berberine may be a challenge and that previously induced tissue or nerve damage by amyloid plaques or fibrils may not be reversible. Dead myocardial tissue cannot regrow, but amyloidosis may be prevented in the first place on infection (or transfection even), or the rate of degeneration of brain or vital organs slowed. More research is urgently required on this subject.

The aim of the present study was to explore the protective effects of Berberine (BBR) against non-alcoholic steatohepatitis (NASH). Male 4-week-old C57BL/6J Apolipoprotein E-deficient (ApoE-/-) mice were divided into the following three groups, which were given different diets: Normal chow diet (SC group); high-fat high-cholesterol diet (HFHC group); and HFHC diet supplemented with BBR (BBR group). Serum biochemical indicators of hepatic function and histological liver tissue changes were evaluated. The expression of neutrophil elastase (NE) and genes involved in the inflammatory response was measured. ApoE-/- mice fed a HFHC diet for 12 weeks developed NASH, characterized by steatosis and liver inflammation. Body weight, and serum triglyceride and cholesterol levels were markedly reduced by BBR. BBR supplementation significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels in mice with HFHC diet-induced NASH, and significantly downregulated hepatic expression and activity of NE, whereas α1-antitrypsin (α1-AT) expression was significantly recovered by BBR (all P<0.05 vs. the HFHC group). Furthermore, treatment with BBR induced a significant reduction in the expression of key genes, including phospoinositide 3-kinase, nuclear factor-κB and interleukin-8, in the C-X-C chemokine receptor type 4 (CXCR4) signaling pathway (all P<0.05 vs. the HFHC group). These results suggest that BBR alleviates NASH in ApoE-/- mice fed a HFHC diet. Restoration of the balance of NE and α1-AT levels, which in turn facilitate the inhibition of the CXCR4 signaling pathways, may be involved in the hepatoprotective effect of BBR. These results indicate that BBR may be a candidate therapeutic agent for the treatment of NASH.

The second is inhibition of the cytochrome chain. Hernandez-Zimbron et al (2012)51 investigated the key part this plays in amyloidosis:

Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious effects on cellular functions. Mitochondria were found to be the target for amyloid-beta, and mitochondrial dysfunction is well documented in AD. In the present study we have shown for the first time that Aβ 1-42 bound to a peptide comprising the amino-terminal region of cytochrome c oxidase subunit 1. Phage clone, selected after screening of a human brain cDNA library expressed on M13 phage and bearing a 61 amino acid fragment of cytochrome c oxidase subunit 1, bound to Aβ 1-42 in ELISA as well as to Aβ aggregates present in AD brain. Aβ 1-42 and cytochrome c oxidase subunit 1 co-immunoprecipitated from mitochondrial fraction of differentiated human neuroblastoma cells. Likewise, molecular dynamics simulation of the cytochrome c oxidase subunit 1 and the Aβ 1-42 peptide complex resulted in a reliable helix-helix interaction, supporting the experimental results. The interaction between Aβ 1-42 and cytochrome c oxidase subunit 1 may explain, in part, the diminished enzymatic activity of respiratory chain complex IV and subsequent neuronal metabolic dysfunction observed in AD.

Rajasekhar et al (2020)52 published a paper on how a berberine derivative (Ber-D), which is less neurotoxic at high doses, is effective at inhibiting multifaceted amyloid toxicity by efficient copper ion chelation, which arrests the ROS generating cytochrome redox cycle:

Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity observed in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromolecules from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD.

Various attempts to use natural products or plant extracts to target AD have shown promising results. Natural products such as curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG) have been shown to effectively decrease the Aβ toxicity in the mice brain attributed to their antioxidant and anti-aggregation properties. EGCG, a bioactive ingredient of green tea, exhibits aggregation modulation, anti-inflammatory, antioxidant, and neuroprotective properties (Ehrnhoefer et al., 2008). In recent times, several other natural products like brazilin, luteolin, tanshinone, and apigenin have been evaluated to assess the modulation of Aβ toxicity (Wang et al., 2013, Du et al., 2015). One of the major limitations of using natural products as anti-AD candidates is their slow relief or sluggish therapeutic action, which is ineffective for the treatment of moderate and advanced stages of the disease. Moreover, some of the drawbacks such as very low natural abundance, poor solubility, cellular toxicity, instability, and most importantly lack of multifunctional efficacy in targeting multifaceted Aβ toxicity limit the use of natural products as anti-AD agents.

Berberine has been shown to interfere with pathological pathways of AD by enforcing a reduction in the levels of Aβ generation by inhibiting secretase enzymes involved in APP processing, ameliorating gliosis, delaying oxidative stress, and preventing neuroinflammation (Cai et al., 2016). Several modifications and functional groups incorporated to the berberine core and their activity against acetylcholinesterase and other aspects have been evaluated (Huang et al., 2010a, Huang et al., 2016, Huang et al., 2010b, Tsai and Lee, 2010, Shan et al., 2011, Zou et al., 2017). The use of berberine as a therapeutic candidate for AD is hampered by its cytotoxic nature at relatively higher concentrations (Kysenius et al., 2014). The absence of a clear safety profile remains a major concern, and various reports have shown that berberine causes an increase in oxidative stress and mitochondrial fragmentation or swelling, decrease in mitochondrial membrane potential (MMP), and depleted ATP production, ultimately leading to neuronal death (Mahmoudi et al., 2016, Singh and Sharma, 2018). Herein, we report Ber-D multifunctional modulator to effectively target multifaceted Aβ toxicity of AD. The simple deprotection of berberine phenolic groups has yielded polyphenolic Ber-D with improved solubility and cell viability compared with the parent natural product. The polyphenolic Ber-D exhibits significantly improved antioxidant, redox metal chelation, and anti-Aβ aggregation properties. The detailed in vitro and in cellulo studies show that Ber-D actively modulates multifaceted Aβ toxicity.

Cai et al (2018)53 conducted a study using simple berberine and APP/PS1 Transgenic Mice, which gave positive results:

Background: Berberine (BBR) has neuroprotective effects on many brain diseases, including Alzheimer's disease (AD). Amyloid -beta (Aβ) senile plaque is the most classical pathological hallmarks of AD. Aβ produces from a sequential cleavage by β-secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) and γ -secretase. The aim of our work was to investigate whether the neuroprotective effects of BBR on AD is related to inhibiting Aβ pathology.
Method: The cognitive function of mice was assessed by the Morris water maze (MWM) test. The Aβ levels were determined by enzyme linked immunosorbent assay; the expression of APP, sAPPα, ADAM10 and ADAM17, sAPPβ and BACE1 was detected by Western blotting; and the activity of γ -secretase complex (NCT, PS1, Aph-1α and Pen-2) was determined by Western blotting and immunohistochemistry.
Results: BBR improved learning and memory deficits of APP/PS1 mice. BBR decreased Aβ levels in the hippocampus of APP/PS1 mice. BACE1 and sAPP -β levels in the BBR-treated groups were significantly reduced in the hippocampus of AD mice. BBR markedly decreased the expression of PS1, Aph-1α and Pen-2, but had no effect on NCT. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of BBR-treated mice significantly increased, compared with the control ones (P<0.05).
Conclusion: BBR inhibits the activity of β/γ-secretases, enhances α-secretases, and lowers the Aβ level in the hippocampus of AD mice, and improves Alzheimer's-like cognitive impairment.

More research and potentially human clinical trials should be commenced forthwith to investigate whether berberin at normal doses or Ber-D at higher doses is safe and effective at inhibiting spike protein induced amyloidosis, thus hopefully reducing the associated surge in cardiovascular deaths & neurological injuries that is being witnessed daily and reported to VAERS and other countries’ surveillance systems.54

As an aside, there was an attempt to market an allopathic drug to treat amyloid beta in Alzheimer's disease sufferers by the name of “Aducanumab”, but it failed to meet even minimal targets for efficacy or safety and it has effectively been withdrawn55:

In their review, Alexander et al. indicate that Study 301 did not meet its primary end point of a reduction relative to placebo in the CDR-SB score.13 Additionally, no statistically valid conclusions could be reached for any of the secondary end points in this study as per prespecified plans. However, in Study 302, statistical significance was obtained on its primary end point, a treatment effect corresponding to a 22% relative reduction in the CDR-SB outcome for high-dose aducanumab when compared to placebo (p=0.01). However, in this study, the low-dose aducanumab group did not produce statistically significant effects when compared with placebo. Based on the prespecified analytic plan for the study, the ability to assess efficacy with respect to secondary outcomes in both the high-dose and low-dose groups was prohibited.

In February US life insurers reported an unprecedented surge in non-COVID related deaths, many of these were cardiovascular in nature56 and excess deaths data has remained elevated since. Transfection induced immunosuppression, as explored in my other Substacks, very likely contributed to the 18.7% surge in COVID deaths too in Q3 compared to Q2-21:

According to a report Wednesday in the Wall Street Journal, US life insurance companies saw nearly a 40 percent rise in death benefit claims in the third quarter of 2021 compared to the pre-pandemic baseline, the largest such increase (so far) in the coronavirus pandemic.
While claims for COVID-related deaths were expected to jump, and did so, up 18.7 percent over the pre-pandemic baseline, there was surprise at the sudden jump in non-COVID death claims, which rose even more, up 19 percent.

This surge correlates as follows57. Insurance actuaries in both Germany58 and the UK59 reported similar findings:

Berberine and a synergistic association with Ferulic acid

DiNicolantonio et al (2021)60 report on the antioxidant and anti-inflammatory effects of ferulic acid, a bacterial metabolite of anthocyanins associated with diets rich in these and long employed in Chinese cardiovascular medicine:

…recent studies indicate that physiologically relevant concentrations of ferulic acid can boost expression of Sirt1 at mRNA and protein levels in a range of tissues. Sirt1, a class III deacetylase, functions to detect a paucity of oxidisable substrate, and in response works in various ways to promote cellular survival and healthful longevity. Sirt1 promotes ‘cell cleansing’ and cell survival by boosting autophagy, mitophagy, mitochondrial biogenesis, phase 2 induction of antioxidant enzymes via Nrf2, and DNA repair—while inhibiting NF-kB-driven inflammation, apoptosis, and cellular senescence, and boosting endothelial expression of the protective transcription factor kruppel-like factor 2. A deficit of the latter appears to mediate the endothelial toxicity of the SARS-CoV-2 spike protein. Ferulic acid also enhances the activation of AMP-activated kinase (AMPK) by increasing expression and activity of its activating kinase LKB1—whereas AMPK in turn amplifies Sirt1 activity by promoting induction of nicotinamide phosphoribosyltranferase, rate-limiting for generation of Sirt1’s obligate substrate NAD+. Curiously, AMPK acts by independent mechanisms to potentiate many of the effects mediated by Sirt1. Hence, it is proposed that ferulic acid may exert complementary or synergistic health-promoting effects when used in conjunction with clinically useful AMPK activators, such as the nutraceutical berberine.

Some key complementary cell protective effects of Sirt1 and AMPK, as discussed earlier. AMPK, AMP-activated kinase; KLF2, kruppel-like factor 2; MB, mitochondrial biogenesis; NAMPT, nicotinamide phosphoribosyltransferase.

You will recognise that many of these are implicated in tumorigenesis if disrupted due to uncontrolled cell division.

FA is commonly found in commelinid plants (rice, wheat, oats, and pineapple), grasses, grains, vegetables, flowers, fruits, leaves, beans, seeds of coffee, artichoke, peanut and nuts [8], [47], [48], [49], [72], [85]. Cell walls (1.4% of dry weight) of cereal grains and a variety of food plants (pineapple, bananas, spinach, and beetroot) contains 0.5–2% extractable amount of FA, mostly in the trans-isomeric form, and esterified with the specific polysaccharides [21], [22], [23], [57]. Table 1 summarizes the content of FA in different known sources.61

Table 1

Content of ferulic acid in different known sources:

Source / Ferulic acid (mg/0.1 kg)

Bamboo shoots: 243.6

Water dropwort: 7.3–34

Eggplant: 7.3–35

Redbeet: 25

Burdock: 7.3–19

Soyabean: 12

Peanut: 8.7

Spinach/frozen: 7.4

Redcabbages: 6.3–6.5

Tomato: 0.29–6

Radish: 4.6

Broccoli: 4.1

Carrot: 1.2–2.8

Parsnip: 2.2

Mizuna: 1.4–1.8

Pot grown basil: 1.5

Chinese cabbage: 1.4

Pot grown lettuces: 0.19–1.4

Green bean/fresh: 1.2

Avocado: 1.1

Grapefruit: 10.7–11.6

Orange: 9.2–9.9

Banana5.4

Berries: 0.25–2.7

Rhubarb: 2

Plum, dark: 1.47

Apples: 0.27–0.85

Sugar-beet pulp: 800

Popcorn: 313

Whole grain rye bread: 54

Whole grain oat flakes: 25–52

Sweet corn: 42

Pickled red beet: 39

Rice, brown, long grain parboiled: 24

Coffee: 9.1–14.3

Boiled spaghetti: 13.6

Pasta: 12

White wheat bread: 8.2

Another study on synergistic associations of berberine and an important anti-cancer chemotherapeutic agent called cisplatin was conducted by Liu et al in 201962.

Cisplatin helps suppress cancer by inducing DNA damage and causing cell apoptosis, but its efficacy when used alone can be limited in some cases due to resistance63.

Results
Our results demonstrated that BBR significantly inhibited the proliferation of OVCAR3 and primary ovarian cancer cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP had a prominent inhibitory effect on cancer cell growth and induced G0/G1 cell cycle arrest. TEM revealed that the majority of cells after BBR or DDP treatment had an increasing tendency of typical apoptotic and necrotic cell death morphology. Besides, BBR and DDP inhibited the expression of PCNA and Ki67 and enhanced the expression and activation of Caspase-3, Caspase-8, RIPK3 and MLKL.
Conclusion
This study proposed that the combination therapy of BBR and DDP markedly enhanced more ovarian cancer cell death by inducing apoptosis and necroptosis, which may improve the anticancer effect of chemotherapy drugs. The apoptosis involved the caspase-dependent pathway, while the necroptosis involved the activation of the RIPK3–MLKL pathway. We hope our findings might provide a new insight for the potential of BBR as a therapeutic agent in the treatment of ovarian cancer.

Bioavailability and dosing guidance

Berberine chloride (BER) is an antineoplastic phytomedicine that combat non-Hodgkin lymphoma. BER suffers from low oral bioavailability due to p-glycoprotein efflux and first-pass metabolism. Lymphatic drug targeting recently gained a profound attention due to circumventing hepatic first-pass metabolism and targeting lymph diseases.64

Berberine has most often been used by adults in doses of 0.4-1.5 grams by mouth daily for up to 2 years. Berberine has also been used in eye drops and gels. Speak with a healthcare provider to find out what type of product and dose might be best for a specific condition.

High blood pressure. Taking 0.9 grams of berberine by mouth daily along with the blood pressure-lowering drug amlodipine reduces blood pressure better than taking amlodipine alone in people with high blood pressure.65

Silymarin is also known as milk thistle and can increase the bioavailability of berberine:

The present findings suggest that the coadministration of berberine and silymarin is associated with an advantageous improvement in lipid and glucose profile, suggesting the possible use of this nutraceutical combination in order to promote the cardiometabolic health.66

Quercetin also improves bioavailability and efficacy when using berberine as an anti-cancer therapeutic. From Quercetin as Natural Bioavailability Modulator: An Overview by Bhimanwar et al (2020)67:

% CDR = % cumulative drug release.

Quercetin and Berberine:
Sarika Narade et.al. (2019) investigated the permeability characteristics of berberine chloride alone and in presence of bioenhancer quercetin on goat intestine using Franz diffusion cell. A full factorial design approach was employed for investigation. The effect of quercetin on permeability of Berberine was examined at three different concentrations (2, 6, and 10 mg) with different levels of pretreatment time (30, 45, and 60 minutes). Results showed the dose dependent positive effect on % CDR and detrimental effect of increase in pretreatment time by quercetin on % CDR. In vitro anticancer activity of optimized batch demonstrated non-significant effect as compared with parent drug. In conclusion, quercetin could be successfully utilized as bioenhancer to improve ex vivo permeability of berberine chloride, which would be expected to improve its bioavailability and reduce the dose resulting in improved patient compliance.

Extracts from the cited research by Narade et al is worthy of inclusion here too68:

The % CDR was decreased with increase in pretreatment time of quercetin (Table 6). Optimized batch was obtained when goat intestine was pre-treated with quercetin10 mg for 30 minutes giving maximum % CDR of 90.91% ± 1.66%, while minimum value of 17.45% ± 2.12% was obtained at 2 mg quercetin pretreated for 60 minutes as compared with berberine chloride alone (control) which has only 8.49% ± 1.45% CDR. Therefore, increased permeability of berberine chloride during pre-treatment study with quercetin might have resulted from the quercetin, which inhibited the efflux pump P-gp. Briefly, inhibition of efflux pump P-gp by quercetin might be duly responsible for permeability enhancement of berberine chloride.
However, no significant improvement in the in vitro anticancer activity of optimized batch was observed as compared with drug berberine chloride. It was previously reported that quercetin and berberine inhibit survivin and STAT 3 expression (which are responsible for cancer development) and reduce cell viability of gastric cancer cells in a dose-dependent manner. As survivin and STAT 3 are present in lung, leukemia and cervical cancer cells also (Chen et al., 2007; Shukla et al., 2010; 2013; Yoshiyasu et al., 2003), it was observed that berberine showed a strong antisurvivin activity at relatively low doses as compared with quercetin which was found to inhibit survivin and STAT 3 expression only at high concentrations (Pandey et al., 2015). In our study, the concentration of quercetin in the optimized batch was equal to that of berberine chloride. Thus, dose difference might be responsible for non-significant in vitro anticancer activity of optimized batch. As in different types of cancers, constitutive activation of STAT3 and expression of survivin have been widely reported, their linkage may extend to many malignancies and be critical to their pathogenesis (Yoshiyasu et al., 2003).
CONCLUSION
In the present investigation, application of 32 full factorial design approach resulted in rational optimization of PreB3 batch during permeability studies of berberine chloride in presence and absence of bioenhancer quercetin. Based on these data, it could be suggested that 10 mg of quercetin for 30 minutes pretreatment time was optimum to increase the permeability of poorly permeable berberine chloride up to a maximum of 90.91% ± 1.66% CDR. However, anti-cancer cell line studies showed non-significant in vitro anticancer activity of optimized batch as compared with parent drug. It could be concluded that the use of quercetin as a bioenhancer would be beneficial for pretreatment to enhance the permeability and bioavailability of the naturally occurring anticancer drug berberine chloride.

One brand of berberine is sold in combination with medium chain triglycerides (MCT’s) & capric acid to assist absorption. Shout-out to https://gab.com/smallervoice for their input.

In practice, comparatively large doses are taken to compensate for poor absorption in comparison to Ivermectin (12mg daily)69:

Human and animal research suggests that 1500mg of berberine, taken in three doses of 500mg each, is equally effective as taking 1500mg of metformin or 4mg glibenclamide, two pharmaceuticals for treating type II diabetes. Effectiveness was measured by how well the drugs reduced biomarkers of type II diabetes.
What are berberine's side-effects and drawbacks?
Berberine has a high potential to interact with medications, and some interactions may be severe. It is generally safe in normal doses, but more long-term research on its safety is needed. Gastrointestinal upset can occur when high doses are used, and due to its ability to reduce blood sugar, it may increase the risk for hypoglycemia in high doses, though this isn't a common occurrence.
Is berberine safe to take?
Tentatively, yes, but a doctor's guidance is highly recommended. Berberine has been the subject of much research and seems to be potent like many pharmaceuticals, but unlike the most well-researched pharmaceuticals, its long-term safety and frequent adverse effects haven't been sufficiently evaluated.70

Berberine has many pharmacological effects, such as antidiabetic, antimicrobial, anti-inflammatory, and antioxidant, but the question remains on how its low oral bioavailability has greatly limited its clinical application. As a safer hypoglycemic agent, we must evaluate the bioavailability of berberine organic acid salts (BOAs) to ensure that the bioavailability of berberine is not negatively affected. It has been proven that the bioavailability of BOAs is higher than that of BH (berberine hydrochloride); especially BF (berberine fumarate) and BS (berberine succinate), which are improved by 1.278-fold and 1.313-fold, respectively. After 1 h of oral administration, berberine mainly acted on the stomach of mice, it also influenced the liver, kidney, lungs, and intestines after 4 h. The accumulation of BF in the lung is more evident than BH. Our analysis shows that these results are closely related to the regulation of organic acids and berberine in the intestinal tract, they also indicate the influence of intestinal flora on berberine metabolism.71

Plasma concentration profiles of berberine hydrochloride (BH) and organic acid salts (BOAs). Mice were treated with intragastric administration of 500 mg/kg BH and BOAs. BF, berberine fumarate; BM, berberine malate; BS, berberine succinate and BC, berberine citrate. (n = 5).

After 4 h of administration, the organ imaging map of nude mice. Mice were treated with intragastric administration of distilled water (A,D), 500 mg/kg berberine fumarate (BF; B,E), and berberine hydrochloride (BH; C,D). (A–C) are the heart, liver, lung, and kidney of nude mice. (D–F) are the intestinal tract of the nude mice, including the small intestine, cecum, and rectum. Exposure time was 5 s, central wavelength 470 nm.

In appearance, purer forms of extracts are yellow-gold in appearance, frequently taken in capsule form.

Flavonoid>flavus, from the Latin for yellow.

On the tip of the tongue it tastes extremely bitter.

Berberine Powder 100% Natural Coptis Chinensis Extract Berberine Hcl Hydrochloride Powder - Buy Berberine Hydrochloride,Coptis Chinensis Extract, Berberine Hcl Powder Product on Alibaba.com

Conclusion

Bioavailability is an issue, but it has been overcome by using nanomedicines, higher doses, adjuncts or by compounding as organic acids. Due to its many varied therapeutic roles, with an acceptable side effect profile for the majority, and especially in the current public health emergency where the need for effective, legal, and especially safe antivirals has never been higher I would consider berberine a “super therapeutic”.

Further studies are warranted but berberine could arguably be rated alongside ivermectin, hydroxychloroquine and fluvoxamine etc in importance for the treatment of those infected by COVID-19 variants, especially if late in the viral course with higher viral loads.

The other many potential health benefits are worthy of attention in their own right.

Thank you for reading, please share if you find this review useful.

Disclaimer

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.

DNA Mutation Comic - Science with The Amoeba Sisters

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Mateus, M. Life insurance companies report a sudden rise in non-COVID-related deaths.

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https://www.wsws.org/en/articles/2022/02/24/life-f24.html

US Coronavirus vaccine tracker (15th May ‘22)

https://usafacts.org/visualizations/covid-vaccine-tracker-states/

Mehr Impf-Nebenwirkungen als bisher bekannt (2022)

https://www.welt.de/politik/deutschland/plus237106177/Coronavirus-Impf-Nebenwirkungen-deutlich-mehr-als-bisher-bekannt.html

UK suffers record period of 'excess' mortality (15th Dec ‘21)

https://www.theactuary.com/news/2021/12/15/uk-suffers-record-period-excess-mortality

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BERBERINE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews

https://www.webmd.com/vitamins/ai/ingredientmono-1126/berberine

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https://www.bibliomed.org/mnsfulltext/19/19-1538762765.pdf?1672940331

Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, Phru CS, Rahman M, Zaman K, Somani J, Yasmin R, Hasnat MA, Kabir A, Aziz AB, Khan WA. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2021 Feb;103:214-216. doi: 10.1016/j.ijid.2020.11.191. Epub 2020 Dec 2. PMID: 33278625; PMCID: PMC7709596.

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https://examine.com/supplements/berberine/

Cui HX, Hu YN, Li JW, Yuan K, Guo Y. Preparation and Evaluation of Antidiabetic Agents of Berberine Organic Acid Salts for Enhancing the Bioavailability. Molecules. 2018 Dec 28;24(1):103. doi: 10.3390/molecules24010103. PMID: 30597911; PMCID: PMC6337101.

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DoorlessCarp’s Scientific Literature Reviews

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