Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, Paper Pub. 4/1/20 - Dr. Prusty

bread.

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I dont know whether this is OT or not.
https://www.sciencedirect.com/science/article/pii/S075333222030024X
The protective effect of cordyceps sinensis extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway
Abstract
Cerebral ischemia is a common refractory brain disease, resulting from a reduction in the blood flow to the brain. Mitochondrial dysfunction leads to ischemic stroke and brain injury. Cordyceps sinensis (CS) is an important traditional Chinese medicine, which has been linked to neuroprotection in recent studies. In this study, we investigated the role of the mitochondrial respiratory chain and the mitochondrial apoptotic pathway on the protective effect of Cordyceps sinensis extract (CSE) against cerebral ischemia injury both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) model, administration of CSE relieved neuronal morphological damage and attenuated the neuronal apoptosis. CSE also reduced neurobehavioral scores and oxygen free radical (OFR), while improving the levels of ATP, cytochrome c oxidase (COX), and mitochondrial complexes I-IV. Furthermore, the mRNA expression of Bax, cytochrome c (Cyt c) and caspase-3 were down-regulated. In brain microvascular endothelial cells (BMECs) exposed to oxygen and glucose deprivation (OGD), CSE prevented OGD-induced cellular apoptosis, and recovered the reduction of mitochondrial membrane potential (MMP). Moreover, CSE treatment induced an increase of Bcl-2 protein expression and a decrease of Bax, Cyt c and caspase-3 protein expression. Meanwhile, the caspase-3, -8, and -9 activities were also inhibited. The results indicate that CSE can relieve cerebral ischemia injury and exhibit protective effects via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway.

I had to go off cordyceps sinensis for the past 45 days due to lockdown. But I received it a week ago and I started taking one capsule initially (Now Foods Cordyceps 750 mg) and then increased it to the recommended 2 capsules and withing 2 hours my energy levels went from 10 % to 50 % both physical and mental. I have been taking cordyceps sinensis for the past 6 years and it has been a great help. From bedbound it has made me home bound with some outside activity. My HUA (Hours upright active) also has gone up from 2 to almost 8 hrs. I prefer Planetary Herbals Cordyceps 450 Full spectrum. But since I could not get it I tried Now Foods and it is also good. Planetary Herbals form has calcium 50 mg which some might not prefer.

It reduces brain fog by 90 % in me. It also has completely eliminated joint pains due to food allergies.

hard to believe, but will try.
 

ZeroGravitas

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The results indicate that CSE can relieve cerebral ischemia injury and exhibit protective effects via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway.
So it promotes oxidative phosphorylation and perhaps prevents mitochondrial fragmentation (?), or something else to discourage cell death...? Opposite to the HHV-6 reactivation effects.

Is this the same substance that was seen in this other recent study, that sounds potentially handy for my pathological sleep pattern [Sciencemag | via Non-24-hour Sub-Reddit]:
They found that the adenosine derivative cordycepin shifted the circadian phase by 12 hours in human cells in vitro and mouse cells ex vivo and accelerated clock acclimation in a mouse model of jet lag.
 

raghav

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Planetary Herbals Cordyceps sinensis Full spectrum label states Contains Adenosine 0.1% equivalent. Maybe this is important. I tried the pure CS-4 variety and it did not give me any energy only the full spectrum which has both CS-4 and Full spectrum.
 

godlovesatrier

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Herbalist Stephen Buhner recommends cordyceps (amongst 5 other herbs) for chronic fatigue and it does absolutely work. However like all adaptogens it will send you up but ultimately just masks the issue and can cause severe anxiety or a worsening of symptoms. However all adaptogens give you a solid boost as opposed to a quick boost which ultimately brings you right back down again. Now if you can actually deal with the side effects then those adaptogens are brilliant. So I am not surprised cordyceps has an effect. However very few people with ME can deal with them.

I'm currently taking siberian ginseng again because for the last 8 months I haven't been able to lift my body out of a lower than normal "state". At any rate if I can deal with the side effects taking this stuff is brilliant for covid-19 as it will slam right into it.
 

raghav

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Cordyceps does not eliminate PEM but considerably minimizes fatigue as long as you pace your day to some extent. It does not cause wired state or aggravate insomnia, at least not in my case. I am also taking Ashwagandha, Rhodiola, Bacopa, Jarrow shilajit. Together they seem to offer the best synergy in my specific case. Adaptogens are a must try for everybody.
 

stefanosstef

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Cordyceps does not eliminate PEM but considerably minimizes fatigue as long as you pace your day to some extent. It does not cause wired state or aggravate insomnia, at least not in my case. I am also taking Ashwagandha, Rhodiola, Bacopa, Jarrow shilajit. Together they seem to offer the best synergy in my specific case. Adaptogens are a must try for everybody.

What do you think shilajit adds to this?I have it and occasionaly take it but I can pinpoint what it does, it's just a feeling that it is good, possibly placebo.
 

raghav

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https://www.jarrow.com/product/579/Shilajit_Fulvic_Acid_Complex
What Does Shilajit Fulvic Acid Complex Do?
Jarrow Formulas® Shilajit Fulvic Acid Complex is a purified and standardized extract containing no less than 60% fulvic acid complex with high levels of combined dibenzo-α-pyrones and dibenzo-α-pyrone chromoproteins. These special compounds are active in the mitochondrial electron transport chain. Shilajit Fulvic Acid Complex works with Co-Q10 in the mitochondria and boosts energy production in brain and muscle tissues during exercise.*
 

Learner1

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I have gotten lab analysis for 2 high quality fulvic acid products, one from Asia and one sourced in Canada. Both had mold and heavy metal contamination. Have you asked Jarrow for a lab analysis?

I may have gotten some positive effect when I tried it, but wasn't as convinced it helped as much as the other things I've been doing for my mitos
 
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If the issue is partially reactivated HHV6 - specifically called out by Prusty as the HHV6 IE protein p41 [1] - then there is one drug that can inhibit this early/partial reactivation cycle. Artesunate was studied as one of the only known inhibitors of early and late stage HHV6 replication in vitro [2] - and the good news is that it has potent inhibitory activity within the safe micromolar range of 1.5μM. The problem is this seems to be the only study showing Artesunate can inhibit early/partial HHV6 activation + it was done in vitro only. I tweeted this at Prusty, who liked the tweet, so hopefully we get some follow up studies over the following years. Artesunate treatment has been tried in ME/CFS as one-off therapies with inconclusive results (no formal studies, just anecdotes), but I would imagine it would take months of daily treatments to see results - which may push the safety profile of Artesunate, which is generally safe for short term usage.


[1]: HHV-6 P41, an IE viral protein that has been implicated during the early phases of viral replication, was detected upon TSA treatment (Fig. 1D), supporting our previous data (15). At the same time, viral protein U94 was not detected after 48 h of TSA treatment (Fig. 1D), which demonstrates that virus reactivation was incomplete. We have also previously shown lack of U94 transcription upon HHV-6A reactivation in U2-OS cells by transcriptomics studies (15). Thus, our results show that partial reactivation of HHV-6A is enough to induce mitochondrial fragmentation that leads to lower ATP content in the cells accompanied by lower innate immune response.
[2]: Levels of early protein p41/38 were diminished by ART treatment below the detection limit, while a cellular control protein (β-actin) showed only marginal alterations (Fig. 2A). The reference drug GCV (an inhibitor of viral DNA replication) at a concentration of 15 μM did not show a similar degree of inhibition of early p41/38 (Fig. 2A, lanes 7–8).
 

junkcrap50

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but I would imagine it would take months of daily treatments to see results - which may push the safety profile of Artesunate, which is generally safe for short term usage.
What are the safety concerns for long term use? Are the concentrations used in the study achievable in tissue in vivo?
 
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What are the safety concerns for long term use? Are the concentrations used in the study achievable in tissue in vivo?

1) Outside of the use of Artesunate for malaria, there isn't much data on long term use. There was one long term compassionate use study for patients with breast cancer - it reported a very low occurrence of adverse events over four weeks. Higher doses (150mg+ daily) saw some patients develop neutropenia, anemia, and gastrointestinal side effects that resolved upon discontinuation.

2) Yep, according to this paper comparing pharmakinetics of oral vs IV Artesunate, 100mg oral Artesunate reaches many times the inhibitory threshold defined in the paper I linked to above. The problem is that Artesunate has a very short half life (largely metabolized within 2hrs), which is fine for treating parasites, but not so great as an antiviral. The metabolite of Artesunate is largely thought to be the reason behind the primary side effects / adverse events.
 

Learner1

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Artesunate was studied as one of the only known inhibitors of early and late stage HHV6 replication in vitro [2] - and the good news is that it has potent inhibitory activity within the safe micromolar range of 1.5μM. The problem is this seems to be the only study showing Artesunate can inhibit early/partial HHV6 activation + it was done in vitro only. I tweeted this at Prusty, who liked the tweet, so hopefully we get some follow up studies over the following years. Artesunate treatment has been tried in ME/CFS as one-off therapies with inconclusive results (no formal studies, just anecdotes), but I would imagine it would take months of daily treatments to see results - which may push the safety profile of Artesunate, which is generally safe for short term usage.
Levels of early protein p41/38 were diminished by ART treatment below the detection limit, while a cellular control protein (β-actin) showed only marginal alterations (Fig. 2A). The
What are the safety concerns for long term use?
Artesunate depolarizes the mitochondrial membrane via generation of reactive oxygen species which disrupt the electron transport chain.

Additionally, in vitro studies demonstrate that artesunate induces DNA breakage in a dose-dependent manner. Artesunate has also been shown to stimulate cell differentiation, arrest the cell cycle in the G1 and G2/M phases, inhibit cell proliferation, and induce apoptosis through mitochondrial and caspase signaling pathways.
 

Learner1

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Artesunate has been successful at killing cancer cells, which have defective mitochondria. It also has been shown antiviral properties against Epstein Barr, etc.

I had several treatments of it with my cancer treatment and then later to try to tackle HHV6 and my other herpes family viruses. It may have helped me beat the cancer, but it didn't help me beat the herpes viruses, and I question whether or not it may have caused trouble for my mitochondria.
 
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Artesunate has been successful at killing cancer cells, which have defective mitochondria. It also has been shown antiviral properties against Epstein Barr, etc.

I had several treatments of it with my cancer treatment and then later to try to tackle HHV6 and my other herpes family viruses. It may have helped me beat the cancer, but it didn't help me beat the herpes viruses, and I question whether or not it may have caused trouble for my mitochondria.

Yep - Artesunate makes a great anti-malarial, but a terrible antiviral due to its pharmakintetics. It's also highly reactive, without being very specific - so not a great clinical option. Research-wise it's an interesting avenue to explore how and why it inhibits early/partial HHV6 replication, since it is one of the few compounds that has been shown to do so. Unfortunately it seems like most drugs that can interfere with HHV6 are fairly toxic to some degree - ganciclovir also has its fair share of (sometimes severe) toxicity problems.

You do bring up an open question around artesunate that researchers are still figuring out - why is artesunate seemingly so toxic, yet clinically has been generally safe? The discussion section of this paper is fairly interesting in that it tries to answer some of that question. The highly complex interactions that artesunate has with intracellular iron seems to explain a lot about why it behaves paradoxically in some cases - but that's tangential to this thread :)
 

Learner1

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Artesunate is a great cancer killer, but not a great antiviral. It may be relatively safe in some settings, but its complex interactions can produce unexpected results, as I believe I may have experienced.

I found valganciclovir to be much safer and more effective for my HHV6.
 
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