quercetin and hydroxychloroquine

This post is exploring possible synergy between hydroxyc.hloroaquin and quercetin.

Hydroxychloroquin for autoimmune disorders

lysosome function as mentioned in terms PubMed annotates. Of the close to 3000 PubMed entries for chloroquine+Covid-19 53, a search for chloroquine+Covid-19+lysosme yielded 53 publications. Hydroxychloroquine dampens the acidification of the lysosome as a mechanism of action for treatment of the malaria parasite, which requires this acidification for part of its life cycle. [1] Autoimmune disorders involved degradation of self antigens and the presentation of these self peptides to immune cells. The notion has arisen that if the pH of lysosomes is increased, less self antigen peptides will be presented. Other mechanisms may be involved in the use of hydroxychloroquin for auto imune conditions.

Some mutations in the CLCN gene family cause a “gain in function” of the CIC Cl^–/H⁺ anti porter in which the pH in the lysosome becomes too acidic for hydrolase enzymes to function. Use of chloroquine or hydroxy chloroquine makes sense.

Doses of hydroxy dhloroquine used in autoimmune diseases

Indication	Dose	title of publication
Malaria (acute)	800 mg followed by 400 mg at 6, 24, and 48 h	CDC guidelines
Rheumatoid arthritis	400–600 mg/day	Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial
SLE	200–400 mg/day	A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.
Palindromic rheumatism	200–400 mg/day	Palindromic rheumatism: a response to chloroquine.
Eosinophilic fasciitis	400 mg/day	osinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases.
Dermatomyositis	400 mg/day	Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine.
Sjögren’s syndrome	6–7 mg/kg/day	Treatment of primary Sjogren’s syndrome with hydroxychloroquine: a retrospective, open-label study.
Porphyria cutanea tarda	250–500 mg/week	Low-dose oral chloroquine in patients with porphyria cutanea tarda and low–moderate iron overload
Polymorphous light eruption	200–400 mg/day	Hydroxychloroquine in polymorphic light eruption: a controlled trial with drug and visual sensitivity monitoring
Granuloma annulare	2–9 mg/gk/day	Treatment of generalized granuloma annulare with hydroxychloroquine.
Lichen planus	200–400 mg/day	ydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial.
Lupus panniculitis	200–400 mg/day	Lupus panniculitis treated by a combination therapy of hydroxychloroquine and quinacrin
Discoid lupus	400 mg/day	Drugs for discoid lupus erythematosus.

What is quercetin doing for lysosomes?

This question was asked in a proximal tenal tubule cell culture model. [2] The proximal tubule absorbs a lot of protein that get filtered through the glomerulus. Some of these proteins, like serum albumin, are degraded by the lysosoms. Fluorescent probe tagged bovine serum albumin was used in assays to detect lsysosome degradation in this study. [2] The heavy metal cadmium is known to be particularly toxic to the renal proximal tubule epithelial cells.

Many figures in this publication examined the ability of 2.5 μM cadmium (Cd) and 1 μg/ml quercetin (Qu) alone, together, and completely absent in the renal proximal tubule cell control. In most cases Qu alone increased lysosomal parameters above the control levels. The largest “take home” message from this study is Qu increases the activity of the TFEB transcription factor that is responsible for producing the cathepsin proteases the ATP61A and ATP61D ATP driven H⁺ pumps that acidify the lysosomes by pumping in H⁺.

TFEB and the FACT complex, life is complicated [3]

The FAcilitates Chromatin Transcription (FACT) complex is a histone chaperone previously implicated in transcription initiation and elongation. Making transcripts of genes is not just about sitting on an upstream regulatory element and waiting for RNA polymerase. It is also about getting the DNA containing the gen off the histone. A recent NIH publication appearing in the journal Autophagy used a technique called mass spectrometry to identify TFEB binding partners as it translocates to the nucleus to activate transcription of lysosome genes. The authors used two different cell lines and two different stressors: oxidative and starvation. The NIH authors identified at least several dozen known and new proteins that interact with TFEB and the FACT complex.

Oxidative stress genes under FACT/TFEB control

These same authors used silencing RNA o knock out the FACT complex. Incubation with sodium aresenite NaAsO₂ (50 μM) for 6 h was used to generate oxidative stress. Figure 5A The FACT complex promotes TFEB-dependent expression of oxidative stress genes as measured by relative quantitative real-time PCR analysis

• PPARGC1A
• FOXO3
• HIF1A
• MAFF
• MAFG
• HMOX1
• PYROXD1
• TXNRD1
• SRXN1
• ADNP2
• SESN2

starvation controlled transcripts

Starvation was induced by These are the transcripts under TFEB/FACT control:

• ATP6V1C1 proton pumps
• ATP6V0D1
• CTSD, cathepsin D a proteolytic enxyme
• HEXA
• LAMP1 lysosomal associated membrane protein 1
• MCOLN1, also known as TRPML, a calcium export channel
• CLCN7 the CIC7 Cl-/H+ antiporter
• SLC38A9, amino acid transporter, uses internal H⁺ gradient to transport amino acids out
• NPC2 exports LDL cholesterol from lysosomes
• RRAGC
• WDR59
• NPRL3
• DEPDC5
• SEC13

Note that many of these genes code for lysosome proteins.

A literature search of Quercetin clinical trials

This table gives some ideas of doses of quercetin used in clinical trials. Only a few autoimmune type conditions were found on PubMed. The real interest seems to be in the treatment of exercise induced muscle damage.

condition	dose	title of publication
rheumatoid arthritis	500mg/day	The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial PubMed
llichen planus	250mg/day	A Randomized Placebo-controlled Double Blind Clinical Trial of Quercetin for Treatment of Oral Lichen Planus Pub Med
10km race muscle damage	140 mg	Supplementation with a Mango Leaf Extract (Zynamite®) in Combination with Quercetin Attenuates Muscle Damage and Pain and Accelerates Recovery after Strenuous Damaging Exercise PubMed
mysocardial infaction	500mg/day	Effects of quercetin supplementation on inflammatory factors and quality of life in post-myocardial infarction patients: A double blind, placebo-controlled, randomized clinical trial PubMed
student athletes	500mg/day	The effects of quercetin supplementation on body composition, exercise performance and muscle damage indices in athletes PubMed
exercise induced muscle damage	200mg/day	Does quercetin and vitamin C improve exercise performance, muscle damage, and body composition in male athletes? PubMed
badminton muscle damage	1000mg/day	Effect of eight weeks of quercetin supplementation on exercise performance, muscle damage and body muscle in male badminton players PubMed

Is mixing quercetin and chloroquine a a bad thing? [2,4]

In their renal proximal tubule cell culture system Zhao and coauthors treated rPT cells with 1 μg/ml quercetin for 9 h and then with with 50 μM chlroquine for another 3 h. [2] This was just a trick for measuring levels of light chain 3, LC3 that may get degraded when the phagosome fuses with the lysosome. A Korean group found that ramping up the authophagy flux in glioma cells followed by inhibition of acidification of lysosomes with chloroquine caused “authophagic catastrophe.” The mitochondira and endoplasmic reticulum were also effected.

Given the strong evidence that quercetin stimulates autophagy, it is probably better not to mix quercetin and chloroquine/hydroxychloroquine. It might be best to test them both individually under the supervision of a medical professional. One would think that gain of function CIC7 that over acidifies the lysosome can be compensated by over active SLC38A9 that uses H⁺ to export amino acids from the lysosome.

References

1. lBen-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012 Apr;42(2):145-53. PMC free paper
2. Zhao Y, Li ZF, Zhang D, Wang ZY, Wang L. Quercetin alleviates Cadmium-induced autophagy inhibition via TFEB-dependent lysosomal restoration in primary proximal tubular cells. Ecotoxicol Environ Saf. 2021 Jan 15;208:111743. PMC free paper
3. Jeong E, Martina JA, Contreras PS, Lee J, Puertollano R. The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3. Autophagy. 2022 Oct;18(10):2333-2349. PMC free article
4. Jang E, Kim IY, Kim H, Lee DM, Seo DY, Lee JA, Choi KS, Kim E. Quercetin and chloroquine synergistically kill glioma cells by inducing organelle stress and disrupting Ca²⁺ homeostasis. Biochem Pharmacol. 2020 Aug;178:114098. PubMed