PCA in the Literature

PCA is truly an amazing potential therapeutic reagent. The following are publications from the scientific literature supporting and proposing many and varied therapeutic applications.

The pathophysiology of COVID 19 is vasculitis everywhere and clinically manifests as pneumonia.

COVID19 is now understood to be a disease of the blood vessels attacking the vascularity.  We have copied quotes, but you may review each in its entirety.

“COVID-19 and vascular disease.” EBioMedicine vol. 58 (2020): 102966. doi:10.1016/j.ebiom.2020.102966.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally characterized as a novel respiratory coronavirus and was thought to primarily target pulmonary tissues in infected patients, similar to its close relative SARS-CoV, which was responsible for the epidemic of SARS in 2003. This preconception turned out to be an underestimation. Although SARS-CoV-2 does indeed infect pulmonary epithelial cells, it might also infect many other cell types, causing systematic inflammation with the cytokine release and affecting multiple critical organs besides the lungs in severe cases.

In some patients, SARS-CoV-2 appears to attack the cardiovascular system, causing numerous cardiovascular complications. Back in January 2020, clinicians from Wuhan (Hubei, China) reported myocardial injury in patients with COVID-19 in a study published by The Lancet. In another study, published in The Lancet Respiratory Medicine on February 17, researchers observed interstitial mononuclear inflammatory infiltrates in the heart tissue of a deceased patient with COVID-19. Furthermore, myocardial damage and heart failure have been reported to contribute to causes of death that were linked to COVID-19 complications. In addition to inducing an overreactive inflammatory response, recent studies have shown that SARS-CoV-2 might also directly attack vascular endothelial cells and disrupt vascular barrier, leading to disseminated intravascular coagulation and inflammatory cell infiltration. As our understanding of the disease pathology improves, evidence is emerging that vascular pathology could have a substantial role in COVID-19 disease outcome.

Siddiqi HK, Libby P, Ridker PM. COVID-19 – A vascular disease. Trends Cardiovasc Med. 2021;31(1):1-5. doi:10.1016/j.tcm.2020.10.005

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to multi-system dysfunction with emerging evidence suggesting that SARS-CoV-2-mediated endothelial injury is an important effector of the virus. Potential therapies that address vascular system dysfunction and its sequelae may have an important role in treating SARS-CoV-2 infection and its long-lasting effects.

Michael Kalafatis, COVID-19: A Serious Vascular Disease with Primary Symptoms of a Respiratory Ailment, The Journal of Applied Laboratory Medicine, Volume 6, Issue 5, September 2021, Pages 1099–1104, https://doi.org/10.1093/jalm/jfab084

Approximately 18 months ago, the first US case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection was reported in Seattle, WA (1). Since then, the heavy casualties of the infection stimulated worldwide collaborations to understand and find early treatments for the disease(s) induced following the virus infection. Nearly 700 000 viral nucleotide sequences were deposited in the National Center for Biotechnology Information database, almost 4 million people died following infection worldwide according to the Center for Systems Science and Engineering at Johns Hopkins University, and the resulting disease was named Coronavirus Disease-2019 (COVID-19). The airborne virus specifically binds the Angiotensin-Converting Enzyme 2 (ACE2) receptor found on most cells in the human body (2, 3). ACE2 is a carboxypeptidase and the major down regulator of the concentration of angiotensin II, promoting the increased concentration of the vasodilator, Angiotensin peptide 1-7 that is responsible for optimum vascular function and generation of antioxidant and anti-inflammatory molecules (4). SARS-CoV-2 enters the human body through the respiratory tract (in most cases, the nasal cavity) (5) following interaction with ACE2 on the epithelial cells of the trachea and primarily infects bronchial cells and pneumocytes (6). Viral infection is propagated through the body if left unchecked. Once the viral particles invade the bloodstream (SARS-CoV-2 enters the bloodstream by breaching the blood–air barrier in the lung capillary adjacent to the alveolus), the infection spreads to the vascular subendothelium and to all vital organs (7, 8).

Blood Thinning Potential of PCA:

Park J, Lee B, Choi H, Kim W, Kim HJ, Cheong H. Antithrombosis activity of protocatechuic and shikimic acids from functional plant Pinus densiflora Sieb. et Zucc needles. J Nat Med. 2016 Jul;70(3):492-501. doi: 10.1007/s11418-015-0956-y. Epub 2016 Mar 3. PMID: 26940320.


Novel Antiplatelet Activity of Protocatechuic Acid through the Inhibition of High Shear Stress-Induced Platelet AggregationKeunyoung Kim, Ok-Nam Bae,Kyung-Min Lim, Ji-Yoon Noh, Seojin Kang,Ka Young Chung andJin-Ho Chung.  Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 704-711; DOI: https://doi.org/10.1124/jpet.112.198242.

Bleeding is the most common and serious adverse effect of currently available antiplatelet drugs. Many efforts are being made to develop novel antithrombotic agents without bleeding risks. Shear stress-induced platelet aggregation (SIPA), which occurs under abnormally high shear stress, plays a crucial role in the development of arterial thrombotic diseases. Here, we demonstrate that protocatechuic acid (PCA), a bioactive phytochemical from Lonicera (honeysuckle) flowers, selectively and potently inhibits high shear (>10,000 s−1)-induced platelet aggregation. In isolated human platelets, PCA decreased SIPA and attenuated accompanying platelet activation, including intracellular calcium mobilization, granule secretion, and adhesion receptor expression. The anti-SIPA effect of PCA was mediated through blockade of von Willebrand factor binding to activated glycoprotein Ib, a primary and initial event for the accomplishment of SIPA. Conspicuously, PCA did not inhibit platelet aggregation induced by other endogenous agonists like collagen, thrombin, or ADP that are important in both pathological thrombosis and normal hemostasis. Antithrombotic effects of PCA were confirmed in vivo in a rat arterial thrombosis model, where PCA significantly delayed the arterial occlusion induced by FeCl3. Of particular note, PCA did not increase bleeding times in a rat tail transection model, whereas conventional antiplatelet drugs, aspirin, and clopidogrel substantially prolonged it. Collectively, these results suggest that PCA may be a novel antiplatelet agent that can prevent thrombosis without increasing bleeding risks.

Diabetes, Insulin, and Obesity:  PCA has a role in insulin control, diabetes, and obesity.

Scazzocchio B, Varì R, Filesi C, Del Gaudio I, D’Archivio M, Santangelo C, Iacovelli A, Galvano F, Pluchinotta FR, Giovannini C, Masella R. Protocatechuic acid activates key components of insulin signaling pathway mimicking insulin activity. Mol Nutr Food Res. 2015 Aug;59(8):1472-81. doi: 10.1002/mnfr.201400816. Epub 2015 May 29. PMID: 25944785.



Insulin resistance represents an independent risk factor for metabolic and cardiovascular diseases. Researchers have been interested in identifying active harmless compounds, as many insulin-sensitizing drugs have shown unwanted side effects. It has been demonstrated that anthocyanins and one of their representative metabolites, protocatechuic acid (PCA), ameliorate hyperglycemia, and insulin sensitivity. This study investigated the mechanism of action of PCA responsible for the glucose uptake upregulation.

Methods and Results

In human visceral adipocytes, PCA stimulated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (+40% with respect to untreated cells) and the downstream events, i.e. phosphoinositide 3-kinase binding to IRS-1 and Akt phosphorylation (+100%, +180%, respectively, with respect to untreated cells). The insulin-like activity of PCA seemed to be mediated by the insulin receptors since by inhibiting its autophosphorylation, the PCA effects were completely abolished. Furthermore, PCA was able to activate adenosine monophosphate-activated protein kinase, a serine/threonine kinase whose activation elicits insulin-sensitizing effects.


This study showed that PCA stimulates the insulin signaling pathway in human adipocytes increasing GLUT4 translocation and glucose uptake. Decreasing insulin resistance is the most desirable aim to be reached for an effective therapeutic/preventive action against metabolic syndrome and type 2 diabetes. Identifying specific food/food components able to improve glucose metabolism can offer an attractive, novel, and economical strategy.

Harini R, Pugalendi KV. Antihyperglycemic effect of protocatechuic acid on streptozotocin-diabetic rats. J Basic Clin Physiol Pharmacol. 2010;21(1):79-91. doi: 10.1515/jbcpp.2010.21.1.79. PMID: 20506690.


Protocatechuic acid (PCA) (3,4-dihydroxybenzoic acid), a natural phenolic compound found in many edible and medicinal plants, is a major benzoic acid derivative with a strong antioxidative effect, 10-fold higher than that of alpha-tocopherol. The present study is aimed at evaluating the antidiabetic effect of PCA on STZ-diabetic rats. Diabetes was induced in male albino Wistar rats by the administration of STZ (40 mg/kg BW, i.p.). PCA was administered orally at three different doses (50, 100, 200 mg/kg BW/day) to STZ-diabetic rats for 45 days. Diabetic rats showed an increase in plasma glucose and glycosylated hemoglobin (HbA1c) and a decrease in plasma insulin and hemoglobin (Hb). The activities of gluconeogenic enzymes like glucose 6-phosphatase and fructose 1,6-bisphosphatase increased whereas the glycolytic enzyme glucokinase decreased in the liver along with glycogen content. The oral administration of PCA or glibenclamide in saline, for 45 days, prevented the changes and improved toward normalcy. No significant effect was observed in normal rats treated with PCA. Thus, our results show that PCA at 100 mg possesses a potential antihyperglycemic effect that is comparable with glibenclamide.