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Daniel Grimaldes MD🇧🇴 Profile picture
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Oct 27 • 25 tweets • 11 min read
☑️ REUSE OF DRUGS: THE ANTIHELMINTICS #NICLOSAMIDE AND #NITAZOXANIDE ARE POTENT ANTAGONISTS OF #TMEM16A 👉 THAT COMPLETELY BRONCHODILATE THE RESPIRATORY TRACT
ncbi.nlm.nih.gov/pmc/articles/P…

☑️ The pharmacology of the TMEM16A channel: therapeutic opportunities:
The intracellular Ca-dependent Cl channel TMEM16A is a key regulator of vascular tone control and local blood flow.

°TMEM16A inhibitors have potential therapeutic uses👉 Asthma, COPD, Cystic Fibrosis, HTA/PAH, CVA, Overactive Bladder, Ca.
sciencedirect.com/science/articl…
°Pharmacological modulators👉 niflumic acid, flufenamic acid and mefenamic acid
💊 Reused 👉 Zafirlukast, Avermectins (Ivermectin), Niclosamide, Nitazoxanide, Cefarantine.
🌱Natural👉 Gallotannins, Evodiamine, Rutaecarpina, Luteolin, Galangina, Quercetin and Fisetin.
frontiersin.org/articles/10.33…
° Biological effects of tmem16a inhibitors:
Inhibit production and secretion of mucus, and saliva
Induce bronchorelaxation
They inhibit inflammatory mediators
Anti-cancer/hypertensive effect
inhibits nociception
Attenuates intestinal contraction and peristalsis (antidiarrheal).
°Vasoconstrictor agonists (ET1, TXA2) > activate Gq protein-coupled receptors (GqPCR) > inositol triphosphate pathway (IP3) and Calcium release > ⬆️⬆️Ca > activate TMEM16A > Cl output (membrane depolarization) > Opening of calcium channels > CELL SHRINKAGE.
🚫 For this reason, tmem16a inhibition > decreases intracellular Ca > attenuates vascular smooth muscle contraction.

°The tmem16a is expressed in:
- airway epithelial cells
- cancer cells
- dorsal ganglion neurons 👉 neuropathies
- interstitial cells of cajal 👉 gastric emptying and motility
- bladder smooth muscle, uterus 👉 overactive bladder, urinary incontinence, myometrial relaxation
- Positive vasodilator and ionotropic effect 👉 heart failure.
✔️Example:
COPD and ASTHMA with rising tmem16a 👉 are characterized by mucus-congested airways, prolonged inflammation (bronchoconstriction), and impaired lung function.

☑️Functions of Cl channels activated by Ca tmem16a in inflammation.
CF, asthma, acute pancreatitis, steatohepatitis, esophagitis, rotavirus diarrhea, Lipopolysaccharide sepsis, cancer, pain, CVD.
sciencedirect.com/science/articl…
TMEM16A > increases vascular permeability and leukocyte adhesion to endothelial cells, release of inflammatory cytokines, and nociceptive stimuli.
° Multiple mechanisms for upregulated tmem16a expression in inflammation:

IL4 and IL13 > STAT6 > tmem16a > Asthma and Rhinosinusitis
IL 13 > STAT6 > tmem16a > Eosinophilic esophagitis
IL 6 > STAT3 > tmem16a > Acute pancreatitis
EGFR > STAT3 > tmem16a > Asthma, COPD, CF
LPS > NF-ΚB > tmem16a > sepsis

°Role of micro-RNAs
Overexpression of ⬆️tmem16a by negative regulation of micro-RNA ⬇️miR-132 and miR-144 in Colorectal Ca.

⬆️miR-9 in inflammation inhibits ⬇️tmem16a (CF, sepsis)

#IDEAS💡
Romulo Daniel Grimaldes Jimenez, MD
Internal Medicine
Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension
erj.ersjournals.com/content/53/6/1…
Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension
sciencedirect.com/science/articl…
Niclosamide repurposed for the treatment of inflammatory airway disease
ncbi.nlm.nih.gov/pmc/articles/P…
Zafirlukast inhibits the growth of lung adenocarcinoma via inhibiting TMEM16A channel activity
sciencedirect.com/science/articl…
Inhibition of TMEM16A Ca2+-activated Cl− channels by avermectins is essential for their anticancer effects
sciencedirect.com/science/articl…
Ameliorative effects of silymarin on HCl-induced acute lung injury in rats; role of the Nrf-2/HO-1 pathway
ncbi.nlm.nih.gov/pmc/articles/P…
The Ca2 gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after Ischemia
jci.org/articles/view/…
Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma
researchpad.co/read/article/p…
The Ca2+-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases?
sciencedirect.com/science/articl…
@DrLBoominathan @PharmOxford @NatRevDrugDisc @GuidetoPHARM @BritJClinPharm @LancetRespirMed @drakchaurasia @CellPressNews
@UnrollHelper
@FrontPharmacol @BrJPharmacol @__ice9 @PRandP_Journal @interna_12 @MedInternaHUPDH

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More from @DrGrimaldesJ

Daniel Grimaldes MD🇧🇴 Profile picture
Oct 20
Exercise the best of diets? The best of pills?🏃‍♂️🚶‍♂️ Image
Exercise + social interaction as the basis of all diets. Image
Exercise + social interaction foundation of health. Image
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Daniel Grimaldes MD🇧🇴 Profile picture
Oct 4
"White gold" is not only used to exploit economically and technologically, but also for the benefit of health.🌎

PREVENT COGNITIVE IMPAIRMENT AND PROLONG LONGEVITY WITH #LITHIUM, benefits: ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
frontiersin.org/articles/10.33…
1. Humans in areas with higher amounts of lithium in drinking water live longer; ncbi.nlm.nih.gov/pmc/articles/P…

2. In the long term, lithium can help maintain longer telomeres; news.ki.se/longer-telomer…

3. Lithium has been shown to regulate genes related to healthy DNA structure;
ncbi.nlm.nih.gov/pmc/articles/P…

4. Lithium appears to slow the rate of brain aging; ncbi.nlm.nih.gov/pmc/articles/P…

5. People with higher lithium intake show better mood;
GSK-3 is an enzyme that plays an important role in regulating metabolism. pubmed.ncbi.nlm.nih.gov/27068460/
Read 35 tweets
Daniel Grimaldes MD🇧🇴 Profile picture
Aug 29
TIGHT JUNCTIONS PLAY AN IMPORTANT ROLE IN THE FUNCTION OF THE INTESTINAL BARRIER.

✅They are composed of different binding molecules, such as claudin and occludin, and regulate the paracellular permeability of water, ions and macromolecules in adjacent cells
👉One of their most important functions is to provide a physical barrier to luminal inflammatory molecules 👉 deterioration of barrier integrity and structure 👉 activates immune cells and produces chronic inflammation in different tissues.
The intestinal barrier system depends on interactions between several components: mucosal gel-adhesive layer, immunoglobulin A, antibacterial peptides, and intercellular tight junctions.
Read 23 tweets
Daniel Grimaldes MD🇧🇴 Profile picture
Jan 22
THERAPEUTIC SUGGESTION
LACTOFERRIN (Lf)

🔥FRONT LINE PROPHYLAXIS AGAINST COVID-19 and other viruses🔥
In addition: Treatment in asymptomatic, mild and moderate.
frontiersin.org/articles/10.33…

Lf is a nutrient found in the milk of mammals.
👉 Lf binds to heparan sulfate proteoglycans (HSPG), a macromolecule present on the cell surface and extracellular matrix.
✔️VIRUSES, BACTERIA interact and join HSPG to enter cells.
In other words, HSPGs are used as an anchor by viruses to enter the cell
👉 the Lf PREVENTS THIS INTERNALIZATION 🎯

Lf uses heparan sulfate proteoglycans (HSPG) on the cell surface to facilitate SARS-CoV-2 entry👇 Image
Read 23 tweets
Daniel Grimaldes MD🇧🇴 Profile picture
Dec 16, 2021
Severe COVID cases present extensive lung damage and the presence of infected multinucleated syncytial pneumocytes.
Sars-CoV2 infected cells fuse with healthy neighboring cells to form syncytia through the peak protein activating calcium-activated chlorine channel TMEM16 proteins
This process is accelerated by the TMPRSS2 protease, but can be restricted by the interferon-induced transmembrane protein IFITM1.
TMEM16A activates NFKB and IL6 👉 inflammation and vasoconstriction👉 Pulmonary Hypertension or Cystic Fibrosis.

TMEM16F👉 thrombosis, endothelial dysfunction, diarrhea (⬆️ LC secretion) and alveolar edema.
erj.ersjournals.com/content/53/6/1…
sciencedirect.com/science/articl…
Read 6 tweets
Daniel Grimaldes MD🇧🇴 Profile picture
Dec 13, 2021
@Parsifaler Protective effects of Epo and derivatives against lung injuries. In normal alveolus: intact cellular component (AEC I, AEC II, fibroblast) and pulmonary capillary.
@Parsifaler In injured alveoli: Treatment with epo protect the lung from injury-induced cell and tissue damage by reducing apoptosis, oxidative stress,and pulmonary fibrosis.Prevent pulmonary edema and inflammatory lesions and,therefore,maintain cell integrity @drakchaurasia @DrLBoominathan ImageImage
@Parsifaler @drakchaurasia @DrLBoominathan EPO plays a key role in neuroprotection, cardioprotection, renoprotection or ventilation control. eurekaselect.com/61013/article europeanreview.org/article/18642 spandidos-publications.com/10.3892/ijmm.2… physoc.onlinelibrary.wiley.com/doi/10.1113/jp…
Read 7 tweets

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