The study aimed to examine the role of bitter taste receptors (T2Rs) in the immune response of patients with cystic fibrosis (CF) to Pseudomonas aeruginosa, a common pathogen in CF. T2Rs are expressed in airway cilia and macrophages, where they detect bitter metabolites produced by gram-negative bacteria and trigger the production of nitric oxide (NO). NO enhances mucociliary clearance and phagocytosis in airway cells and macrophages, respectively. The study found that CF cells had reduced NO production compared to non-CF cells, which was due to the loss of CFTR function. Reduced NO in CF cells also correlated with reduced ciliary beating and antibacterial responses in airway cells, and reduced phagocytosis in macrophages. These results suggest that a deficiency in T2R/NO signaling caused by CFTR loss may contribute to the susceptibility of CF patients to gram-negative bacteria.
Here is a new study on cardiac reprogramming 
Adult cardiomyocytes have limited ability to regenerate, while expression of cardiac fibroblasts (CFs) can induce fibrosis (CF) can cause heart dysfunction and failure.
Overexpression of specific cardiac transcription factors Mef2c/Gata4/Tbx5/Hand2 (MGTH) can directly convert CFs into induced cardiomyocytes (iCMs) and improve cardiac function in acute myocardial infarction (MI).
Researchers created a transgenic mouse system to induce MGTH expression in resident CFs for cardiac reprogramming and fibroblast lineage tracing.
In vivo cardiac reprogramming converted about 2% of resident CFs into iCMs and improved myocardial contraction and reduced fibrosis in chronic MI.
Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by converting profibrotic CFs to a quiescent antifibrotic state and partly by suppressing Meox1, a regulator of fibroblast activation.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.058655
Fibrosis
- The dysfunction in fibrotic diseases occurs due to excessive production and deposition of collagen and extracellular matrix by activated myofibroblasts, which alters the function of the affected organ.
- Myofibroblasts are mesenchymal cells that are implicated in the pathophysiology of fibrosis and they may originate from endothelial cells during a process called endothelial to mesenchymal transition.
- Antifibrotic agents such as pirfenidone and nintedanib have shown promise in treating fibrotic diseases.
- Fibrosis also plays a role in promoting cancer by creating conditions that compromise anti-tumor immunity and treatment response.
Another interesting study: Researchers developed a model of adaptive and fibrotic kidney regeneration by adjusting the ischemic injury dose.
- Their analysis showed that kidney proximal tubule cells are the most vulnerable to injury.
- Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation.
- The researchers identified a specific maladaptive/profibrotic proximal tubule cluster after long ischemia that expressed proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors.
- Druggability analysis showed that pyroptosis/ferroptosis are vulnerable pathways in these profibrotic cells.
Studies of fibrosis in different organs may have specific focus: In skin fibrosis, the involvement of mast cells appeared to be a focus, but complicated:
- Inflammation has been suggested to promote the deposition of scar tissue by fibroblasts.
- Mast cells are one inflammatory cell type that has been implicated in skin scarring and fibrosis.
- Most studies suggest that mast cells play a pro-fibrotic role in skin, as many mast cell-derived mediators stimulate fibroblast activity, and higher numbers of mast cells and/or mast cell activation are generally found in scars and fibrotic skin.
- However, some studies in mast cell-deficient mice have suggested that mast cells may not play a critical role in cutaneous scarring/fibrosis.
new pulmonary fibrosis treatments:
- Two drugs, pirfenidone and nintedanib, have been approved by the FDA for pulmonary fibrosis therapy. They have been shown to improve lung function in clinical trials.
- There are several promising anti-fibrotic therapeutics currently in phase II and III clinical trials, including PRM-151, pamrevlumab, PBI-4050, and GLPG1690. These drugs have shown positive effects on lung function in clinical trials with minimal side effects.
- Gene therapy is being investigated as a potential new therapeutic modality for pulmonary fibrosis treatment. Some studies have shown promising results with gene-targeted therapy in murine models of pulmonary fibrosis, either through enhancing gene expression or suppressing gene expression using RNA interference.
New studies identified the transcription factor ETS-related gene (ERG) as important in lung capillary homeostasis and repair.
- ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury.
- Loss of endothelial ERG enhances paracrine fibroblast activation
- Transcriptional and fibrogenic abnormalities of ERG deficient mouse lungs resemble those associated with aging and human lung fibrosis.
Now people realized that activation of macrophages and monocytes is associated with the molecular pathology of scleroderma, although itās kind of following others in studies of fibrosis, but itās good to be there.
Several points of organ fibrosis:
- Fibrosis is caused by excessive production and deposition of collagen and extracellular matrix in an organ.
- Myofibroblasts are responsible for this process and the major contribution being from local recruitment of connective tissue fibroblasts, may derive via differentiation from bone marrow, endothelial to mesenchymal transition (EndMT) and epithelial to mesenchymal transition (EMT).
- Oxidative damage, chronic inflammation, and several signaling cascades can activate myofibroblasts and perpetuate abnormal fibrosis.
- Organ fibrosis may develop from repetitive exposure to injurious stimuli, genetic, epigenetic, and immunological characteristics.
- Antifibrotic drugs such as pirfenidone and nintedanib have been shown to safely improve quality of life and slow disease progression in lung fibrosis.
- Liver transplant is still an effective treatment option, but newer antiviral medications show promise in restoring liver function and improving life expectancy
- Abnormalities in branched-chain amino acids (BCAAs) are associated with various fibrosis such as hepatic, renal, and cardiac fibrosis.
- BCAAs supplementation showed improving liver fibrosis in rodent models through mTORC1-dependent inhibition of TGF-Ī² signaling in HSCs, less oxidative stress, and improved insulin resistance. but exhibited preliminary deleterious effects in renal and cardiac fibrosis.
- Prx1 is a transcription factor and marker of mesenchymal stem cells
- Prx1+ fibroblasts within human oral mucosa were highly chemotactic, expressing CCL2 and CXCL1 transcripts, they transferred the regenerative powers of the oral mucosa to other epithelial boundaries
*Decreased REV-ERBĪ± abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression
*Rev-erbĪ± agonist (SR9009) treatment prevents bleomycin-induced collagen overexpression in mice
*Rev-erbĪ± agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGFĪ² in human lung fibroblasts
*Loss of REV-ERBĪ± exacerbates fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erbĪ± agonist prevents it
Pan Agonist MHY2013 to PPAR Alleviates Renal Fibrosis in a Mouse Model by Reducing Fibroblast Activation and Epithelial Inflammation
treatment of systemic sclerosis
- Immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, and tocilizumab are used for early dcSSc treatment.
- Autologous haematopoietic stem cell transplantation can improve survival for patients with rapidly progressive early dcSSc.
- Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease.
- Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis.
- Pulmonary arterial hypertension is frequently treated with initial combination therapy and the addition of a prostacyclin analogue.
- Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers, phosphodiesterase 5 inhibitors or intravenous iloprost.
- Bosentan can reduce the development of new digital ulcers.
- Inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches can limit fibrosis progression and even regress fibrosis in human liver slices and mouse models.
- Disrupting the MAIT cell-monocyte/macrophage interaction promotes resolution of fibrosis by increasing the frequency of restorative Ly6Clo macrophages and promoting an autophagic phenotype in both Ly6Clo and pro-fibrogenic Ly6Chi macrophages.
- MAIT cell activation and the consequential phenotype shift of liver macrophages are important pathogenic features of liver fibrosis and could be targeted by anti-fibrogenic therapy.
Role of circRNAs in Liver fibrosis
- CircRNAs serve an essential non-coding function in various cellular processes.
- Competing with pre-mRNA splicing and lowering the levels of linear mRNA isoforms, leading to altered gene expression
- May act as miRNA sponges if they contain multiple miRNA binding sites
- Since circRNAs possess protein binding sites, circRNAs can affect cellular function by controlling activity of their protein partners.
- Despite the lack of a 5ā² cap structure and a 3ā² Poly(A) tail, circRNAs can be translated into proteins via the internal ribosome entry site (IRES) and N 6-methyladenosines (m6A)-mediated cap-independent translation.
- Anti-Fibrotic circRNAs: CircPSD3, CircCREBBP, CircMTO1, circBNC2, circFBXW4, circSCAR, circMTM1
- Pro-Fibrotic circRNAs: circPWWP2A, circUBE2k, circTUBD1, circUBE2K, CircCHD2, circPALLD, circIFT80, circRSF1, circARID1A
- Taxifolin is a natural flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products.
- Taxifolin treatment showed to prevent hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of nonalcoholic steatohepatitis (NASH).
- It inhibited lipid accumulation in hepatocytes and increases brown adipose tissue activity, suppressed body weight gain through direct and indirect pathways.
- Taxifolin treatment after NASH development showed to prevent the development of liver tumors.
- Reduced levels of ubiquitin-editing enzyme A20 observed in scleroderma (SSc) skin and lungs
- Elevated levels of A20ās negative transcriptional regulator - DREAM in SSc
- A20 mitigates profibrotic responses in isolated fibroblasts
- Haploinsufficiency of A20 or fibroblast-specific A20 deletion in mice recapitulates SSc pathology
- DREAM-null mice show protection against SSc-related features
- TGF-Ī² induces A20 expression in DREAM-null fibroblasts compared to wild-type fibroblasts
- Stimulation of A20 expression as a potential therapeutic approach
- Ellagic acid (EA) and punicic acid Ā¶ are the main components of the Punica granatum L (pomegranate) fruit and seed oil respectively.
- They showed antioxidant, anti-inflammatory and anti-fibrotic effects.
- Immunophilins encompass FK506-binding proteins (FKBPs) and cyclophilins (Cyps).
- Immunophilins have been implicated in the pathophysiology of inflammation, cancer, and neurodegenerative disorders.
- Cyclophilin A, FKBP12, and FKBP10 are reported to induce organ fibrosis through the calcineurin or TGF-Ī² pathways.
- FKBP51 is involved in myelofibrosis development via the calcineurin-dependent pathway, STAT5, or NF-ĪŗB pathways.
- Inhibiting specific immunophilins has shown promise in reducing fibrosis extent.