Janus kinases JAKs were identified through sequence comparisons as a unique class of tyrosine kinases that contain both a catalytic domain and a second kinase-like domain that serves an autoregulatory function, hence the homage to the two-faced Roman god.
They were functionally linked to STATs and interferon signaling in powerful somatic cell genetic screens Darnell et al. The binding of extracellular ligand leads to pathway activation via changes to the receptors that permit the intracellular JAKs associated with them to phosphorylate one another. Activated STATs enter the nucleus and bind as dimers or as more complex oligomers to specific enhancer sequences in target genes, thus regulating their transcription Fig.
Human JAK mutations cause numerous diseases, including severe combined immune deficiency, hyperIgE syndrome, certain leukemias, polycythemia vera, and other myeloproliferative disorders Jatiani et al. Because of the causative role in these diseases and their central significance in immune response, JAKs have become attractive targets for development of therapeutics for a variety of hematopoietic and immune system disorders Pesu et al.
Additional Perspectives on Signal Transduction available at www. National Center for Biotechnology Information , U. Cold Spring Harb Perspect Biol. Douglas A. Author information Copyright and License information Disclaimer. Correspondence: Email: ude. Oleanolic acid, a pentacyclic triterpenoid compound, exists in over plant species, especially the Oleaceae family. Its derivatives include novel 3,5-disubstituted isoxazoles derivatives, acyloxyimino derivatives, 3-acetylated derivatives, acetate, ester derivatives, and oximes derivatives.
Bardoxolone is one of the most widely studied derivatives. Moreover, nanometer preparation could improve the biochemical properties of oleanolic acid. Catechins, also named flavanes, belong to the class of flavonoids. Catechins are the major constituent of green tea. Catechins are well-known for their antioxidant, anti-inflammation, and anticancer effects. Artemisinins are extracted from the sweet worm-wood Artemisia annua. Artemisinin is used to treat fever in Chinese history, and it is famous for treating malaria.
Besides, artemisinins also have anticancer, anti-virus, anti-schistosomes, anti-inflammatory properties, and artemisinins are effective in ocular diseases. There are many clinical trials that have been completed or are in progress.
For example, clinical studies on Curcumin are more than on www. Besides, their application covers a wide range of diseases. We will briefly introduce the clinical applications of curcumin, resveratrol, oleanolic acid, catechins, and artemisinins in the following. Clinical trials of curcumin cover cancers, oral diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, neurological diseases, such as oral submucous fibrosis, periodontitis, osteoarthritis, nonalcoholic fatty liver disease, diabetes, IBD, polycystic ovary syndrome, radiation dermatitis, migraine, psychiatric disorders, and COVID Most of them reported positive results, indicating that curcumin was well-tolerated and biologically active.
Adjuvant therapy of curcumin may reduce fatigue in cancer patients. Further studies could explore the application of curcumin in dermatological diseases. Clinical trials regarding resveratrol achieved benefits in many human diseases, such as diabetes, obesity, cardiovascular diseases, neurodegeneration, muscular dystrophies, and cancers. Notably, resveratrol contributes to improve physical functions. For example, resveratrol and curcumin promote the recovery of bone and muscle mass in chronic kidney disease patients.
In clinical trials, oleanolic acid is studied in metabolic diseases including diabetes, obesity, and hyperlipidemia. Based on the published data, Oleanolic acid has anti-inflammatory, anticancer, antiosteoporotic, antioxidant, antiaging, neuroprotective, and hepatoprotective effects. Clinical trials of catechins revealed their therapeutic efficacy in diabetes, hyperlipidemia, hypertension, and obesity. Several clinical studies focus on multiple sclerosis, hepatitis, acute radiation-induced esophagitis.
Notably, catechin may have regional analgesic efficacy for pain relief after surgery. The clinical application of artemisinins is mainly for malaria. In the past 10 years, there have been few reports of clinical trials of artemisinin in the treatment of schistosomiasis. A few clinical trials have revealed that artemisinins are well-tolerated in cancer patients.
A larger scale of clinical trials in cancer or metabolic diseases is needed to identify the optimal dose and efficacy of artemisinins. Nevertheless, there are multiple limitations of natural products. First, many of them simultaneously destroy abnormally proliferating cancer cells and normal cells, partly due to the broad-spectrum inhibition of biological processes. Second, many natural products are underutilized owing to intrinsic pharmacokinetics, including short half-life, low bioavailability, inadequate biological stability, and poor aqueous solubility.
Third, some natural products have hepatotoxicity, kidney toxicity, and reproductive toxicity. New developments aim to overcome these obstacles, such as synthesizing derivatives of natural products and utilizing nanoparticles, exosomes, liposomes, and phospholipids. More studies are needed to further promote their application. Limitations of ASO include elevated liver enzymes, splenomegaly, and thrombocytopenia. They incorporate their guide strands into a structure named the RNA-induced silencing complex.
This process naturally occurs and is termed RNA interference. Peripheral neuropathy and increased mortality are toxicities of concern in siRNA therapy.
New modifications enable lower dosing and exposure levels while maintaining efficacy and will hopefully show fewer adverse effects. The novelty of TD is that it can locally inhibit proinflammatory cytokines in the gastrointestinal tract while minimizing systematic exposure. Newly developed ritlecitinib inhibits JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma kinase family, and ritlecitinib has achieved efficacy in RA patients.
There are still many unanswered questions and challenges in the clinical application of JAK inhibition. First, optimizing dosing and formulation is important. Nevertheless, rare significant anticancer effects are observed except for hematological tumors.
This is partly due to the complex immune microenvironment in cancer patients. Third, for patients with liver impairment, renal impairment, risk of thromboembolism, and chronic virus infection, such as HBV, the dose should be reduced according to the condition. For example, hsp90 inhibitors or histone deacetylase inhibitors promote JAK2 degradation.
Thus, combinational therapy of JAK inhibitor and immune checkpoint blockers may augment therapeutic efficacy. The most important limitation of STAT inhibitors is their toxicity, which comes from several aspects. First, there is considerable homology between different STATs, thus it is difficult to design highly specific STAT inhibitors, which can lead to off-target toxicity. Second, STATs participate in biological processes in the mitochondrion and endoplasmic reticulum.
Therefore, STAT inhibitors may interfere with these processes. There are still some unanswered questions about signal transduction. For example, the functions of STATs in organelles need further to be studied. In addition, JAKs and STATs are regulators of the epigenetic landscape, conversely, they are regulated by the epigenetic landscape, via promoting permissive marks and limiting repressive marks. Third, more research is needed to explain how STAT-mediated transcriptional inhibition works, either through direct binding of genomic locales or through the induction of secondary agents, such as inhibitory transcription factors and miRNA.
Different cytokines are seen as different signals, a putative explanation is that different cytokines activate different phosphorylation levels of various STAT and other signal modules. More studies are needed to support the hypothesis. Moreover, we should aim to maximize efficacy and minimize adverse effects in patients in different stages of certain diseases and to explore biomarkers that predict efficacy and offer prognoses. Darnell, J.
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